Stop Cancer Naturally

50 Things About 50 Cancers

This ebook from medical practitioner and family doctor Dr. Parajuli gives you all of the signs and symptoms that you need to know in order to catch cancer in the very early stages and protect yourself from it. You don't have to worry about if you have cancer anymore, and better yet you don't have to spend thousands of dollars to make sure of that either! All it takes is a bit of knowledge and you are on your way! This book also teaches about other aspects of cancer patients, such as how to live with different kinds of cancer, how to prepare yourself mentally to accept this reality if it IS a reality for you, and how to deal with doctors and insurance companies. This book is easy to read and in PDF format, so you don't have to worry at all about reading it. Make it easy on yourself!

Do I Have Cancer Summary

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My Do I Have Cancer Review

Highly Recommended

The very first point I want to make certain that Do I Have Cancer definitely offers the greatest results.

As a whole, this book contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

Introduction to Cancer

Cancer is a disease in which the control of growth is lost in one or more cells, leading to a solid mass of cells known as a tumor. The initial tumor, known as the primary tumor, often becomes life-threatening by obstructing vessels or organs. However, death is most commonly caused by spread of the primary tumor to one or more other sites in the body (by a process called metastasis), which makes surgical intervention impossible. Other types of cancers known as leukemias involve a build-up of large numbers of white cells in the blood. Using the United Kingdom as an example, in the first three decades of the 1900s, cancer accounted for less than 10 of all deaths, with infectious diseases being the main cause of mortality. However, although dramatic progress has been made in controlling infections, similar progress has not been made in the treatment of cancer. Improved diet, living conditions, and health care have now increased the average life span to the point where cancer, which is a...

Src As A Target For Treatment Of Cancer And Bone Loss

From Cancer Drug Discovery and Development Protein Tyrosine Kinases From Inhibitors to Useful Drugs Edited by D. Fabbro and F. McCormick Humana Press Inc., Totowa, NJ Src originally raised interest as a proto-oncogene in the 1980s and has been extensively studied in cellular models of transformation and animal models of carcinogenesis. The main Src substrates in cellular transformation systems are Fak, p130 Cas, Shc, phospholipase C, and phosphatidylinositol 3-kinase, all components of growth factor-induced intracellular signaling networks (2). Mutated and or constitutively active Src (Tyr527Phe mutant, viral form v-Src or polyoma middle T-activated c-Src) has the ability to transform cells to a malignant phenotype in vitro and to cause tumors in vivo (3,4). Such mutations have not been well documented in human cancers, but instead, nonmutated Src is overexpressed in certain tumors and cooperates with receptor tyrosine kinases such as c-Met and the EGFR family (5), in some cases via...

Src Inhibitors Activity In Cancer Models

There is little information available on the effects of Src inhibitors in cancer models. The pyrrolopyrimidine CGP76030 and olomoucine NVP-AAK980 potently inhibited tyrosine phosphorylation in colon carcinoma cells (Fig. 5A) and the pyrrolopyrimidine CGP77675 inhibited PC3 cell migration and invasion at submicrolmolar concentrations (21) (Fig. 6). Both CGP76030 and NVP-AAK980 were active at inhibiting the growth of human colon cancer cell lines in vitro, with similar potency to the clinically used compound 5-fluorouracil (Fig. 5B) however the IC50 values of the Src inhibitors did not perfectly align with Src expression levels in these cell lines. Both CGP76030 and NVP-AAK980 were orally active, and possessed pharmacokinetic profiles demonstrating superior drug levels in tumor tissue as compared to plasma (Fig. 5C and data not shown). Subcutaneous HT29 cell tumor xenografts in female BALB c nude mice were subsequently used to test for anti-tumor activity. NVP-AAK980 was inactive in...

Strategies To Enhance Cancer Drug Delivery

Chemotherapy is a major therapeutic approach for the treatment of both localized and metastasized cancers. Since chemotherapeutic agents are neither specific nor targeted to the cancer cells, improved delivery of anticancer drugs to tumor tissues in humans appears to be a reasonable and achievable challenge (45). Current cancer drug delivery is no longer limited to traditional methods and dosage forms. It utilizes extensively some state-of-the-art technologies, such as nanotechnology, polymer chemistry, and electronic engineering (46). Our expanding knowledge of the molecular biology of cancer and the pathways involved in malignant transformation of cells have revolutionized cancer treatment with a focus on targeted cancer therapy. New approaches to cancer treatment not only supplement conventional chemotherapy and radiotherapy, but also aim to prevent damage to the normal tissues and overcome drug resistance. Innovative methods of cancer treatment require new concepts of drug...

Noninvasive Breast Cancer Ductal Carcinoma in Situ

Undergo a lumpectomy as their initial therapy. Data from three randomized trials have indicated that the addition of radiation treatment to the breast after lumpectomy reduces the probability of recurrence. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial, which randomized 818 patients with DCIS to either radiation therapy or observation after lumpectomy, found that radiation therapy decreased the risk of local recurrence at 12 years from 31.7 to 15.7 (p

Advanced Breast Cancer

Tamoxifen is used in postmenopausal women with estrogen-receptor-positive tumors, patients with long disease-free intervals following treatment for early breast cancer, and those with disease limited to bone or soft tissues. However, aromatase inhibitors, such as letrozole or anastrozole, may be more efficacious and are regarded as the preferred treatment in postmenopausal women. Ovarian ablation or a gonadorelin analog should be considered in premenopausal women. Progestogens such as medrox-yprogesterone acetate continue to be used in advanced breast cancer in postmeno-pausal women. They are as effective as tamoxifen but are not as well tolerated. However, they are less effective than the aromatase inhibitors. Cytotoxic chemotherapy is preferred for advanced estrogen-receptor-negative tumors and for aggressive disease, particularly where metastases involve visceral sites (e.g., the liver) or where the disease-free interval following treatment for early breast cancer is short.

Anticancer Agents and St Johns Wort

Clearance of imatinib mesylate, an anticancer drug, is also increased due to administration of St. John's wort resulting in reduced clinical efficacy of the drug. Imatinib is used in the treatment of Philadelphia chromosome positive chronic myeloid leukemia and gastrointestinal stromal tumors. In one study involving 10 healthy volunteers, 2-week treatment with St. John's wort significantly reduced maximum plasma concentration by 29 , AUC by 32. The half-life of the drug was reduced by 21 (47). St. John's wort also showed significant interaction with another anticancer drug irinotecan. In one study involving five patients, ingestion of St. John's wort (900 mg day) for 18 days resulted in an average 42 reduction in concentration of SN-39, the active metabolite of irinotecan. This reduction also caused decreased myelo-suppression (48).

Future Challenges for Combined Modality Rectal Cancer Treatment

The use of total mesorectal excision for mid and low rectal cancer. With this optimized surgery, local control rates have been markedly increased and local failure rates above 15-20 are now no longer acceptable. Technical advances in radiotherapy, including tumor- and radiobiologically optimized fractiona-tion, 3D treatment planning and intensity-modulated radiation therapy, will further allow realization of more sophisticated treatment volumes to reduce irradiation of normal tissue and increase the therapeutic index. Moreover, novel chemotherapeutic and biological agents, e.g., capecitabine, oxaliplatin, iri-notecan, cetuximab, and bevacizumab, are currently incorporated in multimodality regimens. Evidently, the current monolithic approaches, established by studies more than a decade ago, to either apply the same schedule of preoperative or postoperative 5-FU-based radiochemotherapy to all patients with TNM stage-II III rectal cancer or to give preoperative intensive short-course...

Organ Preservation in Urinary Bladder Cancer Theoretical Aspects

Radical cystectomy is considered as standard of care for muscle-invasive bladder cancer by most urologists however, the concept of organ preservation by limited surgery and radiochemotherapy which is currently used in larynx, other head and neck, or anal-canal cancers may also be effective in urothelial bladder cancer. Despite evidence from several series, this approach is so far not widely accepted (Gospodarowicz 2002). In a survey, Moore and coworkers (1988) asked expert physicians about their attitude on treatment of locally advanced bladder cancer. Nearly all U.S. urologists and medical oncologists favored radical cystectomy as standard approach. In contrast, one-third of the British urologists recommended radiotherapy (Table 19.1). The best explanation for these discrepancies is the fact that radiotherapy has been widely used as primary treatment for locally advanced bladder cancer in the UK. Large series from single institutions in Great Britain and the largest randomized trial,...

Adjuvant and Neoadjuvant Chemotherapy in Non Metastatic Urothelial Bladder Cancer Meta Analyses

On the basis of the high frequency of micrometa-static spread at diagnosis, chemotherapy has been used as adjuvant or neoadjuvant (preoperative) treatment of muscle-invasive urothelial cancers in combination with radical surgery. The results of the prospective randomized studies have recently been investigated in three meta-analyses (Ghersi et al. 1995 Advanced Bladder Cancer Meta-Analysis Cooperation 2005a, 2005b). The results demonstrate that adjuvant chemotherapy after surgery has no impact on survival, neoadjuvant chemotherapy prior to radical surgery has a modest, but significant, impact on mortality and increases the 5-year overall survival by absolute 5 . Chemotherapy concurrent with radiotherapy has been investigated in only one small study and the results with respect to overall survival rates were not significant however, the relative reduction of mortality (hazard ratio) was more pronounced in this study as compared with studies which used chemotherapy together with...

Aubry and B McGibbon Cancer 55 907 1985

Armstrong and A Kriecker in I. M. Leigh, J. A Newton Bishop, and M. L. Kripke, Eds., Skin Cancer, vol. 26, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1996, pp. 133-154. 281. F. Urbach in F. F. Becker, Ed., Cancer, Plenum Press, New York, 1969, pp. 441-451. 282. A. Kricker, B. K. Armostrong, D. R. English, and P. J. Heenan, Int. J. Cancer, 48, 650

PhaseIII Chemo Radiation Trials of Cytotoxic Agents in Vulvar Cancer

There have been fewer prospective chemo-radiation trials in women with vulvar cancer, and most have focused on advanced disease. A GOG trial evaluated pre-operative cisplatin and 5-FU chemo-radiother-apy in 71 women with advanced vulvar cancer using split-course radiation to 47.5 Gy (Moore et al. 1998). A 47 clinical CR rate was seen, and 67 of patients were disease-free at a median of 45 months. Grade-3 or grade-4 skin and mucosal toxicity was seen in 54 of patients. In another pre-operative trial, 46 women with advanced nodal disease (N2 N3) were treated with a similar chemo-radiation schedule (MontanA et al. 2000). Thirty-eight patients (83 ) had resect-able nodal disease following treatment, including two with pulmonary metastases. Of 37 women who underwent node dissection (the other patient had a vulvectomy alone), negative nodes were found in 15 patients. Twelve patients were alive and free of disease at a median of 78 months. Other single-institution and retrospective studies...

Epigenetic Therapy Of Cancer

The initiation and progression of cancer is controlled by both genetic and epige-netic events. The term ''epigenetic'' refers to alterations in gene expression that are not associated with changes in DNA sequence. Unlike genetic alterations, epigenetic aberrations are potentially reversible. The best studied epigenetic alterations are DNA methylation and histone tail modifications, and epigenetic gene silencing by these mechanisms has become an attractive anticancer target.51 The main enzymes involved in establishing epigenetic patterns are the following DNMTs are responsible for the methylation of the C-5 position of cytosine, and almost exclusively at CpG dinucleotides. This is an epigenetic mechanism used for long-term silencing of gene expression because structural changes in DNA associated to methylation close to a transcription start site inhibit gene expression either directly, by blocking binding of transcriptional factors, or indirectly, by recruitment of transcription...

Aerosol Delivery To Treat Lung Cancer

To date, reports of aerosolized chemotherapy for the treatment of lung cancer and pulmonary metastases have been quite limited. Table 1 summarizes all known studies that have investigated local lung delivery of anticancer agents including cytotoxics, gene therapy, chemopreventative agents, proapoptotic activities in cell culture. The combination treatment showed a significant reduction in tumor volume in comparison to either treatment alone in murine model of cancer dose dependent anticancer effects against renal cell pulmonary metastases. Toxicity was weight loss at highest dose of CsA Liquid aerosol Hamster Both compounds resulted in a significant increase in the percent of cancer-free animals immunomodulating agents, or any combination of these treatments. In almost all instances of in vitro, in vivo, or human clinical trials, inhaled chemotherapy resulted in positive outcomes relative to controls. Several broad generalizations may be garnered from a review of these studies...

Future Directions in Anal Cancer Treatment with New Agents

Given the positive results of combination chemotherapy and radiation therapy in the above-mentioned phase-III trials, a pilot study in the United Kingdom (ACT II pilot) is currently testing a triple chemotherapy and radiation approach with integration of 5-FU, MMC, and cisplatin into the combined modality treatment of anal cancer. A phase-II study at the M.D. Anderson Cancer Center (Houston, Texas) investigates the role of capecitabine and oxalipla-tin with radiation therapy in patients with locally advanced anal cancer (AJCC stage II-IIIB). In this trial, patients received capecitabine (1650 mg m2 orally Monday through Friday), weekly oxaliplatin (50 mg m2) and radiation therapy (45 Gy for T1, 55 Gy for T2, or 59 Gy for T3-T4 lesions). Preliminary data indicate the feasibility of this approach (Eng et al. 2005). In a recent randomized phase-II trial, the addition of another radiosensitizing agent, namely int-racavitary hyperthermia, to RCT with 5-FU and MMC resulted in a...

Chemo Radiation in Endometrial Cancer

Endometrial cancer is treated very successfully with surgery and radiation when diagnosed early unfortunately, advanced disease is still often seen and in this setting treatment outcome is poorer. Randan et al. (2006) have recently reported the results of a pivotal phase-III study in 422 patients with advanced (stage III or IV) endometrial cancer who underwent debulking surgery with less than 2 cm of residual disease, and were subsequently randomized to chemotherapy with doxorubicin and cisplatin or whole abdominal radiation. This study demonstrated a significant improvement in overall and progressionfree survival, favoring chemotherapy. Interestingly, even though all patients had advanced disease, 42 of those treated with radiation and 55 of those who received chemotherapy were alive at 5 years, demonstrating the significant activity of both modalities. Studies combining chemotherapy and radiation are underway. Many of these studies are using sequential treatment, but concurrent...

Antiemetic effect in cancer chemotherapy

Cannabinoids can prevent the nausea and vomiting induced by cancer chemotherapy (Dewey, 1986). Both clinical and animal studies indicate that certain cannab-inoids have therapeutic potential as antiemetic agents. Vomiting is the expulsion of contents of the gut, largely by forces generated by the respiratory muscles (Levitt, 1986). Cannabinoids can affect cerebral function, above the level of the vomiting reflex (Steele, 1980). Therefore, cannabinoids may suppress vomiting through descending inhibitory connections to the lower brain stem centers (Levitt, 1986). However, other possible mechanisms have been investigated (Levitt, 1986) and no agreement about the mode of action has been reached.

Applications in Head and Neck Cancer

Radiotherapy Imrt Head And Neck

Head and neck (H&N) cancer refers to a heterogeneous group of epithelial tumors involving the oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, salivary glands, and paranasal sinuses. In this chapter we focus discussion primarily on squamous cell carcinoma of the H&N, particularly cancers involving the oral cavity, pharyngeal axis, and larynx. In 2006 there will be approximately 43,000 cases of H&N cancer diagnosed in the United States with over 500,000 cases worldwide (American Cancer Society 2005). Tobacco and alcohol use are major risk factors for the development of H&N cancer. For selected H&N tumors, data also implicates Epstein-Barr virus (EBV) and human papilloma viruses (HPV) in the pathogenesis (GiiiiSON et al. 2000). Historically, patients with early-stage disease (stages I II) are effectively treated with single modality therapy using radiation (RT) or surgery alone. Patients with more advanced-stage disease (stage III-IVb) have generally received combined modality...

Anticancer Drugs Targeting Tubulin and Microtubules

Miscellaneous Anticancer Drugs Acting Medicinal Chemistry of Anticancer Drugs 2008 Elsevier B. V. Microtubules are the main target of cytotoxic natural products, and most of the drugs discussed in this chapter have been discovered in large-scale screens of natural materials. These compounds are highly successful in cancer treatment,3 and it has been argued that microtubules represent the best known cancer target. Vincristine and vinblastine are complex molecules produced by the leaves of the rosy periwinkle plant Catharanthus roseus (Vinca rosea), whose potent cytotoxicity was discovered in 1958. They were introduced in cancer chemotherapy in the late 1960s and remain in widespread clinical usage to this day. Despite their very similar structures and common mechanism of action, they have widely different toxicological properties and antitumor spectra. Thus, vinblastine is currently used in the treatment of Hodgkin's disease and metastatic testicular tumors, where it is combined with...

DNA Interactions of Novel Platinum Anticancer Drugs

Platinum compounds constitute a discrete class of anticancer agents, which are now widely used in the clinic. The interest in antitumor platinum drugs has its origin in the 1960s, with the serendipitous discovery by Rosenberg of the inhibition of division of bacterial cells by platinum complexes 1 . The first platinum anticancer drug in clinical use was cisplatin (cis-diamminedichloroplatinum(II)), which is a very simple and purely inorganic molecule (Fig. 8.1). In spite of its simplicity, it is one of the most potent drugs available for anticancer chemotherapy 2-4 . It is highly effective for the treatment of testicular and ovarian cancer and is used in combination regimens for a variety of other carcinomas, including bladder, small lung tumors and those of head and neck 5 . However, cisplatin toxicity in tumor cclls is couplcd with several drawbacks (such as nephrotoxicity, neurotoxicity, and emetogenesis) 2 hence there has been strong interest in the development of improved...

Anti-cancer Drugs References

U. (2004). Curr. Cancer Drug Targets 4,313. 6. Tiseo, M., Loprevite, M., and Ardizzoni, A. (2004). Curr. Med. Chem. Anticancer Agents 4,139. 9. Herbst, R. S., Fukuoka, M., and Baselga, J. (2004). Nat. Rev. Cancer 4, 956. 11. Rosell, R., Ichinose, Y., Taron, M., Sarries, C., Queralt, C., Mendez, P., S nchez, J. M., Nishiyama, K., Moran, T., Cirauqui, B., Mate, J. L., Besse, B., et al. (2005). Lung Cancer 40,25. 14. Rusnack, D. W., Affleck, K., Cockerill, S. G., Stubberfield, C., Harris, R., Page, M., Smith, K. J., Guntrip, S. B., Carter, M. C., Shaw, R. J., Jowett, A., Stables, J., et al. (2001). Cancer Res. 61, 7196. 17. Nyati, M. K., Maheshwari, D., Hanasoge, S., Sreekumar, A., Rynkiewicz, S. D., Chinnaiyan, A. M., Leopold, W. R., Ethier, S. P., and Lawrence, T. S. (2004). Clin. Cancer Res. 10, 691. 20. Scotlandi, K., Manara, M. C., Nicoletti, G., Lollini, P.-L., Lukas, S., Benini, S., Croci, S., Perdichizzi, S., Zambelli, D., Serra, M., Garc...

Rectal and Anal Cancer

Although the 1990 NIH consensus recommended adjuvant radio-chemotherapy for stage-II and stage-III rectal cancer without an upper age limit, this recommendation was far from being accepted for the wide majority of elderly patients treated in the 1990s (Neugut et al. 2002 Schrag et al. 2001). Neugut et al. (2002) carried out a population-based study on the use of adjuvant chemotherapy and radiation therapy for rectal cancer among patients 65 years or older who were diagnosed between 1992 and 1995. A total of 983 patients with stage-II and 824 patients with stage-III disease who had received surgery were identified in the Surveillance, Epidemiology, and End-Results (SEER) Medicare data base. Of the total population 28 received surgery alone, 11 received surgery plus radiation therapy, 14 received surgery plus adjuvant 5-FU and 37 received surgery with radiation plus adjuvant 5-FU chemotherapy. Of the patients with combined radio-chemotherapy 89 received treatment postsurgically, 10...

Safety and Efficacy of Phytomedicines in Cancer Prevention and Treatment

Abstract In this review we discuss some aspects of herbal use either to prevent cancer or to treat the disease or the side effects of chemotherapy. The most powerful reasons, for cancer patients, to use phytomedicines are related to the wish to leave no option untried and to the dissatisfaction with mainstream oncology treatments. In the review, herbs commonly used in cancer and their mechanism of action are referred. Moreover, clinical trials about the use of some herbs for treating the side effects of chemotherapy and radiation are cited. As regards the safety data of phytomedicines in cancer patients, considering the narrow therapeutic window of chemotherapic drugs, the risk of clinically relevant herb-drug interactions can increase in the USA more than 100,000 deaths per year can be attributed to drug interactions, most of them connected to the use of herbs. Some experts believe that the potential risk of herb drug interactions is enough to recommend patients on chemotherapy not...

The Racket In Cancer Control

The best of medical statistics indicates that one out of every eight human beings dies of cancer. And it is equally a matter of record that cancer has increased manifold since the Drug Trust sold the medical profession on its highly profitable immunization program. Koch and Loffler and Blass and Hoxsey have proven that cancer is a condition in which the blood stream is overloaded with toxins. They have cured cancer by cleaning these toxins out. Orthodox medical methods have never cured a case of cancer in all its history unless you consider that stoppage of the patient's sufferings by death is a cure. The reason medical orthodoxy cannot cure cancer is that it follows orthodox textbooks, and these textbooks say cancer is caused by a bug which medical science has failed to discover in 3,000 years of trying. The medical profession has further handicapped itself by following its political leaders in opposing successful methods which do away with the profits from the use of X-ray, radium...

Natural Products in Cancer Chemoprevention and Chemotherapy

Abstract Medicinal plants are an important source of diverse chemical compounds that have been used for the past several centuries in the treatment of cancer. About 25 of drugs in the modern pharmacopoeia are derived from plants, including several anticancer drugs currently in clinical use such as vincristine, vinblastine, pacli-taxel, podophyllotoxin, camptothecin and combretastatin. These natural products, their derivatives and analogues based on these drugs constitute an arsenal against various types of neoplasms. The traditional use of plants provides a lead for cancer chemopreventive molecules. The development of new derivatives from bioactive compounds of food origin has been a viable way to reduce toxicity and increase their effectiveness against cancer. The combined efforts of botanists, pharmacologists, chemists and biologists are required to discover new effective drugs to fight cancer. An evaluation of the mode of action of these bioactive molecules will be helpful in...

Anticancer Drugs Acting On Apoptotic Signalling Pathways

Cancer Drugs Pathways

Apoptosis is normally defined as programmed active cell death. Although at first sight cell death might be viewed as a pathological phenomenon, each second about one million cells in a human body undergo apoptosis. Several genes involved in the apoptosis process have been found to be defective in cancer cells, specially the BCL2 and caspase-family genes.123 Most of the caspase-related molecules are not typical drug targets (e.g. cell surface receptors), and for this reason small-molecule drugs are only of limited use and other approaches (monoclonal antibodies, antisense oligonucleotides) are often needed. Many anti-cancer drugs discussed elsewhere in the book, specially those that can induce DNA strand breaks or microtubule damage, are also apoptosis inducers, but this section is dedicated only to those drugs that are aimed at specific targets in the apoptotic pathways,124-126 which are summarized in Fig. 9.32. ultimate sensitivity or resistance of cells to a number of apoptotic...

Randomized Trials of RCT in Anal Cancer

Although these phase-II trials of combined modality anal cancer treatment demonstrated the feasibility and efficacy of this approach, the value of sensitizing chemotherapy remained unproven. Two European phase-III trials compared combined RCT with radiotherapy alone (Table 18.12). The EORTC trial required a locally advanced tumor (T3-4 or T1 2 N+), whereas the UKCCCR trial allowed patients with any stage of disease (Bartelink et al. 1997 UKCCCR Anal Cancer Trial Working Party 1996). Although no overall survival benefit was observed, both studies revealed increased tumor regression and a significantly improved local control rate with the combined-modality treatment using continuous infusion 5-FU and bolus MMC thus, these two randomized trials gave clear evidence of the benefit of concomitant chemotherapy in primary anal cancer treatment. Table 18.11. Selected phase-II trials and retrospective studies of concurrent radio- and chemotherapy for anal cancer Table 18.11. Selected phase-II...

Carcinogenic Effects Of

It has repeatedly been mentioned in the literature that LSD might have carcinogenic potential. This speculation appeared for the first time in the paper by Cohen, Marinello and Back. (22) The authors drew this conclusion from their findings of a markedly increased frequency of chromosomal breakage and a quadriradial chromosome exchange figure in a patient with paranoid schizophrenia who had undergone extensive LSD psychotherapy. This is a combination occurring in three inherited disorders Bloom's syndrome, Fanconi's anemia and ataxia teleangiectatica. These disorders are connected with a high incidence of leukemia and other neoplastic diseases. The authors also pointed out that cells of neoplastic origin show a variety of chromosomal aberrations, many of which are not unlike those they had found in subjects after ingestion of LSD. In addition, some of the agents known to produce similar chromosome aberrations, such as radiation and various viruses, are known carcinogens. The...

Photodynamic Therapy Of Cancer

Photodynamic therapy (PDT) of cancer is based on the use of compounds that are able to absorb harmless visible light energy and transfer it efficiently to other molecules in their vicinity or alternatively use it for photochemical reactions with biomolecules.100 These compounds are normally known as photosensitizers (PS). After irradiation with light of the suitable wavelength, the PS molecules are excited from the ground state (1PS0) to a singlet excited state (1PS*) that can reverse to the ground state by nonradiative internal crossing (IC) or by fluorescent emission (F), the latter of which can be used for imaging and detection (photo-diagnosis). Alternatively, it may undergo an electronic rearrangement to the excited triplet state (3PS*) by intersystem crossing (ISC, Fig. 4.45). Most reactions of relevance to PDT take place in the triplet state, which must be sufficiently long-lived to give intermolecular reactions before its deactivation by emission of phosphorescence (P). In the...

Cancer Drugs And Alcohol

Carcinogenesis In studies in which water containing ethanol is administered to laboratory animals, a dose-related increase has been noted in hepatocellular adenomas and carcinomas (U.S. National Toxicology Program, 2004) in head and neck carcinomas, fore-stomach carcinomas, testicular interstitial-cell adenomas, and osteosarcomas of the head and neck (Soffritti et al., 2002) and in mammary adenocarcinomas in female rats (Watabiki et al., 2000). The carcinogenic effect also increased when the ethanol was co-administered with known carcinogens. The conversion of alcohol (ethanol) to acetal-dehyde (the major metabolite of alcohol) in the liver requires the enzyme alcohol dehydrogenase, and acetaldehyde is transformed to acetic acid by the enzyme aldehyde dehydrogenase. Deficiencies in aldehyde dehydrogenase (which is most common among those of Asian descent) result in high levels of accumulated acetaldehyde in the body, which contribute to the development of malignant esophageal tumors...

Examples of Anticancer and Chemopreventive Agents Derived from Natural sources and Their Mechanisms of Action

It is also worth noting a resurgence of interest in ethnopharmacology (or eth-nopharmacy), the study of plant materials or other natural products that have been used by a local community as a traditional cure for a particular disease. The assumption is that these materials may contain an active constituent that can be identified, purified, and obtained in large amounts (by extraction or synthesis) for further studies. One recent example of this approach is the identification of a novel agent potentially useful for the treatment of leukemia and nonmelanoma skin cancers. Researchers at the University of Birmingham (U.K.) and Peplin Ltd. (Brisbane, Australia) discovered a new agent (known as PEP005 or 3-Angelate) in the sap of a weed (petty spurge, milk weed, Euphorbia peplus) traditionally used for treating corns and warts, on the basis that constituents apparently able to control cell growth and cause cell death may also have useful antitumor activity. The isolated agent has been shown...

The Microenvironment in Cervical Cancer

The microenvironment in which cancer cells exist is abnormal, and is a potential target for novel drugs designed to enhance the cytotoxic effects of radiotherapy or more conventional chemotherapy. This has been explored in cervical cancer, and is a strong focus of ongoing new drug development. The microenvironment refers to the physiological and biochemical state of the extracellular space that surrounds the malignant cells, which is determined mainly by the tumor vasculature and interstitial matrix. The cellular and extracellular compartments are tightly coupled aspects of the microenvironment are known to influence cell proliferation, gene expression, metastatic potential and response to treatment, whereas cytokines produced by malignant cells are important in the development and ongoing remodeling of the vasculature and interstitium (Heldin et al. 2004 HiCKlin and Ellis 2005) therefore, treatment strategies that target the microenvironment, or the underlying structural and...

Pharmacokinetics Of Inhalation Aerosols Implications For Cancer Treatment

Figure 3 Pharmacokinetics of liposomal 9-NC. Mean (+SD) plasma levels in five cancer patients following treatment with 9-NC liposome aerosol by mouth-only breathing. Source From Ref. 60. Figure 3 Pharmacokinetics of liposomal 9-NC. Mean (+SD) plasma levels in five cancer patients following treatment with 9-NC liposome aerosol by mouth-only breathing. Source From Ref. 60. The distribution of pulmonary administered chemotherapy agents is important for clinical effectiveness. Thus, for practical purposes, chemotherapy absorption rates, lung residence time, and the potential for significant systemic exposure depend on the location of drug deposition and the physicochemical nature of the drug. Typical physicochemical properties of chemotherapeutics commonly employed for lung cancer chemotherapy generally possess low water solubility and high lipophilicity. For example, the octanol water partition coefficient of paclitaxel is high ( 100) and will therefore exhibit very rapid absorption from...

Cannabis for cachexiaanorexia associated with AIDS wasting syndrome and cancer

Wasting syndrome is a debilitating or lethal complication, occurring in two-thirds of cancer patients and nearly 90 of AIDS patients. It is defined as greater than 10 loss of body weight. The debilitating disease processes of cancer and AIDS deplete the body's stores of protein by metabolizing muscle tissue to fuel critical functions. Anorexia and cachexia are the two complications that begin a downward nutritional spiral. Anorexia is the loss of appetite or desire to eat. Cachexia is a general term, which describes a wasting or malnourished process resulting from illness. Both anorexia and cachexia are probably caused by increased metabolism created by cancerous tumors or the AIDS virus combined with decreased absorption of nutrients. This depletion can quickly spiral out of control leading to nausea, vomiting, poor appetite, diarrhea and subsequent weakness which further blocks the body's ability to combat the disease. As patients are weakened, resistance to infection creates...

Introduction Of Anticancer Drugs Slideshares

Some General Remarks About Cancer and Cancer Chemotherapy 1 Cancer Chemotherapy 3 3. Natural Products in Cancer Chemotherapy 5 4. A Brief Comment About Cancer Nanotechnology 6 1. SOME GENERAL REMARKS ABOUT CANCER AND CANCER CHEMOTHERAPY Cancer is a collective term used for a group of diseases that are characterized by the loss of control of the growth, division, and spread of a group of cells, leading to a primary tumor that invades and destroys adjacent tissues. It may also spread to other regions of the body through a process known as metastasis, which is the cause of 90 of cancer deaths. Cancer remains one of the most difficult diseases to treat and is responsible for about 13 of all deaths worldwide, and this incidence is increasing due to the ageing of population in most countries, but specially in the developed ones. Cancer is normally caused by abnormalities of the genetic material of the affected cells. Tumorigenesis is a multistep process that involves the...

Prodrugbased Anticancer Drug Targeting Smallmolecule Prodrugs

One approach that allows improving the selectivity of cytotoxic compounds in cancer therapy is the use of prodrugs that are selectively activated in tumor tissues.1 This selective activation may be based on the exploitation of some unique aspects of tumor physiology, such as selective enzyme expression, hypoxia, and low extracellular pH. Other approaches are based on tumor-specific delivery techniques that allow the selective activation of prodrugs by exogenous enzymes, which are delivered into the tumor using monoclonal antibodies antibody-directed enzyme prodrug therapy (ADEPT) or generated in tumor cells from DNA constructs that contain the corresponding gene using nonviral (gene-directed enzyme prodrug therapy (GDEPT) or viral virus-directed enzyme prodrug therapy (VDEPT) vectors. One example, previously discussed in Section 4.3 of Chapter 2, is the selective bioactivation in tumors of capecitabine, a 5-fluorouracil prodrug. This prodrug is rapidly absorbed after oral...

Types of Cancer Vaccines

At present, there are two major categories of cancer vaccines. The first represents vaccines designed for prophylactic use (to prevent cancer), and the second represents vaccines used to treat existing cancers. Both T cells and B cells can be activated as part of an immune response for the purpose of either cancer prevention or treatment. With preventive vaccines targeted against infectious agents that are known to cause cancer (e.g., hepatitis B and HPV), the activated B cells produce antibodies that bind to the infectious agents and interfere with their ability to infect cells. Because the agents must infect cells to transform them, this lowers the chance of the cancer occurring. For vaccines designed to treat cancer, antibodies specific for cell-surface antigens on cancer cells can target the antigens and, by a number of indirect mechanisms, cause the cell to die. Part of the challenge of developing vaccines in either category is that the immune system has the almost impossible...

Estrogens And Their Involvement In Carcinogenesis

Steroidal Hormone Antibodies

The natural estrogens induce tumors in a variety of organs in laboratory animals, and high estrogen levels increase the risk of breast and uterine cancer.1 Several mechanisms have been proposed that explain the development of estrogen-dependent tumors. In the first place, the transcription process initiated by the binding of estrogens to their receptors ultimately induces cell proliferation in some target tissues. Examples are breast tissue, where estrogens trigger the proliferation of cells lining the milk glands, thereby preparing the breast to produce milk in case of pregnancy, and the endometrium of the uterus, where they stimulate cell proliferation in order to prepare the uterus for implantation. This proliferative action is one of the physiological roles of estrogens, but it can also lead to the development of breast or uterine cancer because if cells from these tissues already possess a DNA mutation that increases the risk of developing cancer, they will proliferate (along...

Janus Carcinogens and Mutagens

Many substances reported to be antimutagens or anticarcinogens have, themselves, been shown to be promutagenic or carcinogenic. Chemicals belonging to such a category are termed Janus carcinogens and mutagens after the ancient Roman god Janus, who is depicted as having one head with two faces, one looking forward and one looking backward 86 . Several other recent reports have also addressed or emphasized the biphasic nature of many active substances reported to modulate the mutagenicity and or carcinogenicity of heterocyclic amines. The majority of these modulating substances are plant products or extracts. A compendium of the antimutagenicity literature by Waters et al. 87 showed that a number of chemicals have both antimutagenic and mutagenic effects. For instance, p-caro- tene was the first presumptive anticarcinogen to be included in large-scale, clinical intervention trials, but the trials were terminated prematurely upon revelation that p-carotene treatment was associated with...

Localized Pancreatic Cancer Clinical Studies

Initial Management of Pancreatic Cancer 216 15.6.5 Neoadjuvant Chemoradiation for Pancreatic Cancer Clinical Studies 222 15.8.3 Intensity Modulated Radiotherapy (IMRT) or Stereotactic Radiation Therapy for Pancreatic Cancer 226 Department of Radiation Oncology, Box 97, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA G. VaraDHACHarY, MD R. A. Wolff, MD Department of Gastrointestinal Medical Oncology, Box 426, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA P. W. T. PiSTers, MD Douglas B. Evans, MD D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA When the use of chemoradiation for localized pancreatic cancer is considered, it is important to appreciate several disease characteristics that differ greatly from those of most other malignancies. In patients who cannot undergo curative resection the median survival is usually less than 1 year, with eventual radiographic...

Optimizing Therapeutic Outcomes In Cancer

As described in the previous section, numerous approaches are being studied to improve drug delivery to cancer cells. As our understanding of the barriers to effective cancer therapy continues to increase, new strategies are being investigated to target drug delivery to the tumor cells. Through this research, scientists continue to devise new drug formulations and delivery systems to improve therapeutic outcomes for cancer patients disorders. While the advent of new biological therapies (e.g. monoclonal antibodies) has dramatically impacted cancer therapy, novel formulations have recently been developed for conventional chemotherapeutic drugs (doxorubicin, pacltixel, cytarabine, carmustine) and hormones (histrelin), resulting in improved therapeutic outcomes (Table 5). These formulation strategies for specific cancer medications are highlighted below.

Potential Effects of Marijuana on Respiratory Carcinogenesis

Several lines of evidence suggest that marijuana smoking may be a risk factor for the development of respiratory cancer (Table 3). First, the tar phase of marijuana smoke contains more of some pro-carcinogenic polycyclic aromatic hydrocarbons, including benz a pyrene, than the tar collected from tobacco cigarettes (3,4,7). Second, because of the manner in which marijuana cigarettes are smoked, approximately fourfold more of the particulate phase of the smoke (tar) is deposited in the human respiratory tract than occurs during tobacco smoking (6). This enhanced lung deposition during marijuana smoking, combined with the high concentration of known carcinogens in marijuana smoke, significantly magnifies the level of exposure to carcinogens from each marijuana cigarette. Third, THC can interact with the aryl hydrocarbon receptor and, independent of other components in the smoke, activate transcription of cytochrome P4501A1 (7). Cytochrome P4501A1 is involved in the biotransformation of...

Applications to Gynecological Cancers

Cytotoxic Agents in Cervical Cancer 303 of Cytotoxic Agents in Cervical Cancer 305 of Cytotoxic Agents in Vulvar Cancer 306 20.2.4 Chemo-Radiation in Endometrial Cancer 306 20.3 Biologically Targeted Treatment of the Tumor Microenvironment in Gynecological Cancer 306 20.3.1 The Microenvironment in Cervical Cancer 306 20.4.5 Targeted Agents in Endometrial Cancer 312 References 313

Emerging Cancer Therapies Gene Therapy

Cancer is a multigenic disorder involving mutations of both tumor suppressor genes and oncogenes. A large body of preclinical data, however, suggest that cancer growth can be arrested or reversed by delivering a single growth inhibitory or pro-apoptotic gene, or a gene that can elicit immune responses against the tumor. Gene therapy is a technique that is currently being developed to treat a number of different cancers. A main requirement for gene therapy is the development of efficient, non-toxic gene carriers that can encapsulate and deliver foreign genetic materials into specific cell types such as cancer cells (11). Both viral and non-viral vectors have been developed. Many gene transfer vectors are modified viruses that retain the capability of the virus for efficient gene delivery but are safer than the native virus due to modifications that eliminate or alter one or more essential viral functions. The field of viral-based gene transfer vectors for the treatment of cancer has...

Integration of Chemotherapy Hormonal Therapy Biological Therapy with Surgery and Radiation in the Management of Breast

The majority of breast cancer patients are currently treated with a combination of surgery, radiation, and systemic therapy. This is because all these approaches have proven to be valuable for patients with non-invasive disease, patients with early stage disease, and patients with locally-advanced breast cancer. How to best integrate surgery, radiation, and systemic treatments has become a highly relevant clinical question, and one that affects hundred of thousands of patients each year therefore, it has become very important for breast cancer patients to be managed by a multidisciplinary team, with participation of the surgeons, radiation oncologists, medical oncologists, pathologists, and diagnostic radiologists. Multidisciplinary management allows for better coordination of each treatment modality, which may increase the efficacy of the combined treatment, while minimizing its toxicity. This chapter focuses on discussing the role of radiation therapy and systemic therapy in the...

PhaseIII Chemo Radiation Trials of Cytotoxic Agents in Cervical Cancer

A number of prospective trials exploring cytotoxic agents in addition to cisplatin chemo-radiation have been undertaken, as well as trials evaluating different platinum compounds such as carboplatin. An interesting randomized phase-II trial comparing weekly cisplatin chemo-radiotherapy with cisplatin (40 mg m2) and gemcitabine (125 mg m2) prior to radical hysterectomy was recently reported. Eighty-three women with stage-IB to stage-IIB disease were entered, with a 55 pathological complete response (CR) in the cisplatin arm compared with 77.5 (p 0.02) in the cisplatin-gemcitabine group. Toxicity was greater with cisplatin-gemcitabine, predominantly hematological and gastrointestinal, with only 63 of the cisplatin-gemcitabine group completing the planned six cycles, compared with 82 of the cisplatin group (p 0.01 Duenas-Gonzalez et al. 2005). In locally advanced disease a dose-escalation trial recommended the same doses of weekly gemcitabine and cisplatin, with manageable toxicity (

Not One Documented Case of Cancer

While tens of millions of Americans smoke pot regularly, cannabis has never caused a known case of lung cancer as of December 1997, according to America's foremost lung expert, Dr. Donald Tashkin of UCLA. He considers the biggest health risk to the lungs would be a person smoking 16 or more large spliffs a day of leaf bud because of the hypoxia of too much smoke and not enough oxygen.

Targeted Agents in Endometrial Cancer

Despite being the commonest gynecological cancer, there are few trials incorporating targeted agents with radiation in this malignancy however targeted agents alone have been used in endometrial cancer with some success. We have conducted a phase-II clinical trial with single agent erlotinib, an EGFR tyrosine kinase inhibitor, in women with recurrent or metastatic disease who were chemotherapy naive. Overexpression of EGFR is seen in up to 70-80 of endometrial cancers. Our results demonstrated an overall objective response rate of 12.5 , and a 21 response rate in EGFR positive tumors (Jasas et al. 2004). To put these results in context, endometrial cancer was at least as responsive, if not more, as lung or pancreatic cancers, for which erlotinib has been licensed. This also raises the attractive possibility of combining erlotinib with chemotherapy, radiation, or both in this disease.

Rationale For Pulmonary Delivery Of Anticancer Agents

As with other respiratory diseases treated locally through the use of inhalation aerosols, there are numerous pharmacokinetic and pharmacodynamic arguments favoring this delivery route in cancer therapy. In general, chemotherapy is characterized by a dose dependent response (cell apoptosis) coupled to a high degree of non-specificity, so that despite the introduction of several newer generations of chemotherapy agents, toxicity remains the principle limitation for effective anti-tumor response. Accordingly, the rationale for pulmonary delivery of these agents primarily focuses on the ability to increase regional targeting and the associated benefits arising from this pharmacokinetic advantage. These additional potential benefits are briefly described here, and are specific to the nature of the tumor microenvironment to which inhalation aerosols are targeted.

Locally Advanced Breast Cancer

Locally advanced breast cancer (stage-III disease) requires multimodality treatment. Many of the same principles regarding the integration of systemic treatment and radiation for patients with advanced disease are similar to those discussed for patients with early stage breast cancer however, patients who present with locally advanced breast cancers are at higher risk for both locoregional and distant disease recurrence and require multidisciplinary care for optimal disease management. Some patients presenting with advanced primary and nodal disease have unresectable disease. In the 1980s investigators began exploring a sequencing approach that used chemotherapy prior to surgery for such patients. These early studies demonstrated that anthracycline containing chemotherapy regimens could achieve a partial or complete clinical response in over 80 of treated patients. This permitted many patients with initially unresectable disease to become operative candidates. With this success, the...

Cancer Treatments

The tumorigenic effects of chemicals and radiation have been previously discussed. Unfortunately, this association means that the chemotherapeutic agents and radiation therapy given to patients (particularly children) with cancer can themselves raise the risk of developing cancer later in life. This appears to manifest as soft tissue sarcoma, a disease affecting mostly fat and muscle tissues. According to one study reported in the International Journal of Cancer in 2004, soft tissue sarcoma is one of the most common new types of malignant disease appearing in young adults and teenagers who were treated with anticancer drugs during childhood. Researchers from the Gustave Roussy Institute (France) followed more than 4,000 patients who had survived a first cancer during their childhood and observed the occurrence of 16 soft tissue sarcomas at least 3 years after diagnosis of the first disease. Although this rate of occurrence appears low, it is more than 50 times greater than that...

Breast Cancer

The management of patients with breast cancer involves surgery, radiotherapy, drug therapy, or a combination of these treatments. Originally, the most common cytotoxic chemotherapy regimen for both adjuvant use and metastatic disease was a combination of cyclophosphamide, methotrexate, and fluorouracil. However, anthracy-cline-containing regimens are now increasingly used and are regarded as standard therapy unless contraindicated (e.g., in cardiac disease). In metastatic disease, the chemotherapy regimen chosen reflects whether the patient has previously received adjuvant treatment and also the presence of any comorbidity. For patients who have not previously received chemotherapy, either cyclophosphamide, methotrexate, and fluorouracil or an anthracycline-containing regimen is the standard initial therapy for metastatic breast disease. However, patients with anthracycline-refractory or resistant disease should now be considered for treatment with a taxane either alone or in...

Cancer

Currently, no data reveal definitive increases in rates of lung cancer among people who smoke marijuana but not tobacco. A retrospective study of over 64,000 patients showed no increases in risk for many types of cancer once alcohol and cigarette use were controlled (Sidney, Quesenberry, Friedman, & Tekawa, 1997). Nevertheless, a few lines of research suggest that cases of cannabis-induced lung cancer may appear in the years ahead. THC is not carcinogenic itself. Yet when isolated cells are exposed to marijuana smoke, they change in ways that parallel the early stages of cancer (Leuchtenberger, 1983). Biopsies taken from the lung tissue of cannabis users reveal cellular changes that could lead to tumors (Roth et al., 1996). A number of reports suggest considerable marijuana use among young people with cancers of the lung, oral cavity, and esophagus (IOM, 1999). These data are comparable to early studies of tobacco and cancer and suggest that cannabis smoke is capable of damaging the...

Marijuana and Cancer

It is currently unclear whether long-term smoking of marijuana causes cancer. As mentioned above, marijuana smoke contains more carcinogenic chemical constituents than tobacco smoke (31) thus, one might expect to see more cases of lung cancer than with tobacco smoking. However, no significantly large number of cases of lung cancer or other cancers has been reported in marijuana smokers, possibly because no such studies have ever been conducted. Recently, after controlling for age, sex, race, education, alcohol consumption, pack-years of cigarette smoking, and passive smoking, Zhang and colleagues (78) reported that the risk of squamous cell carcinoma of the head and neck was increased with marijuana use in a strong dose-response pattern. The researchers also suggested that marijuana use might interact with mutagenicity and other risk factors to increase the risk of head and neck cancer. However, the investigators noted that the results should be interpreted with some caution in...

Colorectal Cancer

Endocannabinoids are known to inhibit the proliferation of breast cancer cells, prostate cancer cells, and rat thyroid cancer cells (Bifulco and Di Marzo 2002). Ligresti and colleagues (2003) showed that the levels of anandamide and 2-AG were increased relative to controls in adenomatous polyps and carcinomas, but there appeared to be no differences in the expression of CB1 and CB2 receptors or FAAH levels among the tissues. To determine if cannabinoids affect colorectal cancer cell growth, the authors used CaCo-2 (which express CB1 receptor) and DLD-1 cells (which express both CB1 and CB2 receptors, with CB1 receptor less expressed than in CaCo-2 cells). Anandamide, 2-AG and HU-210, as well as an inhibitor of anandamide inactivation, potently inhibited CaCo2 cell proliferation (relative potencies HU-210 anandamide 2-AG), while DLD-1 cells were less responsive to cannabimimetics than CaCo-2 cells (Ligresti et al. 2003). Such data suggest that CB1 receptors are more important than CB2...

Cancer Stem Cells

There are two competing theories of tumor development and metastases. According to one theory, all cells making up a tumor are basically identical and equally likely to divide to maintain tumor growth or to metastasize to form new tumors. The other theory maintains that only a small number of select cells from each tumor, known as cancer stem cells, have the ability to start new tumors. It is argued that these stem cells are highly robust and resilient to drugs and radiation. Therefore, the second theory may explain why a tumor returns after the original (i.e., the primary tumor) has been carefully removed by surgery (i.e., if one or more stem cells are left behind) and also why tumors are often so resistant to chemotherapy and radiation (i.e., it is the stem cells that survive and then repopulate the tumor mass). The concept of cancer stem cells has been around since the 1950s. Only recently has evidence started to accumulate that supports the hypothesis regarding cancer stem cells....

Cancer chemotherapy

In a review it was suggested that thiamine when given to patients with cancer may interfere with chemotherapy in that thiamine may promote nucleic acid ribose synthesis and tumor cell proliferation via the transketolase pathway. The authors suggest that an oversupply of thiamine may actually do harm and may be responsible for the failure of therapeutic attempts to terminate cancer cell proliferation (14). Thiamine is directly involved in ribose synthesis in pancreatic adenocarcinoma cells through transketolase-catalysed non-oxidative pentose phosphate reactions. In addition, the chemically modified co-factor oxythiamine inhibited tumor cell proliferation in vitro and in vivo by 40 and 91 in two distinct tumor models (14). According to a review of thiamine supplementation in patients with cancer this raises serious suspicions that routine thiamine administration may not be warranted and could possibly be harmful (15). Thiamine deficiency in cancer patients is most often observed during...

Anticancer Effects

The symptomatic benefits of cannabis and its derivatives in patients with cancer has been discussed above, but considerable evidence has accumulated from in vitro and in vivo animal studies that cannabinoids may inhibit the growth of various types of tumour cell (For a review see Guzman's contribution in this volume and Guzman 2003). Possible mechanisms include the selective promotion of cancer cell apoptosis and inhibition of tumour vascularisation. Preliminary clinical studies have been initiated but no results reported at the time of writing. An issue to be determined is whether effects will be apparent at the tissue levels achievable in humans by systemic dosing in some circumstances it may be preferable to seek ways to deliver the cannabinoid direct to the target site (Guzman 2003).

Lung Cancer

Despite the decades of awareness, and the introduction of newer therapies and treatment regimens, overall lung cancer survival rates remain low, and the urgency of replacing conventional approaches with novel or combination therapies exhibiting enhanced anti-cancer efficacy is now being recognized. The most telling statistic regarding lung cancer is that the annual number of deaths attributed to this disease continues to rise with each passing year (Fig. 1). This dual lack of success in both lung cancer treatment and prevention has garnered increasing attention with not only the popular media, but also among policy makers, recently prompting the U.S. Congress to declare lung cancer a national public health priority and eliciting a call for an inter-agency attack on the primary cause of cancer death. Apart from the inexorable increase in overall lung cancer deaths, another consideration is the shift in the frequency among the different types of lung cancer. Adenocarcinoma has emerged...

Cancer Therapy

Solid dispersion technologies have also been explored for improving drug therapies for the treatment of various conditions associated with cancer. Many anticancer drugs have poor aqueous solubility characteristics that preclude the efficacy of traditional oral dosage forms. Therefore, these drugs are commonly administered to the patient as parenteral injections. Since intrusive methods of drug administration are inconvenient and undesirable for the patient, there would be substantial benefit to the development of effective oral dosage forms with respect to ease of administration and patient compliance. Many researchers are therefore pursuing advanced formulation design strategies to develop solid oral dosage forms for cancer therapy drugs that provide equivalent bioavailability and therapeutic efficacy to the injectable dosage forms. One such study was conducted by Etienne et al. in which the bioavailability of a new solid dispersion oral preparation of medroxyprogesterone acetate...

Prostatic Cancer

Prostatic cancer is mainly hormone dependent, being promoted by the androgen dihydrotestosterone (DHT), which is derived from testosterone by the action of 5a-reductase. Thus, one obvious form of treatment involves removal of the DHT stimulus. Prostatic cancer is usually well developed on presentation, so survival rates are low and treatment is aimed at increasing the survival time and quality of life. Removal of the DHT stimulus to tumor growth can be achieved either by blocking its synthesis or the action at its receptor. Surgical removal of the prostate or testes (orchidectomy) is less prevalent, having been largely replaced by endocrine therapy (estrogens) and, in more recent years, by treatment with anti-androgens and luteinizing hormone releasing hormone (LH-RH) analogs. One problem with surgical removal of the prostate is that it can lead to incontinence and sexual dysfunction. Hormonal therapy does not provide a cure for prostate cancer because the tumor usually becomes...

Bladder Cancer

Goffin et al. (2004) reviewed their data on patients aged 70 years or older who received radio-chemotherapy for T2-T4 bladder cancer. Three different protocols were applied Seven patients received radiation therapy to a total dose of 44 Gy with 3 Gy bid on days 1, 3, 15, 17, then 2.5 Gy bid on days 63, 65, 77, 79 with concurrent cisplatin (15 mg m2) and 5-FU (400 mg m2) on days 1-3, 15-17, 63-65 and 77-79. Six patients were treated with conventionally fractionated radiation therapy to doses of 52-60 Gy with concurrent cisplatin (20-30 mg m2 weekly during radiation). One patient received 40.8 Gy in a bid regimen with concurrent cisplatin, metothrexate and vinblastine. Six of 14 patients experienced grade-3 or grade-4 toxicity including 1 patient with cispla-tin hydration-induced heart failure. The median survival was 19 months 5 patients had local recurrences and 7 patients developed distant metastasis. A study by Patel et al. (2005) analysed toxicity and outcome of concurrent...

Oesophageal Cancer

The Roswell Park Cancer Institute reviewed their experience with combined radio-chemotherapy in patients aged 70 years or older with oesopha-geal cancer (Nallapareddy et al. 2005). Data on 30 patients were available. Radiation doses ranged from 45 to 64.8 Gy in 1.8-Gy daily fractions. Various chemotherapy regimens were applied on an outpatient basis. 5-FU continuous infusion was used in 26 patients at a median dose of 1220 mg m2 per week. In 13 patients it was combined with cisplatin (27-36 mg m2 per week) and in 8 patients with oxaliplatin (3146 mg m2 per week). Four patients received pacli-taxel (50-80 mg m2 per week). The following grade-3 or grade-4 toxicities were observed haematologi-cal 17 febrile neutropaenia 13 mucositis 40 dehydration diarrhoea that required hospitalisation 50 pulmonary 20 cardiac 7 and neuropathy 7 . Median survival was 10 months 6 patients died of local recurrence and 7 of metastatic disease. A Japanese group analysed the efficacy and toxicity of...

Esophageal Cancer

Standard treatment in the United States for inoperable cancer of the esophagus is chemoradiation with cisplatin, 5-fluorouracil, and radiation to 50.4 Gy at 1992). Long-term results show that at 5 years 26 of patients with non-metastatic disease at diagnosis are alive with chemoradiation but with locoregional failure remaining a significant problem. Investigators looked for additional agents that might add further radiosensitization to address persistence of local disease. Iison et al. (1999, 2003) reported on phase-I and phase-II trials looking at cisplatin and irinotecan combined with radiation for esophageal cancer. Nineteen patients with clinical stage-II to stage-III esophageal squamous cell or adenocarci-noma were enrolled. Induction chemotherapy with weekly cisplatin 30 mg m2 and irinotecan 65 mg m2 was administered for four treatments during weeks 1-5. Radiotherapy was delivered weeks 8-13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg m2 and escalating-dose...

Early Breast Cancer

All women with early breast cancer should be considered for adjuvant therapy following surgical removal of the tumor because adjuvant therapy can help eradicate the micrometastases that cause relapse. The choice of adjuvant treatment is determined by the risk of recurrence, the estrogen-receptor status of the primary tumor, and menopausal status. Tamoxifen, an estrogen-receptor antagonist, is presently the preferred choice of adjuvant hormonal treatment for all women with estrogen-receptor-positive breast cancer. It is supplemented in selected cases by cytotoxic chemotherapy. Premenopausal women may also benefit from treatment with a gonadorelin analog or ovarian ablation. Treatment with tamoxifen delays the growth of metastases and increases survival. If tolerated, treatment should be continued for 5 years. Tamoxifen also lowers the risk of tumor formation in the other breast. Anastrozole is also licensed for the adjuvant treatment of estrogen-receptor-positive early breast cancer in...

Prostate Cancer

Results from a second multicenter Phase II study of GVAX vaccine, designed for the treatment of prostate cancer, were recently reported. The trial found that for 22 patients with advanced hormone-refractory metastatic prostate cancer who were receiving the highest dose, the final median survival was not less than 24.1 months, compared with 18.9 months for patients treated with Taxotere and prednisone. A Phase III clinical trial is presently underway of GVAX in combination with Taxotere and prednisone.

Electromagnetic Radiation

It is now well established that electromagnetic radiation from the higher-energy part of the electromagnetic spectrum (Scheme 1.1), such as ultraviolet (UV) radiation and Y- or X-rays, can damage cellular DNA and lead to tumorigenesis. More recently, there has been a growing concern about the potential for radio waves and microwaves to cause cancer. The UV band, which is invisible to the human eye, constitutes one particular part of the spectrum of sunlight and makes up approximately 3 of all the solar radiation reaching the Earth's surface. Three types of UV light have been identified. One of these, UVC (200 to 290 nm), is generally thought to be the most carcinogenic. UVB (290 to 320 nm) causes the most sunburn, and UVA (320 to 400 nm), which can be up to 1,000 times stronger than UVB, is able to penetrate underlying tissues of the skin leading to skin damage, including photoaging. Fortunately, the ozone layer absorbs most of the more carcinogenic UVC radiation, although there is...

Pharmacogenomic Markers of Toxicity

Currently, much research is underway to identify pharmacogenomic markers of both efficacy and toxicity for anticancer therapies. This knowledge would allow patients to be screened to predict the risk of developing serious side effects to a particular drug. One example where this is already possible is with 5-fluorouridine. A small percentage of people (3 -5 ) are deficient in the enzyme dihydropyrimidine dehydrogenase (DPD), which is important for metabolizing the agent. Due to a buildup

Inhibitors of 14ademethylase and 17ahydroxylase

One procedure for the treatment of metastatic prostate cancers that do not respond to antiandrogens is the administration of ketoconazole, an imidazole derivative that is primarily used as an antifungal agent because it inhibits the biosynthesis of ergosterol, a key component of fungal membranes. Ketoconazole inhibits 14a-demethylase, a cytochrome P450 enzyme necessary for the conversion of lanosterol to ergosterol (in fungal cells) or to cholesterol (in mammalian cells), by coordination of the unsubstituted nitrogen atom to the iron atom in the active site. Since cholesterol is the precursor of all steroidal hormones, in a route that involves the participation of several other cytochrome P450 enzymes (Fig. 3.23), high doses of ketoconazole lead to androgen deprivation.38 The use of ketoconazole as an antiandrogen normally involves short treatments due to its toxicity, and normally it is associated with corticoids to prevent adrenal insufficiency. Another compound acting in this...

Mutations in Protein Kinases

A number of examples in which specific kinases have become mutated in cancer cells are known. For example, a mutation of the protein kinase ABL (i.e., BCR-ABL) is the etiologic agent in CML. The cytoplasmic tyrosine kinase BCR-ABL, which is constitutively active, is present in 15 to 30 of cases of adult acute lymphoblastic leukemia (ALL) and virtually all cases of CML. This mutation has been put to good use in the design of imatinib (Gleevec ). A second example can be found in patients with multiple endocrine neoplasia (type 2), in which mutations in RET tyrosine kinase may be responsible for development of the disease. Finally, EGFR mutations with enhanced kinase activity have been detected in several human tumor types.

Overexpression of Protein Kinases

Expression of EGFR and its associated primary ligands epidermal growth factor (EGF) and transforming growth factor a (TGF-a) has been studied in several human malignancies with coexpression of EGFR and EGF observed to have both prognostic significance and a possible role in the pathogenesis of several human cancers. Specifically, overexpression of EGFR and EGF in several tumor types significantly reduces patient prognosis. For example, members of the EGFR kinase family (EGFR, ErbB-2, HER2 neu, ErbB-3, and ErbB-4) are known to be overexpressed in some types of breast tumors. The HER2 neu RTK has been found to be amplified up to 100 times in the tumor cells of approximately 30 of cancer patients with invasive breast disease, and its presence is also associated with poor prognosis. Similarly, overexpression of PDGF and PDGFR has been reported in meningioma, melanoma, and neuroendocrine cancers as well as tumors of the ovary, pancreas, stomach, lung, and prostate. Elevated levels of SRC...

Other Novel Ras Pathway Inhibitors

Further down the Ras pathway are the key regulators of cell signaling, MEK1 and MEK2, which are at the hub of several pathways (see Scheme 5.9). MEK1 and MEK2 are able to activate further proteins called ERK1 and ERK2 that can, among other actions, initiate cell division and activate some genes associated with tumors. Overactivation of MEK occurs in several forms of cancer, including breast tumors. Array BioPharma, in collaboration with AstraZeneca, is developing a potent and specific inhibitor of MEK known as ARRY-142886 (also called AZD6244) Phase I trials began in 2004.

Antibodybased Approaches

Monoclonal antibodies (MAbs) have been developed for both the diagnosis and treatment of cancer, and several MAbs are already commercially available as cancer therapies. MAbs can be used as single agents, paired with powerful cytotoxics or radiopharmaceuticals to create tumor-specific agents, or they can be used in an X-DEPT approach such as ADEPT. Therapies based on MAbs have been slow to Rather than use MAbs alone, an alternative approach to enhance efficacy is to attach a cytotoxic agent through a chemical linker. The linker can be designed to cleave specifically at the tumor site, thus releasing the cytotoxic agent. For example, conjugates have been reported that contain linkers designed to cleave on exposure to the enzyme cathepsin, which is overexpressed in some tumor cell types. With this type of construct, in which exposure to the cytoplasm within the cell is important for drug release, it is necessary to demonstrate that, once bound to the tumor cell, the drug-antibody...

Vasculartargeting Strategies

It is now recognized that for any tumor to grow beyond a volume of 1 to 2 mm3, a so-called angiogenic switch must be present, prompting the formation of new vasculature (i.e., neovascularization) (Figure 7.1 and Scheme 7.1). Since Folkman's original observations, key molecules in the angiogenesis process have gradually been identified, such as VEGF and its receptors, culminating in the recent clinical proof of the concept of targeting VEGF in colorectal cancer with the humanized MAb bevacizumab (Avastin ). Many small-molecule inhibitors of VEGF receptors are also now in clinical development (e.g., SU11248 and PTK787 ZK22854). SCHEME 7.1 Mechanism of action of anti-angiogenic agents and VDAs. (Adapted with permission from Kelland, L.R., Curr. Cancer Ther. Rev., 1 1-9, 2005).

Anti Angiogenic Agents

The concept of blocking the growth of new tumor vasculature was first described in the early 1970s, although a practical application has only just emerged, more than 30 years later. Early enthusiasm for angiogenesis inhibitors was lost after a number of promising agents were unsuccessful in increasing survival in pivotal Phase III clinical trials. Only more recently have the colorectal cancer trials of bevacizumab established a survival benefit through this mechanism of action. This has not only demonstrated proof of concept, but has also provided more treatment options for colorectal cancer patients with metastatic disease. As a result, many more anti-angiogenic agents, both antibody-based and small molecules, are now in development.

Xdept Biphasic Strategies

The usefulness of traditional cytotoxic chemotherapeutic agents is usually restricted by their low therapeutic indices. One approach to improving this situation has been the development of strategies that allow the conversion of an inactivated form of an anticancer drug (i.e., a prodrug) to an active agent specifically at the tumor site. One such tactic relies on the activation process being carried out by an enzyme that has been targeted to the surface of tumor cells via a suitable antibody. This therapy, known as antibody-directed enzyme prodrug therapy (ADEPT), is presently in Phase I evaluation. An alternative tactic, also being evaluated in Phase I, involves activation of a prodrug by an enzyme caused to be expressed (i.e., not naturally expressed) within the tumor cells. This therapy, known as gene-directed enzyme

Novel Drug Delivery Approaches

Effective drug delivery remains a challenge in the management of cancer. Existing drugs could be significantly more effective if techniques could be developed to deliver them selectively to the tumor site while avoiding healthy tissues. Therefore, there is a focus on the development of sophisticated targeted delivery systems that will not only supplement conventional chemotherapy and radiotherapy but may also prevent the occurrence of drug resistance. Knowledge and experience from areas such as nanotechnology, advanced polymer chemistry, and electronic engineering are being drawn upon to help develop these novel approaches. Examples from the areas of gene therapy, nanotechnology, novel polymers, and ultrasound are highlighted below.

Nanotechnology Based Drug Delivery

Nanobiotechnology is a research area being applied to the improvement of drug delivery in various cancer therapies. It has been known for some time that encapsulation of cancer drugs in particles such as liposomes can modify their behavior after administration. Advantages of polymeric micellar drug delivery systems include (1) long circulation time in the blood and stability in biological fluids (2) appropriate size (10 to 30 nm) to escape renal excretion but to allow for extravasation at the tumor site (3) simplicity in incorporating the drug compared to covalent bonding of the agent to a polymeric carrier and (4) drug delivery that is independent of drug characteristics. Some micellar systems are dynamically stable because their solid-like cores dissociate slowly at concentrations below their critical micelle concentration. Others are not so stable and require additional stabilization that may be achieved, for instance, by cross-linking the micelle core. In a study of the...

Examples of Vaccines in Development

There are too many experimental cancer vaccines in early-stage clinical trials to discuss here in detail. Instead, some examples are listed below to provide insight into the range of clinical studies presently underway. It is important to note that, for vaccines, the promise observed in early-stage clinical trials, which often enroll only a small number of patients, is not always sustained in larger trials. For example, in one recent trial of a melanoma vaccine, the early findings suggested that the vaccine might help prevent melanoma from recurring in patients at high risk from this. However, in a subsequent larger trial that include approximately 750 patients who were at high risk for melanoma recurrence, high-dose interferon proved superior to the vaccine in preventing return of the disease.

Epigenetic Based Therapies

Heritable changes in gene function can occur without modifications to the DNA sequence itself. This area of study is known as epigenetics, a term that is sometimes used more broadly to describe the mechanisms involved in the development of an organism, such as gene silencing and imprinting. For decades the mechanism of heredity has appeared to be a relatively simple one that is coded and translated through the sequence of DNA. However, recent discoveries have highlighted how inherited changes in gene function can occur outside of this, through the modification of DNA or chromatin structures. These so-called epigenetic changes are present from birth to death and are involved in the first crucial steps that govern embryonic development, and also in influencing the expression or silencing of genes in epigenetic diseases. Researchers are now trying to understand how these epigenetic mechanisms interact with each other, how their disruption can lead to such conditions as cancer and mental...

Heat Shock Protein HSP Inhibitors

The molecules that carry out the folding process are proteins themselves and are known as chaperone molecules or heat shock proteins (HSPs, or Hsps). One particular protein of this type, HSP90, is important because it is a master protein that controls a series of other HSPs. It is crucial for the folding of several client proteins, many of which are highly relevant to cancer. For example, client proteins include mutated p53 (important in most cancers), Bcr-Abl (important in acute lymphoblastic leukemia), human epidermal growth factor receptor 2 (HER2) neu (important in breast cancer), Raf-1, ErbB2 and other kinases, Cdk4, c-Met, Polo-1, Akt, telomerase hTERT, and steroid hormone receptors. Because cancer cells typically have a large number of mutated proteins that might not fold properly, they often compensate by overexpressing HSP90. The result is that even mutated proteins are folded sufficiently well to avoid disposal by the proteasomes, which allows cancer cells to survive....

New Biological Agents 9221 Growth Factors

Growth factors, or cytokines, are proteins that influence cell growth and maturation. Recombinant technology has allowed the production of large amounts of cytokines, and several are being evaluated in clinical trials. For example, hematopoietic growth factors have found use in counteracting the myelosuppressive side effects associated with many anticancer agents. Granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) boost the circulating number of neutrophils, eosinophils, and macrophages by inducing inflammation. It has been shown that some tumor cells possess receptors for these CSFs, and a number Inhibiting certain growth factors can lead to useful antitumor activity, and known inhibitors include octreotide (Sandostatin ), which is already in clinical use (see Chapter 6), and suramin (a polysulfonated naphthylurea). These two agents are analogs of somatostatin, a naturally occurring growth hormone. Octreotide is administered...

Near InfraredActivated Nanoshells

A new form of targeted cancer therapy based on photothermal technology is being developed by researchers at Rice University (Houston, TX, U.S.A.) in collaboration with Nanospectra Biosciences, Inc. It is a noninvasive treatment that uses nontoxic gold nanoshells in combination with near-infrared light that passes harmlessly through soft tissue. The near-infrared light, which is just outside the visible spectrum, is used to raise the temperature of the nanoshells that have accumulated selectively in the tumor, thereby destroying the cancer cells with heat. In theory, healthy tissue should not be damaged, and antitumor efficacy for the treatment has been demonstrated in in vivo models. The multilayered nanoshells, invented by Naomi Halas (Rice University) in the 1990s, consist of a silica core covered by a thin gold shell, and are approximately 20 times smaller than a red blood cell. The composition, shape, and size of the nanoshells all affect their unique optical characteristics. In...

Gene Hunting and DNA Sequencing

Advances in molecular biology allow new genes to be identified and then sequenced with great rapidity. Modern methods of DNA sequencing are based on the technology and sequencing machines developed for the Human Genome Project during the 1990s. A remarkable number of cancer-related genes, such as the breast-cancer related BRCA1 and BRCA2, have been discovered and identified during the last decade. Hunting for new cancer-related genes (oncogenes) is now a major activity by both commercial and academic research groups throughout the world, and the list of known oncogenes is rapidly expanding. The genes are normally discovered by applying modern molecular biology techniques to the study of cancer-related biochemical pathways in cancer cells growing in vitro. Once a new cancer-related gene has been identified, then its importance to the survival of the cell, and hence its value as a potential therapeutic target, can be validated using techniques such as RNAi to knock out the gene followed...

Sources of New Lead Molecules

As previously described, modern methods of anticancer drug discovery involve identification and purification of a novel biological target (i.e., an enzyme or receptor), followed by its employment in a high-throughput screen against libraries of diverse compounds from either commercial or in-house sources. However, one of the main drawbacks of libraries of synthetic compounds is that even molecules from so-called diverse libraries occupy only a relatively small volume of possible three-dimensional space. Conversely, plants, bacteria, and fungi are rich sources of organic molecules, which generally occupy a much greater proportion of three-dimensional space because they produce highly complex molecules rich in stereochemistry developed through millions of years of evolution. This may help explain why such a high proportion of anticancer agents in clinical use today have their origins in natural products (Table 9.1).

Ascorbic Acid Vitamin C

An authoritative analysis published in The Lancet in 2004 concluded that there is no evidence that vitamins (including vitamin C) help prevent the occurrence of common gastro-intestinal (GI) cancers. (see Structure 9.23)The study included more than 170,000 people at high risk for GI cancers and pooled 20 years of research data. However, despite this result, some experts still believe that antioxidants play a role in chemoprevention in certain individuals, and other studies are still ongoing. Ergothioneine, a constituent of white button mushrooms, the type most commonly consumed in the U.S. and Europe, has been proposed as an antioxidant vitamin with cancer chemopreventive and cardiovascular properties (Structure 9.24). White mushrooms are the best known source of ergothioneine, containing about 4 times more than chicken liver (previously considered the best source) and about 12 times more than wheat germ, also a good source of the nutrient. Even exotic mushrooms such as shiitake,...

Examples of Genes Associated with Specific Tumor Types

Cancer Type identify the up-regulation of single genes that may be associated with more-aggressive cancers (see Table 10.1), in the future it should be possible to study sets of key relevant genes and the way they interact which should more reliably inform prognosis and treatment decisions. The way in which genes interact, and the consequences of this for both normal and cancer cells, has given rise to new areas of research such as systems biology and the study of gene networks. In order to use genomics in cancer diagnostics, prognostics, and treatment, it is necessary to determine which sets of genes and gene interactions are important in different types and subsets of cancers. Analyses can be carried out that link the pattern of gene expression in tumor cells to the individual's response to therapy or the likelihood of recurrence of the cancer. Results from studies of this type can be used to create a genomic profile (or signature) of an individual's tumor that, in the future,...

Therapy Directed At Other Targets

The basic idea of antisense oligonucleotide (ASO)-based therapy is to interrupt the flow of genetic information from a gene to a protein by using synthetic oligonu-cleotides targeted to specific mRNA sequences, the ''sense'' sequences, by recognition of Watson-Crick complementary bases. Because ribosomes cannot translate double-stranded RNA, the translation of a given mRNA can be inhibited by a segment of its complementary sequence, the so-called antisense RNA. This results in blocking the translation of the RNA message to generate a specific protein and in the degradation of the mRNA strand by ribonuclease H (Rnase H), as shown in Fig. 10.25. Since overexpression or mutation of specific genes (oncogenes) causes cancer, downregulation of their expression offers the possibility of a selective tumor ablation. To reach this goal, it is necessary for the oligonucleotides not only to have a high and selective affinity toward the target mRNA sequence but also to elude the action of...

Screening For Risk Of Recurrence Of Disease

A number of genomics-based commercial assays are now available that claim to be able to predict the risk of cancer recurrence. For example, Oncotype DX from Genomic Health (as discussed in Section 10.3) is a physician-requested laboratory test for women with newly diagnosed, early-stage invasive breast cancer that is designed to predict the risk of disease recurrence, as well as facilitating choice of the best chemotherapy strategy for the patient. Clearly, information regarding the risk of a cancer returning is potentially distressing for patients and so must be handled sensitively by physicians. It is the view of most clinicians that predictive tests of this type should never be freely available to the public.

Selecting Best Treatments For Patients

Much research is ongoing to develop methods to predict the best treatments for individual cancer patients. For example, there is widespread agreement that traditional methods for determining which women need the most aggressive therapy for breast cancer are unsatisfactory. For example, it is particularly difficult to decide which patients whose lymph nodes are clear of cancer should still have follow-up therapy. As a result of this uncertainty, many more patients receive chemotherapy than actually need it, and some who might benefit from follow-up treatment do not get it. The hope is that genomic and proteomics tests can be developed that will help in this decision-making process. An alternative approach is chemosensitivity testing in which the most appropriate chemotherapeutic agent (or combination of agents) is selected based on the sensitivity of biopsied tumor cells from individual patients grown in vitro and exposed to a wide range of single agents and combinations (see Section...

Genomic and Proteomic Tests

One example of progress in this area is the discovery of epidermal growth factor receptor (EGFR) mutations in some tumors, a discovery that has ushered in a new era linking diagnostics with targeted therapeutics. Recently, researchers at the Dana-Farber Cancer Institute (Boston, MA) and the Massachusetts General Hospital (Boston, MA) reported that mutations in the EGFR gene help to predict which patients respond to drugs that target the EGFR receptor, including such high-profile products as Iressa (AstraZeneca) and TarcevaTM (Genentech and Roche). Based on these observations, a test has now been developed to identify patients most likely to respond to these EGFR-targeting cancer drugs, and a commercial organization (Gen-zyme Genetics www.genzymegenetics.com) signed an agreement in 2005 with these two cancer centers to put this approach into practice. Similarly, KuDOS Pharmaceuticals Ltd. has identified stand-alone activity of their poly-ADP-ribose polymerase (PARP) inhibitors against...

Chemosensitivity Testing

An alternative approach to personalized treatment known as chemosensitivity testing that does not require sophisticated genomic or proteomic methodologies is being evaluated by a number of researchers. This simple approach has a parallel in antibiotic treatment, whereby samples from patients (e.g., blood, urine, sputum, throat or wound swabs) are incubated in growth medium in the laboratory to establish which microorganisms are present and the best antibiotic to use. Chemosensitivity testing involves taking a biopsy from the patient (including blood or bone marrow in the case of leukemia patients) and growing the cells in the laboratory, usually in the form of a primary culture. A number of different anticancer agents can then be incubated with the cells to discover which is the most effective. Although there is anecdotal evidence that this approach is beneficial, several clinical trials are underway to try to validate it.

Pharmacogenomics In Clinical Trials

The rapidly growing introduction of so-called personalized medicine and phar-macogenomics will almost certainly lead to changes in the way clinical trials of anticancer agents are designed and carried out. This claim is based on the principle that it should be possible, even at the early Phase I stage, to design trials to identify subgroups who should respond rather than simply establishing toxic side effects and maximum-tolerated doses (MTDs). A number of prominent U.S. and European cancer organizations are now calling for the traditional clinical trials format to be redesigned, and are advocating additional testing before and during clinical trials to establish differences in drug responses between individual patients more rapidly. This has coincided with the U.S. Food and Drug Administration's (FDA's) March 2005 release of guidelines for personalized medicine. Traditional clinical trials test initially for safety (i.e., Phase I) and later for efficacy (i.e., Phase II), but some...

Prednisolone and Dexamethasone

Prednisolone is an orally administered synthetic corticosteroid widely used in oncology for its significant antitumor effect in Hodgkin's disease, non-Hodgkin's lymphomas, and acute lymphoblastic leukemia, where it is often used in combination with other anticancer agents (see Structure 11.4). However, it is also used in the palliative treatment of the final stages of cancer to stimulate appetite and induce a feeling of well-being.

DNA Intercalators and Topoisomerase Inhibitors

Intercalation Dna

Medicinal Chemistry of Anticancer Drugs 2008 Elsevier B. V. Many anticancer drugs in clinical use (e.g. anthracyclines, mitoxantrone, dactinomy-cin) interact with DNA through intercalation, which can be defined as the process by which compounds containing planar aromatic or heteroaromatic ring systems are inserted between adjacent base pairs perpendicularly to the axis of the helix and without disturbing the overall stacking pattern due to Watson-Crick hydrogen bonding. Since many typical intercalating agents contain three or four fused rings that absorb light in the UV-visible region of the electromagnetic spectrum, they are usually known as chromophores. Besides the chromophore, other substitu-ents in the intercalator molecule may highly influence the binding mechanism, the geometry of the ligand-DNA complex, and the sequence selectivity, if any. S-16020 is another important antitumor pyridocarbazole derivative, bearing a (dimethylamino)ethylcarboxamide side chain that increases its...

Fluorouracil 5FU and floxuridine

Mechanism Action

The main inhibitors of TS are 5-FU and its deoxynucleoside floxuridine (5-FUdR), and these fluoropyrimidines represent the most widely prescribed class of anticancer drugs worldwide.15 In particular, 5-FU is widely used in the treatment of cancers of the aerodigestive tract, breast, head, and neck, and especially in colo-rectal cancers in combination therapies with oxaliplatin and irinotecan.17 Administered as a cream, it is also useful for the treatment of some skin cancers. 5-FU was developed in the 1950s following the observation that rat hepatomas utilized uracil at a higher rate than normal tissues, which suggested that uracil metabolism could be a relevant antitumor target. Floxuridine is employed in the treatment of colorectal cancer metastatic to the liver. Because of its nucleoside structure it has a very poor oral bioavailability and is administered in intra-arterial injection.

Mitoxantrone And Related Quinones

Mitoxantrone is active in breast cancer, acute promyelocitic or myelogenous leukemias, and androgen-independent prostate cancer. Although early reports seemed to indicate that its cardiotoxicity was lower than that of the anthracy-clines,56 this claim has been subsequently challenged.57 Mitoxantrone has been recently approved for treatment of secondary progressive multiple sclerosis (MS).58 The rationale for this application stems from the fact that MS is considered to be an autoimmune disease where a heightened immune action results in the destruction of the myelin of the central nervous system, causing nerve impulses to be slowed or halted and leading to the symptoms of MS. Since chemotherapeutic

Thiopurines and related compounds

Among nonnatural purine derivatives assayed as antitumor agents, 6-mercapto-purine (MP) and 6-thioguanine (TG) are the most active. These compounds are among the oldest cancer chemotherapeutic drugs in clinical use MP is used for lymphoblastic and myeloblastic leukemias, and the more toxic TG is employed for the treatment of acute non-lymphocytic leukemia. The main degradative pathways of MP are its S-methylation by thiopurine methyltransferase (TPMT) and its oxidation by xanthine oxidase to an 8-oxo derivative and further to 6-thiouric acid (TUA) (Fig. 2.38). Allopurinol is a structural analog of hypoxanthine that is a competitive inhibitor of xanthine oxidase. It is also a substrate for xanthine oxidase and is converted slowly to alloxanthine, which also inhibits the enzyme. Since allopurinol interferes with the metabolism of MP, increasing its levels and leading to an interaction between both drugs, patients taking allopurinol should have their MP dose reduced by up to 75 ....

Androgenrelated Antitumor Agents

Most prostatic tumors are androgen dependent, and for this reason hormone treatment of prostate cancer is based on the modulation of testosterone to achieve medical castration levels. This can be achieved directly by administration of antiandrogens or indirectly by inhibition of 5a-reductase, the enzyme responsible for the reduction of testosterone to its more active metabolite. Androgen production can also be controlled by inhibition of the release of LH (see Section 7).

Steroid Sulfatase Inhibitors

It was previously mentioned that in postmenopausal women, who show the highest incidence of breast cancer, estrogens are produced in adipose tissues and in the breast by the action of aromatase on androstenedione. However, the clinical response to aromatase inhibitors is not as high as expected, and often it is not superior to the one obtained with antiestrogens or with other antihormones. Furthermore, there appears to be no relationship between the clinical response and the degree of suppression of circulating estradiol levels, which suggests that other factors besides the classical estrogens must be involved in tumor growth.33 Steroids with estrogenic properties can be biosynthesized by a route involving the steroid sulfatase (STS) enzyme, which regulates the formation of estrone by hydrolysis of estrone sulfate (E1S) and also controls the hydrolysis of dehydroepian-drosterone sulfate (DHEA-S) to dehydroepiandrosterone (DHEA). The latter compound can be reduced to 5-androstene-3p,...

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