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Cancer Chemotherapy Agents and Mechanisms
- 5. Schematic of P-glycoprotein www.freelivedoctor.com
- 6. Legend Drug Class Sub-class Prototype Drug www.freelivedoctor.com Alkylating Agents Nitrogen Mustards Ethylenimines Nitrosoureas Alkyl Sulfonates Cyclophosphamide Thiotepa Busulfan Carmustine
- 8. Alkylating Agents Mechanism of Action www.freelivedoctor.com
- 13. Platinum Coordination Complexes These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity. To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic, or induce chloride diuresis with 0.1% NaCl. www.freelivedoctor.com
- 16. Legend Drug Class Sub-class Prototype Drug www.freelivedoctor.com Antimetabolites Folic Acid Analogs Purine Analogs Pyrimidine Analogs Methotrexate Mercaptoguanine Fluorouracil
- 20. Major Enzymatic Reactions Requiring Folates as Substrates* GAR GAR transformylase AICAR IMP AMP GMP AICAR transformylase 10-formylTHF Formate + THF (3) DHF b e 5,10-CH 2 THF 5-CH 3 THF c Methionine Homocysteine d (2) dUMP dTMP DNA a (1) a,thymidylate synthase; b, dihydrofolate reductase; c, methylenetetrahydrofolate reductase; d, methionine synthase; e, serine hydroxymethyl transferase *from Bowen www.freelivedoctor.com
- 34. Activation of 5-FU www.freelivedoctor.com
- 44. Cancer Chemotherapy Jillian H. Davis Department of Pharmacology Howard University www.freelivedoctor.com
- 45. www.freelivedoctor.com Plant Alkaloids Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes Vinblastine Etoposide Topotecan Paclitaxel
- 47. Vinca Alkaloids 3 3 Inhibit microtubules (spindle), causing metaphase cell arrest in M phase. www.freelivedoctor.com
- 83. Legend Drug Class Sub-class Prototype Drug www.freelivedoctor.com Hormonal Agents Estrogen & Androgen Inhibitors Gonadotropin-Releasing Hormone Agonists Aromatase Inhibitors Tamoxifen Leuprolide Aminogluthethimide
- 102. Mechanisms & Actions of Useful Chemotherapeutic Drugs in Neoplastic Disease www.freelivedoctor.com
Editor's Notes
- Factors for incidence of cancer sex, age, genetic predisposition, environmental carcinogens overexpression of oncogenes, deletion or alteration of tumor suppressor genes (p53) mutates from a tumor suppressor to an oncogene Cancer is a disease of the cells characterized by a shift in the control mechanisms that govern cell proliferation and differentiation Cells proliferate excessively Tumor stem cells (small subpopulation) undergo repeated cycle of proliferation and migrate, therefore causing metastatis Next to heart disease cancer is the major cause of death in the US About 50% can be cured with chemotherapy contributing
- CellCycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction CCNS drugs bind to DNA and damage it. Are useful in low growth fraction solid tumors as well as high growth fraction tumors CCS kill only cycling cells, whereas CCNS drugs kill cell that are cycling or in G0 (quiescent) Cycling cells are more sensitive
- CCNS
- Hemorrhagic cystitis resulting from toxic metabolite, acrolein , can be prevented with MESNA, mercaptoethane sulfonate, which provides electrons from sulfhydryl group. To prevent DNA repair by guanosine-O6-alkyl-a-transferase (GOAT), O6-benzyl guanine is given.
- Non-cross reactive with other alkylating agents All require biotransformation by nonenzymatic decomposition Highly lipophilic and cross the BBB therefore Tx Brain Tumors Streptozocin- Tx insulin secreting islet cell carcinoma of the pancreas
- Mechanism of Action involves alkylation Cisplatin-an inorganic metal complex, kills cells in all phases of the cell cycle thru cross-linking
- Necrosis at the injection site necessitates changing sites frequently. These agents are vesicants, and inhalation destroys (blisters) the mucus membranes and lungs.
- Methotrexate is a weak acid, so urine pH 5 causes precipitation in the renal interstitium with subsequent renal failure. Sodium bicarbonate is given to alkalinize the urine to facilitate excretion of the soluble salt. Alimpta (Permatrexate) is a new drug that is a multi-targeted antifolate (MTA). It acts on thymidylate synthase, DHFR, and purine generating enzymes GAR transformylase and AICAR transformylase. Leucovorin , a fully reduced folate co-enzyme, is converted to other active folate co-factors. Therefore, it can be used to terminate the toxic effects of methotrexate.
- 1. Deoxycytidine is the rate-limiting enzyme that produces AraCMP 2. Increase in CTP synthase causes increased levels of dCTP which block the actions of AraCTP on DNA synthesis 3. Cytidine deaminase is the degradative enzyme that deaminates AraC to a nontoxi metabolite, arauridine
- Gemcitabine is similar to cytarabine in its structure and metabolic pathway Gemcitabine crosses the cell membrane better than cytarabine It has a longer intracellular retention and a greater affinity for deoxycytidine kinase in comparison to cytarabine
- Natural products A wide variety of compounds possessing antitumor activity have been isolated from natural substances, such as plants, fungi, and bacteria. Likewise, selected compounds have semisynthetic and synthetic designs based on the active chemical structure of the parent compounds, and these, too, have cytotoxic effects.
- All derived from plant extracts
- Derived from the vinca rosea, the periwinkle plant Microtubules are an important part of the cytoskeleton and the mitotic spindle “ Spindle Poison”
- Neurotoxicity- Limits its use to short courses (nerve damage)
- They are semisynthetic derivatives of podophyllytoxin Podophyllotoxin (podofilox) and its derivatives, etoposide and teniposide, are all cytostatic (antimitotic) glucosides . Podofilox is an extract of the mayapple which generally acts as a cell poison which cells undergoing mitosis (division) are particularly vulnerable to. It isn't itself used as a chemotherapy agent; instead, it is used in creams such as Oclassen's Condylox as a treatment for genital warts. Genital warts, which are caused by the human papillomavirus (HPV), have been associated with cancers of the genitals (squamous cell carcinomas).
- Top II binds tightly to DNA double helix and make transient breaks in both strands The enzyme then causes a second stretch of the DNA double helix to pass thru the break, and finally reseals the break Etoposide and teniposide both block the cell cycle in two specific places: they block the phase between the last division and the start of DNA replication (the G1 phase) and they block the replication of DNA (the S phase). However, researchers don't have a very good understanding of how the compounds do this. The drugs are water in soluble and require a solubilizing vehicle for clinical formulation After IV administration they are protein bound and distributed throughout the except the brain excreted in the urine
- Etoposide (which is sold by Bristol-Myers Squibb as VePesid, aka VP-16) is administered intravenously or orally as liquid capsules. It is used mainly to treat testicular cancer which hasn't responded to other treatment and as first-line treatment for small-cell lung cancers. It is also used to treat chorionic carcinomas , Kaposi's sarcoma , lymphomas and malignant melanomas . Major side effects include hair loss, nausea, anorexia, diarrhea, and low leukocyte and platelet counts. Very rarely, some people have severe allergic reactions to the drug. It can also cause genetic damage and may increase a patient's risk of developing leukemia . Etoposide is known to cause fetal damage and birth defects, and so it should not be used by pregnant or nursing women. Teniposide is used less often than etoposide; mainly, it is used to treat lymphomas. It has similar side effects.
- TOP I reversibly cuts a single strand of the double helix They have both nuclease(strand-cutting) and ligase (strand-resealing) activities Create a nick in the strand and then reseal to relieve supercoils
- Irinotecan diarrhea,(causing hypovolemia) that occurs acutely appears to involve a different mechanism from the diarrhea that occurs later The hematopoietic effects of both drugs are dose limiting
- The taxanes are a group of drugs that includes paclitaxel ( Taxol ®) and docetaxel (Taxotere®) These agents are mainly used to treat breast cancer
- Taxanes have a unique way of preventing the growth of cancer cells : they affect cell structures called microtubules, which play an important role in cell functions. In normal cell growth, microtubules are formed when a cell starts dividing. Once the cell stops dividing, the microtubules are broken down or destroyed. Taxanes stop the microtubules from breaking down; cancer cells become so clogged with microtubules that they cannot grow and divide
- Side Effects of Paclitaxel For example, paclitaxel can cause hypersensitivity (allergic) reactions such as flushing of the face, skin rash, or shortness of breath. Patients often receive medication to prevent hypersensitivity reactions before they take paclitaxel. Paclitaxel can also cause temporary damage to the bone marrow. The bone marrow is the soft, sponge-like tissue in the center of large bones that produces blood cells, which fight infection , carry oxygen, and help prevent bleeding by causing blood clots to form. Bone marrow damage can cause a person to be more susceptible to infection, anemia (a condition in which the number of red blood cells is below normal), and bruise or bleed easily. Other side effects may include joint or muscle pain in the arms or legs; diarrhea; nausea and vomiting; numbness, burning, or tingling in the hands or feet; and loss of hair. Nevertheless, for many patients with cancer, the benefits outweigh the risks associated with this drug. Side Effects of Docetaxel The side effects of docetaxel are similar to those related to paclitaxel. Additionally, docetaxel can cause fluid retention , which is the accumulation of fluid in the body. This can result in shortness of breath, swelling of hands or feet, or unexplained weight gain . Before receiving docetaxel, patients are often given medication to prevent fluid retention.
- Paclitaxel In 1984, NCI began clinical trials (research studies with people) that looked at paclitaxel's safety and how well it worked to treat certain cancers. In 1989, NCI-supported researchers at The Johns Hopkins Oncology Center reported that tumors shrank or disappeared in 30 percent of patients who received paclitaxel for the treatment of advanced ovarian cancer. Although the responses to paclitaxel were not permanent (they lasted an average of 5 months, some up to 9 months), it was clear that advanced ovarian cancer patients could benefit from this treatment. In December 1992, the U.S. Food and Drug Administration (FDA) approved the use of paclitaxel for ovarian cancer that was resistant to treatment (refractory). Paclitaxel was later approved as initial treatment for ovarian cancer in combination with cisplatin . Women with epithelial ovarian cancer are now generally treated with surgery followed by a taxane and a platinum (another type of anticancer drug). The FDA has also approved paclitaxel for the treatment of breast cancer that recurred within 6 months after adjuvant chemotherapy (chemotherapy that is given after the primary treatment to enhance the effectiveness of the primary treatment), or that spread (metastasized) to nearby lymph nodes or other parts of the body. Paclitaxel is also used for other cancers, including AIDS–related Kaposi’s sarcoma and lung cancer. Docetaxel Docetaxel, a compound that is similar to paclitaxel, is also used to treat cancer. Docetaxel, like the semi-synthetic paclitaxel, comes from the needles of the yew tree. The FDA has approved docetaxel to treat advanced breast, lung, and ovarian cancer.
- Most of the antibiotics work by binding to DNA thru 1) intercalation btw base pairs and (-) of new RNA or DNA 2) cause DNA strand scission 3) and interference with cell replication All of the clinically useful anticancer antibiotics are products of various strains of the soil fungus Streptomyces
- The generation of free radicals lead to cardiac toxicity thru oxygen radical mediated damage to membranes
- Cardiac toxicity involves excessive intracellular production of free radicals with the myocardium, Tx with antioxidants like vitamin E
- 3 D’s intercalate between base pairs Ribosomal RNA formation being most sensitive to drug action DNA replication is less effected, while protein is blocked The degree of cytotoxic effect is determined by the cells ability to accumulate and retain the antibiotic Drug is mainly excreted in the bile
- Wilms’ tumor- a cancerous tumor of the kidney, in young children
- Is thought to be a CCNS alkylating agent Hypoxic tumor stems cell of solid tumors Hypoxic tumor stems cell of solid tumors Useful in hypoxic tumors
- Squamous cell- a flat scaly cell, painless bump due to over-exposure to the sun Adenocarcinomas-tumor of the glands
- A mixture of 11 different glycoproteins are used in therapy, the major components being A 2 and B 2
- Inflammation is the connective tissue in the lungs
- Because sex hormones are concerned with the stimulation and control of proliferation and function of certain tissues, like the mammary and prostate glands, cancers arising from these tissues my be inhibited or stimulated by appropriate changes in hormone balance The sex hormones are used in cancer of the female and male breast, prostate, and cancer of the endometrium of the uterus In prostate cancer, estrogens lead to suppression of androgen production All of these agents can produce fluid retention through their sodium-retaining effects Prolonged use of the androgens and estrogens will cause masculinization and feminization, respectively Extended use of adrenocortical steroids can cause HTN, diabetes, and cushingoid appearance
- These analogs are more potent than the natural hormone and fxn as GnRH agonist, with paradoxic effects on the pituitary
- Like the anthracyclines (doxorubicin & daunorubicin)