Cyclopropanepyrroloindole CPl Dimer Bizelesin

The experimental agent bizelesin is similar to SJG-136 in binding in the minor groove of DNA and spanning approximately six base pairs. However, it cross-links two adenines on opposite strands via their N3 positions, as opposed to the G-G cross-link formed by SJG-136. In the case of bizelesin, the alkylating moieties are cyclopropane rings that form in situ. Thus, bizelesin itself is a prodrug that undergoes FIGURE 3.4 (a) Schematic diagram of the SJG-136 DNA adduct showing the molecule bound...

Overview Of Mechanisms Of Action Of Chemotherapeutic Agents

The anticancer agents either in clinical use today or in development work through a wide variety of different mechanisms in order to interfere with tumor cell growth, motility or survival, or with angiogenesis. By far, the largest and most diverse group of agents is those that interact with DNA (see Chapter 3) (Scheme 1.4). Some do this by blocking the synthesis of DNA (e.g., 6-mercaptopurine), while others become incorporated into DNA and then interfere with its function (e.g., 6-thioguanine)....

Introduction

Plants and trees have been an invaluable source of medicinal compounds throughout the centuries, including numerous anticancer agents such as the vinca alkaloids and the taxanes. These two families of agents work by interfering with microtubule dynamics (i.e., spindle formation or disassembly) in the cell but by different mechanisms. Microtubules are polymers of tubulin that are integral components of the mitotic spindle, and microtubule assembly (through polymerization) and disassembly...

Role of Estrogen in Tumor Growth

Estrogen has effects on the growth and function of reproductive tissues and also preserves bone mineral density, thus reducing the risk of osteoporosis and protecting the cardiovascular system by reducing cholesterol levels. Estrogens act as promoters, rather than initiators, of breast tumor development and can also facilitate tumor invasiveness by stimulating the production of proteases, which can degrade the extracellular matrix. Estrogen action is conducted through estrogen receptors (ERs)....

Cyclophosphamide Endoxana

The design of this mustard prodrug, first synthesized in 1958, was based on the concept that the P O group should decrease the availability of the nitrogen lone pair in an analogous manner to the phenyl ring of the aromatic mustards, thus reducing the electrophilicity of the molecule (Structure 3.8). Furthermore, it was postulated that the P O group might be cleaved by phosphoramidase enzymes that were thought to be overexpressed by some tumor cells, thus releasing the nitrogen lone pair and...

Aromatic Nitrogen Mustards

The aromatic nitrogen mustards were introduced in the 1950s and are milder alkylating agents than the aliphatic mustards. For these agents, the aromatic ring acts as an electron-sink, withdrawing electrons from the nitrogen atom and discouraging aziridinium ion formation. In comparison to aliphatic mustards, the central nitrogen atom is not sufficiently basic to form a cyclic aziridinium ion because the nitrogen electron pair is delocalized through interaction with the electrons of the aromatic...

Interferon Alpha

Interferon alfa has demonstrated limited antitumor activity in certain lymphomas and solid tumors, and has also been used to treat chronic hepatitis B and C. Three preparations (IntronA , Roferon-A , and Viraferon ) are licensed in the U.K., all administered by subcutaneous injection. IntronA , which is interferon alfa-2b (rbe), is licensed for use in hairy cell leukemia, chronic myelogenous leukemia (CML), lymph or liver metastases of carcinoid tumors, follicular lymphoma, and maintenance of...

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

Interleukins, Asparaginase Chemopreventive It follows that there should be a greater chance of obtaining hits in high-throughput assays if natural product extracts are screened rather than libraries of synthetic compounds. However, with the upsurge of interest in parallel and combinatorial libraries in the 1990s, the desirability of using extracts of plant, bacterial, and fungal materials waned due to issues relating to their availability and stability, and especially the fact that they are...

Novel Therapeutic Targets 9211 Resistance Inhibitors

Because drug resistance can develop in most classes of agents, it provides a major obstacle to successful cancer chemotherapy. The various mechanisms of resistance available to the cancer cell can be categorized as non-class-specific, class-specific, or drug-specific. The main non-class-specific mechanism available to most cancer cells involves the induction of proteins such as multiple drug resistance protein (MDRP) and breast cancer resistance protein (BCRP), which can actively transport a...

Inhibition Of Ras Pathway Signaling 531 Introduction

Approximately 30 of all human tumors are thought to start from a mutated Ras oncogene. For example, approximately 50 of colon cancers and 90 of human pancreatic carcinomas have point mutations in their corresponding Ras genes. Ras is also proving to be one of the most prevalent oncogenic mutations in myeloma, in which mutations in 39 of newly diagnosed patients have been observed along with a correlation between Ras mutation and shorter survival, a characteristic that can be used...

Surgery

If a tumor is small or reasonably well defined, it can sometimes be surgically removed. However, additional treatment with chemotherapy or radiotherapy is often required to eliminate any cancer cells that may have remained behind or metasta-sized. Alternatively, radiotherapy or chemotherapy may be administered prior to surgery in order to shrink (or debulk) the tumor, thus facilitating its removal. Where possible, a large area of surrounding healthy tissue (including neighboring lymph glands...

Aziridines

Rather than form aziridinium ions as reactive intermediates through an activation process (as with the mustards), thiotepa and related analogs, such as the experimental agents AZQ and BZQ, have an aziridine ring already incorporated into their structures (Structure 3.11). Ring-opening of the aziridines with nucleophiles is slower than that the fully charged aziridinium ions formed from mustards. However, depending on the pKa of the aziridine nitrogen, significant protonation at physiological pH...

Chemicals

Certain chemicals in the environment and some encountered through diet, lifestyle, and occupation can lead to tumorigenesis. For example, the link between cigarette smoke and lung cancer is now well-established. It is also known that carcinogenic polycyclic aromatic hydrocarbons, which form when red meat is overcooked (especially through frying or barbecuing), can lead to colon tumors. Carcinogenic amines form in the stomach as a result of the bacterial degradation of nitrites used as...

Diagnosis And Screening

All too often, cancer is only diagnosed when a solid tumor has grown to sufficient size to become noticeable to the patient either directly by its size and location, where it may cause obstruction a feeling of pressure or pain (e.g., in breast, esophagus, head and neck tumors) or through indirect symptoms, such as traces of blood in the urine or feces (e.g., in bladder or bowel cancer) or severe coughing (e.g., in lung cancer). Even worse, a secondary tumor may be detected, by which time it may...

Biological Response Modifiers Brms

Interferons, interleukins, antibodies, and other agents that act through the immune system to treat cancer are known as biological response modifiers (BRMs). They work by modifying the interaction between the immune system and cancer cells in order to boost the body's own ability to deal with them. Growth, colony-stimulating, and tissue necrosis factors are also considered to be BRMs but these are in the early stages of development as therapeutic agents (see Chapter 9). This area of research is...

Aclarubicin

Aclarubicin is produced by Streptomyces galilaeus, and its general properties are similar to those of doxorubicin (Structure 3.19). It is used for acute nonlymphocytic leukemia in patients who have relapsed or are resistant or refractory to first line chemotherapy. STRUCTURE 3.20 Structures of the semi-synthetic anthraquinone antitumor antibiotics, epirubicin (Pharmorubin ) and Idarubicin (Zavedos ).

Aromatase Inhibitors

Aromatase inhibitors work predominantly by blocking the formation of estrogens from androgens in the peripheral tissues. They do not inhibit ovarian estrogen synthesis and thus should not be used in premenopausal women. Androstenedione and testosterone are converted by the cytochrome P450 aromatase enzyme (P450arom) to estrone and estradiol, respectively, as the final step in the steroidogenesis pathway from cholesterol (see Scheme 6.3). Selective inhibition of aromatase leads to reduced...

Temozolomide

Temozolomide (Temodal ) is a more-recently introduced alkylating agent (a meth-ylating agent) licensed for the second-line treatment of malignant gliomas and also used experimentally for melanomas (Scheme 3.2). It is structurally related to dac-arbazine but is more similar to the nitrosoureas in terms of its spectrum of activity and cross-resistance profile. As with dacarbazine and the nitrosoureas, temozolo-mide's major dose-limiting toxicity is bone marrow suppression. However, one...

Oleic Acid

An article in Annals of Oncology (2005) suggests that ingesting olive oil may reduce the risk of developing breast cancer. This finding was based on a study in which oleic acid (Structure 9.25), the main mono-unsaturated fatty acid component of olive oil, was found to prevent overexpression of the oncogene HER2 neu, which is known to be a significant factor in the development and management of certain types of breast tumors. Overexpression of HER2 neu is seen in about 20 of breast cancers and...

Flavone8Acetic Acid FAA and DMXAA

Interest in this nontubulin class of VDAs began in the mid-1980s, with the serendipitous discovery of the antitumor properties of flavone-8-acetic acid (FAA), a molecule originally synthesized as a nonsteroidal anti-inflammatory agent by Lyonnaise Industrielle Pharmaceutique (Structure 7.3). FAA was found to be active (even curative) against a wide variety of preclinical solid tumor models, and its mechanism of action appeared to be related to the production of tumor necrosis factor (TNF)....

Vinca Alkaloids

The two alkaloids vinblastine and vincristine are minor constituents of the Madagascar periwinkle (Vinca rosea) (see Figure 4.2). The periwinkle is the common name for herbs of the dogbane family, which make up the genus Vinca of the family Apocynaceae. The lesser periwinkle, a native of many parts of Europe, grows in FIGURE 4.2 The periwinkle (Vinca rosea), which produces the anticancer agents vinblastine and vincristine. FIGURE 4.2 The periwinkle (Vinca rosea), which produces the anticancer...

HDM2p53 Binding Inhibitors

The transcription factor protein p53, often referred to as the guardian of the genome, is activated in response to cell stress (e.g., low oxygen levels, heat shock, DNA damage), which prevents further proliferation of the stressed cell by promoting cell cycle arrest or apoptosis. Therefore, it plays a pivotal role in regulating the growth of many tumors and in their response to cytotoxic agents. For example, tumors with mutated p53s generally respond poorly to cytotoxic agents, and there is a...

Pyrrolobenzodiazepine PBD Monomers

The pyrrolo 2,1-c 1,4 benzodiazepine (PBD) family of antitumor agents is based on the natural product anthramycin, which was the first member to be isolated from Streptomyces refuineus var. thermotolerans in the early 1960s (Structure 3.4). Other Anthramycin (R H) Anthramycin Imine Anthramycin (R H) Anthramycin Imine STRUCTURE 3.4 Structure of the pyrrolobenzodiazepine anthramycin showing the N10-C11 carbinolamine, carbinolamine methyl ether, and imine forms. well-known members of the family...

GDEPT or VDEPT

GDEPT, also known as VDEPT, is a two-phase polymer-leased strategy to treat solid tumors. First, a gene coding for a nonhuman enzyme is targeted to the tumor in a vector suitable for expression. In the second phase, a nontoxic prodrug capable of being activated by the tumor-associated enzyme is administered systemically. The important feature of this concept is that the enzyme genes are expressed exclusively, or with a relatively high abundance, in the tumor cells compared to healthy cells....

A

Accessibility of drugs to tumor cells, 17 Aclarubicin, 73 Acute lymphyoblastic leukemia, see ALL Adenosine deaminase inhibitor, 35 ADEPT, 157, 174-76 Adjuvant enzymes, 282-83 Adjuvants, 26 ADME considerations, 17 Aflatoxins, 8 Alemtuzumab, 194 Aliphatic nitrogen mustards, 50-51 Alkylating agents, 38-47 Ecteinascidin-743, 44-45 methylating agents, 38-44 PBD monomers, 45-47 ALL, 193, 198 Amsacrine, 81 Anastrozole, 128, 136, 137 structure, 138 Anti-androgens, 146-151 bicalutamide, 150 cyproterone...

Drug Resistance

The development of drug resistance is one of the most significant problems encountered in cancer chemotherapy, since up to 50 of tumors have either de novo drug resistance or otherwise develop resistance to anticancer drugs after initial treatment. Therefore, preliminary selective cytotoxicity toward a tumor can sometimes be followed by a rapid recovery in the rate of tumor growth, and the degree of resistance may increase after each subsequent administration to the point where the...

Diethylstilbestrol

Diethylstilbestrol (DES), also known as stilbestrol or DHS, is a synthetic nonsteroidal estrogen first reported in 1938. Its structure is interesting from the medicinal chemistry perspective, as the two ethyl and two phenolic substituents arrange themselves around the central double bond to mimic a steroidal four-ring system in a similar manner to the estrogen inhibitor tamoxifen. STRUCTURE 6.27 Structure of diethylstilbestrol (DES). STRUCTURE 6.27 Structure of diethylstilbestrol (DES). The use...

Chemotherapy

Chemotherapy involves the use of low-molecular-weight drugs to selectively destroy a tumor or at least limit its growth. Nitrogen mustards were the first agents to be used clinically their use resulted from the accidental discovery that the mustard gas used in World War II had antileukemic properties. Since then, important advances have been made in the development of new anticancer drugs. For example, cisplatin, which was also discovered serendipitously, provided a major advance in the...

Chlormethine Mustine

The only example of a simple aliphatic nitrogen mustard in clinical use is chlormethine Mustine see Structure 3.5 . The high chemical reactivity of the aliphatic nitrogen mustards toward DNA and also their vulnerability to attack by a wide range of nucleophiles is thought to account, in part, for the observed toxicities. STRUCTURE 3.5 Structure of chlormethine Mustine . Under physiological conditions, chlormethine and related compounds undergo initial internal cyclization through elimination of...

Nitrosoureas

The nitrosoureas alkylate DNA and lead to both mono-adducts and interstrand cross-links at a number of different sites. The study of a large number of nitrosourea analogs has established the structural unit for optimal activity as the 2-chloroet-hyl-N-nitrosoureido moiety, and the likely mechanism of both monoalkylation and cross-linking is shown in Scheme 3.12. Although these molecules possess chloro-ethyl fragments, their activity is not associated with aziridinium ion formation as in the...

BCG Bladder Instillation

BCG is a live, attenuated strain of bacterium derived from Mycobacterium bovis that works by stimulating the immune system at a local level in the bladder. The two commercial products, ImmunoCyst and OncoTICE , are derived from the Connaught and TICE strains of bacteria, respectively. BCG is licensed as a bladder instillation for the treatment of primary or recurrent bladder carcinoma, and for the prevention of recurrence following transurethral resection. BCG is contraindicated in patients...

Bicalutamide

Bicalutamide Casodex is a nonsteroidal peripherally active anti-androgen first reported by the then ICI in 1984 Structure 6.22 . Interestingly, the structure allows a hydrogen-bonded pseudo five-membered ring to form in a similar manner to the active metabolite of flutamide hydroxyflutamide , and this is thought to contribute to its activity. STRUCTURE 6.22 Structure of bicalutomide Casodex . STRUCTURE 6.22 Structure of bicalutomide Casodex . Licensed in the U.K. for the treatment of prostate...

Nxc unwinding

SCHEME 9.9 Mechanism of gene silencing via RNAi. dsRNA is first cut into shorter fragments of 21 bases i.e., to siRNA by the enzyme Dicer, and these fragments attach to a RISC protein complex, after which one strand is stripped off to leave the complementary strand. The RISC complex then uses this single-stranded RNA as a template to locate and bind mRNA containing the matching sequence. Once a match has occurred, the mRNA is then enzymatically degraded. binds the target RNA using its...

Adenosine Deaminase Inhibition

The one adenosine deaminase inhibitor in clinical use is pentostatin Nipent see Structure 2.7 . Pentostatin was initially isolated from Streptomyces antibioticus in the mid-1970s, and a full synthesis was reported in 1982. Administered intravenously on alternate weeks, pentostatin is highly active in hairy cell leukemia and is capable of inducing prolonged remissions. It is potentially toxic, causing myelosuppression, immunosuppression, and a number of other side effects that can be severe.

Lycopene

Lycopene is an unsaturated open-chain carotenoid, also known as all-trans -lyco-pene, that provides fruits such as pink grapefruit, rosehip, watermelon, guava, and especially tomatoes with their red coloration Structure 9.27 . It is present in higher concentrations in ripe fruit, particularly in tomatoes 1 kg of fresh ripe tomatoes can yield as much as 0.02 g of pure lycopene . Although first isolated in impure form in 1910, its structure was not elucidated until the late 1920s. However, due to...

Goserelin

Goserelin Zoladex is a synthetic peptide gonadorelin analog agonist of LH-RH first synthesized by the then ICI in 1977 Structure 6.13 . It is licensed in the U.K. for the treatment of prostate cancer, estrogen-receptor-positive early breast cancer, and advanced breast cancer in premenopausal women. STRUCTURE 6.13 Structure of goserelin Zoladex . For breast or prostate cancer, a 3.6-mg acetate implant Zoladex is administered every 28 days into the anterior abdominal goserelin wall by...

Dhfr Inhibitors Antifolates 221 Methotrexate

Tetrahydrofolic acid is produced by the action of the enzyme dihydrofolate reductase DHFR on dihydrofolic acid and is required for the synthesis of thymine, which becomes incorporated into DNA Scheme 2.1 . In the late 1940s, slight modification of the structure of folic acid produced the lead antimetabolite aminopterin, which is now used as a rodenticide. Methotrexate, which was shown to be more selective, followed in the 1950s also see Scheme 2.1 . It binds more strongly to the active site of...

Gonadorelin Analogs LHRH Analogs Agonists and Antagonists

Luteinizing hormone-releasing factor LH-RF , also known as luteinizing hormone-releasing hormone LH-RF , gonadorelin, gonadotropin-rel easing factor, gonado-liberin, or luliberin, is a neurohumoral hormone of molecular weight 1182.29 kDa produced in the hypothalamus see Structure 6.11 . It stimulates production of the pituitary hormones, luteinizing hormone LH , and follicle-stimulating hormone FSH , which in turn produce changes that result in females, in the induction of ovulation. In males,...