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! Continue reading...

Do I Have Cancer Overview

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My Do I Have Cancer Review

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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...

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.

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...

Estrogens And Their Involvement In Carcinogenesis

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...

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...

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...

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...

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...

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< 0.000005 FisHer et al. 2001). The European Organization for Research and Treatment of Cancer (EORTC) 10853 trial randomized 1010 patients with DCIS treated with lumpectomy to either radiation therapy or no radiation therapy (JulieN et al. 2000). The results of this study also showed that radiation therapy decreased local recurrence (4-year rates 16 vs 9 p 0.005). Finally, a phase-III trial conducted by the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) DCIS Working Party found a similar...

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.

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...

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).

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.

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...

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

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 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 (<...

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...

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...

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...

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.

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...

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...

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...

Early Stage Breast Cancer

Most of the patients diagnosed with breast cancer either present with stage-I or stage-II disease and are usually treated with a combination of surgery, radiation, and systemic therapy. Typically, patients who present with relatively small primary tumors (i.e., < 3 cm) undergo surgery as their initial treatment. For such patients, surgery can consist of either BCT or a modified radical mastectomy (MRM). Several large randomized trials have conclusively demonstrated that the outcome associated with both of these treatment modalities is equivalent. One example of these trials is the NSABP B-06 trial, which was reported in 2002 with 20 years of follow-up (Fisher et al. 2002). The results of this trial showed that patients treated with BCT achieved equivalent disease-free survival, distant disease-free survival, and overall survival rates as patients treated with MRM. This trial also examined the value of radiation therapy after lumpectomy for patients treated with BCT. In this study,...

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...

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...

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...

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...

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...

Anticancer Effects

The anticancer potential of curcumin has been demonstrated in various in vitro and in vivo models 40 . Curcumin has been shown to block transformation, tumor initiation, tumor promotion, invasion, angiogenesis, and metastasis. In in vivo studies, curcumin suppressed carcinogenesis of the skin, forestomach, colon, and liver in mice. Curcumin has been shown to inhibit proliferation of a wide variety of tumor cells, including B-cell and T-cell leukemias 41-44 , colon carcinoma 45 , epidermoid carcinoma 17 , head and neck squamous cell carcinoma 46 , multiple Fang et al. reported that rat thioredoxin reductase activity in thioredoxin-dependent disulfide reduction was inhibited by curcumin 50 . By using mass spectrometry and blotting analysis, they showed that this irreversible inhibition by curcumin was caused by alkylation of both residues in the catalytically active site (Cys (496) Sec (497)) of the enzyme. Kang et al. reported that exposure of human hepatoma cells to curcumin led to a...

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...

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...

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...

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...

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...

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.

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...

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...

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...

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...

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...

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...

Substrate analogs as RNR inhibitors

Tezacitabine (fluoromethylenedeoxycytidine, FMdC) is a nucleoside prodrug that shows a dual mechanism of action. Following intracellular phosphorylation, the tezacitabine diphosphate irreversibly inhibits RNR, while the tezacitabine triphosphate can be incorporated into DNA during replication or repair, resulting in DNA chain termination.9 After initially promising clinical data, analysis of the data from a Phase II trial in patients with gastroesophageal cancer prompted the decision to discontinue further development of tezacitabine.

Biological Response Modifying Agents

Many so-called biological response modifiers (BRMs), or biologicals, are either in use or development. These include agents as diverse as antibodies, antibody-drug conjugates, interferons, interleukins, enzymes, vaccines, and other types of immune stimulants (see Chapter 8). For example, several tumor types, including some types of breast cancer, have been found to produce specific tumor antigens on their cell surfaces, and this has led to the development of monoclonal antibodies specific for these tumors (e.g., Herceptin see Chapter 5 and Chapter 7 ). Tumor-specific antibodies can also be used to selectively deliver a cytotoxic agent (e.g., Mylotarg ) or a radionuclide (see Chapter 7) to the tumor site. An antibody-enzyme conjugate designed to release an active form of a cytotoxic agent from a nontoxic prodrug selectively at the tumor site (i.e., antibody-directed enzyme prodrug therapy ADEPT see Chapter 7) is presently being evaluated in clinical trials. Finally, research is ongoing...

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

Topoisomerase I Inhibitors

Topo I is an essential DNA topology-controlling enzyme that works by transiently breaking one DNA duplex and passing the second strand through the break followed by resealing. This is an absolute requirement of many nuclear processes, including replication, transcription, and recombination. Topo I inhibitors work by keeping the chromosomes wound tight so that the cell cannot make proteins and cell death results. Because some cancer cells grow and reproduce at a much faster rate than normal cells, they are thought to be more vulnerable to topoisomerase inhibition, which is one possible explanation for their selective toxicity. The lead structure for Topo I inhibitors is the natural product camptothecin, which is a cytotoxic quinoline-based alkaloid with a unique five-ring system extracted from the barks of the Chinese camptotheca tree (e.g., Camptotheca acuminate) and the Asian nothapodytes tree. Camptothecin and related compounds cause cancer cell death by inhibiting the enzyme DNA...

Topoisomerase II Inhibitors

Other agents such as the ellipticines and semisynthetic derivatives such as podophyllic acid ethyl hydrazide have been synthesized and studied but none have been commercialized. Amsacrine is also a known topsisomerase II inhibitor. As a class, topo II inhibitors appear to have activity in certain cancers, including testicular cancer, oat-cell carcinoma of the bronchus, malignant teratomas, and various leuke-mias and lymphomas.

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 Potential Targets

In addition to the kinases discussed above, many other types of kinases might be targeted with potential clinical benefit, and the list is growing ever longer due to the rapidly progressing work of molecular biologists in the cancer field. For example, attempts are being made to develop inhibitors for the insulin-like growth factor (IGF)-1R receptor pathway, which is triggered by the IGF-1 and IGF-2 growth factors and is important for many cellular functions, including transformation and proliferation (see Scheme 5.7). Mutant Flt-3 is also of interest and is known to be important in leukemic (AML and ALL) cells (see Scheme 5.8). Other areas of research include the MET and SRC kinases, and the flos ERK1-2, AKT and STAT pathways. The attraction of MET kinase is that it is important in the process of metastasis which, if controlled, could allow more focus on the treatment of primary tumors.

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.

Cell Cycle Inhibitors

The D-type cyclins and corresponding partner kinases, CDK4 and CDK6, act as central integrators of extracellular signals and operate during the G1 phase of the cell cycle by phosphorylating the tumor suppressor protein pRb, thus contributing to its inactivation. Mutations that can influence the operation of cyclins CDK4 and CDK6, their regulating proteins, or pRB can be found in most human tumors. Furthermore, cyclin D1 expression can be up-regulated by the Ras signaling pathway, which is itself up-regulated in many cancer cells. use in combination with capecitabine (an oral prodrug of 5-fluorouracil) in advanced breast cancer. A further trial is studying the effect of CYC-202 in glomerulonephritis, an inflammatory disease of the kidney.

Proteasome Inhibitors

Cells, which degrades it to the constituent peptides and free ubiquitin. This disposal pathway can be crucial for tumorigenesis, tumor growth, and metastasis because the sequenced and temporal degradation of many key control proteins, such as tumor suppressors and cyclins, is critical for cell cycle progression and mitosis. Hence, in some cases, proteasome inhibitors should arrest or retard cancer progression by interfering with degradation of these regulatory molecules. One example is that a reduction in expression of the NF-KB-dependent cell adhesion molecule should make dividing cancer cells more sensitive to apoptosis. Therefore, as the proteasome is involved in activating NF-kB by degrading its inhibitory protein IkB, inhibition of proteasome-mediated IKB degradation may increase levels of NF-KB and promote apoptosis in tumor cells. Another example is that NF-kB plays an important role in the response of cells to environmental stress or exposure to cytotoxic agents by promoting...

Oxidation of DNA bases

Attack of hydroxyl radicals to purine or pyrimidine bases produces other DNA damages. The structures of the degradation products arising from this reaction have been established mainly from studies with ionizing radiation,9 but many of them were similarly isolated from patients receiving anthracyclines for the treatment of breast cancer.10

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.

Polymer Drug Conjugates

A related polymer uptake effect can be utilized by entrapping anticancer drugs in liposomes of an appropriate size. For example, Caelyx is a liposomal form of doxorubicin that is licensed for advanced AIDS-related Kaposi's sarcoma and for advanced ovarian cancer when platinum-based chemotherapy has failed. A similar product, Myocet , is licensed for use with cyclophosphamide for metastatic breast cancer. Due to the different pharmacokinetic profiles of these liposomal preparations compared to doxorubicin itself (i.e., accumulation at the tumor site), the incidence of cardiotoxicity is also lowered, as is the potential for local necrosis at the site of administration (see Chapter 3).

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

Prodrug Activation by Constitutively Overexpressed Tumor Enzymes

It is worth noting that subtle genetic modifications (i.e., base pair changes) in the gene coding for the P450 drug metabolizing enzymes are often used to explain differences between the response of individuals to cancer chemotherapy agents. Thus, it is thought that relatively modest genetic changes can have an impact on the pharmacodynamic and pharmacokinetic characteristics of any anticancer drug and may have an especially significant effect on those agents with narrow therapeutic indices. The detection of variations in the P450 genes is therefore growing in importance as a means to select the most beneficial anticancer drugs for an individual, and the most appropriate doses and dose schedules to use. This approach has led to the identification of many different types of P450 enzymes, such as those in the CYP2C and CYP3A families, as well as CYP1B1 and CYP2D6. In particular, studies on the CYP2C and CYP3A families have shown that polymorphisms (i.e., subtle changes of base-pair...

Cosubstrate Mediated Prodrug Therapy

The prodrug used in this system is CB1954 (see Scheme 7.6), which is activated by conversion to a 4-hydroxylamine derivative thus generating a potent DNA cross-linking agent (see Section 7.4.2) when administered together with NRH (see Structure 7.5). Interestingly, although activation has been shown to occur in some rat tumors, human cancer cells are inherently resistant to CB1954 because they cannot efficiently catalyze this conversion. Also, the expression of DT-diaphorase (NQO1), an enzyme known to be expressed in high concentrations in certain human tumors, appears to be related to NQO2 activity.

Photoactivated Drugs Photodynamic Therapy

This prodrug photoactivation concept was extended into cancer therapy in the early 1990s, when it was discovered that porphyrin-type molecules are selectively taken up by some tumors. This led to the development of porfimer sodium (Photofrin ) and temoporfin (Foscan ), which are now used in the photodynamic treatment of various tumors (Structure 7.8 and Structure 7.9). After systemic administration, these drugs accumulate in malignant tissue and can then be activated by laser light to produce cytotoxic effects. Indications are presently limited to obstructing esophageal cancer and NSCLC, and to situations in which a tumor manifests near the skin surface (e.g., advanced head and neck cancers). However, recent progress in the development of surgical lasers with flexible optical fibers has allowed experimental use of these agents for the treatment of tumors in inaccessible places, such as parts of the GI tract and the ovaries. An intense nonlaser light source has also been developed for...

Boron Neutron Capture Therapy Bnct

Boron Neutron Capture Therapy (BNCT) is a targeted biphasic approach to cancer therapy in which boron-10 (10B)-enriched delivery agents are first administered intravenously and are taken up by tumors to varying extents. Once maximal tumor uptake has been achieved, the target area is then irradiated with low-energy neutrons (epithermal neutrons in the 1 to 10,000 electron volt energy range), which become

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...

Intracranial Delivery

The improvement of cancer drug delivery to the brain is now a major area of research. One of the current limitations of the treatment of brain tumors is the lack of a suitable method to deliver therapeutic agents directly to the lesion. The challenge for systemic therapy is to develop methods to allow drugs to cross the blood-brain and brain-tumor barriers in order to allow higher concentrations to be obtained within the tumor bed. There are also opportunities in local drug delivery, and one commercially successful product of research in this area, Gliadel , is based on local, controlled delivery of carmustine by a biodegradable polymer implanted at the tumor site after surgical resection (see Chapter 3). This allows effective concentrations of carmustine to reach any remaining tumor cells, a situation not usually achieved with systemic administration due to dose-limiting bone marrow toxicity. It also avoids some of the other adverse effects of carmustine, such as cumulative renal...

Triazines Hexamethylmelamine And Trimelamol

Hexamethylmelamine (HMM, altretamine) was originally prepared as a resin precursor, but it was studied as an antitumor compound because of its structural analogy with the previously mentioned aziridine derivative TEM. Although it is active in several types of tumors, its main therapeutic role is in the treatment of recurrent ovarian cancer, following first-line treatment with cisplatin. The precise mechanism of altretamine cytotoxicity is unknown, although several proposals have been made. The main metabolic pathway is oxidative cytochrome P450-catalyzed N-demethylation, with carbinolamine 5.59 as an intermediate, which yields the pentamethyl derivative 5.62, formaldehyde, and smaller amounts of inactive compounds arising from further demethylation. Alternatively, elimination of the hydroxy group from 5.59 gives the iminium species 5.60. In the case of altretamine, the pattern of adduct formation suggests that 5.60 is the alkylating species,56 reacting with DNA to give 5.61 rather...

Direct Use of Tumor Antigens

This approach involves the identification of unusual or unique cancer-related molecules (i.e., tumor antigens) that appear on the surface of cancer cells but are rarely present on the surface of normal cells. These tumor antigens then form the basis of vaccines. More than 60 of research and development in the vaccine area is based on this approach. Apart from this being the most logical path to cancer vaccine development, other advantages include higher specificity, ease of production, lower cost of manufacture, and reduced levels of concern related to product contamination.

Manufacture of Vaccines

Approximately 75 of the current cancer vaccine pipeline is comprised of generalized or off-the-shelf vaccines based on specific carbohydrates, proteins, or other easily replicated structures that are capable of being mass produced. The remainder consist of personalized, vaccines (i.e., based on antigens harvested from an individual patient's tumor cells). This trend reflects the fact that generalized vaccines are simple to manufacture and commercially viable on a large scale. However, mainly due to their limited range of relevant antigen expression, they are associated with a higher rate of clinical failure than personalized approaches. To date, despite concerns relating to the complexity of manufacture and formulation, as well as product sterility and distribution problems, the personalized dendritic cell-based vaccine approach has provided the most convincing clinical evidence of efficacy. For example, Den-dreon's Provenge is based on patient-specific dendritic cells loaded with a...

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.

Telomerase Inhibitors

Telomeric DNA has emerged in the last decade as a novel anticancer target. Telomeres are short, repeat DNA sequences at the ends of chromosomes (5'-TTAGGG-3' 3'-chromosome end ) that protect sequence information near the chromosome ends from degradation and ensure complete replication of chromosome ends. Somatic cells have a finite lifespan because normal DNA polymerase is unable to fully replicate the ends of telomeric DNA due to its mechanism of action. Therefore, their telomeres progressively shorten with each successive round of replication until they become critically short, at which point they enter irreversible replicative senescence and ultimately apoptosis. This is thought to act as a type of biological clock, leading to natural cell death when the telomeres have been depleted, a process that can be linked to aging. Telomerase is a reverse transcriptase enzyme capable of adding telomeric repeats back on to the ends of chromosomes. Although the telomerase enzyme is not...

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...

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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