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Cancer chemotherapy
 

Cancer chemotherapy

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  • 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)

Cancer chemotherapy Cancer chemotherapy Presentation Transcript

  • CancerChemotherapy Jillian H. Davis Department of Pharmacology Howard University
  • Cell CycleCell Cycle Specific Agents Cell Cycle Non-Specific Agents• Antimetabolites • Alkylating Agents• Bleomycin • Antibiotics• Podophyllin Alkaloids •Cisplatin• Plant Alkaloids • Nitrosoureas
  • Resistance to Cytotoxic Drugs Increased expression of MDR-1 gene for a cell surface glycoprotein, P-glycoprotein MDR-1 gene is involved with drug efflux Drugs that reverse multidrug resistance include verapamil, quinidine, and cyclosporine MDR increases resistance to natural drug products including the anthracyclines, vinca alkaloids, and epipodophyllotoxins
  • Schematic of P-glycoprotein
  • Alkylating AgentsNitrogen Mustards Ethylenimines Alkyl Sulfonates NitrosoureasCyclophosphamide Thiotepa Busulfan Carmustine Legend Drug Class Sub-class Prototype Drug
  • Alkylating Agents Mechanism of Action Alkylate within DNA at the N7 position of guanine Resulting in miscoding through abnormal base-pairing with thymine or in depurination by excision of guanine residues, leading to strand breakage Cross-linking of DNA and ring cleavage may also occur
  • Alkylating Agents Mechanism of Action
  • Nitrogen Mustards Cyclophosphamide Ifosfamide Mechlorethamine Melphalan Chlorambucil
  • Cyclophosphamide Metabolism
  • Nitrosoureas Carmustine Lomustine Semustine Streptozocin-naturally occuring sugar containingM.O.A.- cross-link through alkylation of DNA All cross the blood brain barrier
  • Alkylating-Related Agents Procarbazine Dacarbazine Altretamine Cisplatin Carboplatin
  • Platinum CoordinationComplexes 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.
  • Alkylating Agents Toxicity Bone marrow depression, with leukopenia and thrombocytopenia Cyclophosphamide/Ifosfamide - hemorrhagic cystitis  Reduced by coadministration with MESNA Cisplatin/Carboplatin - ototoxic and nephrotoxic  Nephrotoxicity reduced by chloride diuresis and hydration
  • Alkylating Agents Therapeutic Uses Used to treat a wide variety of hematologic and solid tumors Thiotepa – ovarian cancer Busulfan – chronic myeloid leukemia Nitrosoureas - brain tumors Streptozocin – insulin-secreting islet cell carcinoma of the pancreas
  • AntimetabolitesFolic Acid Analogs Purine Analogs Pyrimidine Analogs Methotrexate Mercaptoguanine Fluorouracil Legend Drug Class Sub-class Prototype Drug
  • Folic Acid Analogs Methotrexate Trimetrexate Pemetrexed
  • Folate An essential dietary factor, from which THF cofactors are formed which provide single carbon groups for the synthesis of precursors of DNA and RNA To function as a cofactor folate must be reduced by DHFR to THF
  • Methotrexate Mechanism of Action The enzyme DHFR is the 1º site of action MTX prevents the formation of THF, causing an intracellular deficiency of folate coenzymes and accumulation of the toxic inhibitory substrate, DHF polyglutamate The one carbon transfer reactions for purine and thymidylate synthesis cease, interrupting DNA and RNA synthesis
  • Major Enzymatic Reactions Requiring Folates as Substrates* GAR transformylase AICAR transformylase AMP GAR AICAR IMP GMP (3) 10-formylTHF (2) Formate Methionine b + DHF THF e (1) c d dTMP 5,10-CH2THF 5-CH3THF a Homocysteine DNA dUMP a,thymidylate synthase; b, dihydrofolate reductase; c, methylenetetrahydrofolate reductase;*from Bowen d, methionine synthase; e, serine hydroxymethyl transferase
  • Resistance
  • Methotrexate Mechanism of Resistance1. Decreased drug transport2. Altered DHFR3. Decreased polyglutamate formation4. Increased levels of DHFR
  • Methotrexate Therapeutic Uses Methotrexate- psoriasis, rheumatoid arthritis, acute lymphoblastic leukemia, meningeal leukemia, choriocarcinoma, osteosarcoma, mycosis fungoides, Burkitt’s and non-Hodgkin’s lymphomas, cancers of the breast, head and neck, ovary, and bladder
  • Trimetrexate Therapeutic Uses Trimetrexate- Pneumocystis carinii pneumonia, metastatic colorectal carcinoma, head and neck carcinoma, pancreatic carcinoma, non-small cell carcinoma of the lung
  • Pemetrexed Therapeutic Uses Pemetrexed- Mesothelioma
  • Methotrexate Toxicity Bone marrow suppression  Rescue with leucovorin (folinic acid) Nephrotoxic  give sodium bicarbonate to alkalinize the urine
  • Purine Antagonists Mercaptopurine Thioguanine Fludarabine Phosphate Cladribine
  • Mercaptopurine/Thioguanine Must metabolized by HGPRT to the nucleotide form This form inhibits numerous enzymes of purine nucleotide interconversion
  • Fludarabine Phosphate M.O.A.- phosphorylated intracellularly by deoxycytidine kinase to the triphosphate form The metabolite inhibits DNA polymerase-α and ribonucleotide reductase Induces apoptosis Tx- non-Hodgkin’s lymphoma and chronic lymphocytic leukemia
  • Cladribine M.O.A. -phosphorylated by deoxycytidine kinase and is incorporated into DNA Causes DNA strand breaks Tx- hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkin’s lymphoma
  • Pyrimidine Antagonists Fluorouracil - S-phase Cytarabine Gemcitabine Capecitabine
  • MTX X 5-FU XFigure 2. This figure illustrates the effects of MTX and 5-FU on thebiochemical pathway for reduced folates.
  • Mechanism of Action 5-FU 5-FU inhibits thymidylate synthase therefore causing depletion of Thymidylate 5-FU is incorporated into DNA 5-FU inhibits RNA processing
  • Activation of 5-FU
  • Therapeutic Uses of 5-FU Metastatic carcinomas of the breast and the GI tract hepatoma carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas Combined with levamisole for Tx of colon cancer
  • Cytarabine It is activated to 5’ monophosphate (AraCMP) by deoxycytidine kinase Through a series of reactions it forms the diphosphate (AraCDP) and triphosphate (AraCTP) nucleotides Accumulation of AraCTP potently inhibits DNA synthesis Inhibition of DNA synthesis is due to competitive (-) of polymerases and interference of chain elongation
  • Cytarabine It is a potent inducer of tumor cell differentiation Fragmentation of DNA and evidence of apoptosis is noticed in treated cells AraC is cell-cycle specific agent, it kills cells in the S-phase
  • CytarabineMechanisms of Resistance deficiency of deoxycytidine kinase increased CTP synthase activity increased cytidine deaminase activity decreased affinity of DNA polymerase for AraCTP decrease ability of the cell to transport AraC
  • Cytarabine Therapeutic Uses Induction of remissions in acute leukemia Treats meningeal leukemia Treatment of acute nonlymphocytic leukemia In combination with anthracyclines or mitoxantrone it can treat non-Hodgkin’s lymphomas
  • Cytarabine Toxicities Nausea acute myelosuppression stomatitis alopecia
  • Gemcitabine Gemcitabine is S-phase specific it is a deoxycytidine antimetabolite it undergoes intracellular conversion to gemcitabine monophosphate via the enzyme deoxycytidine kinase it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine triphosphate
  • Gemcitabine Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA strands do to an addition of a base pair before DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repair Gemcitabine-induced cell death has characteristics of apoptosis
  • Gemcitabine Therapeutic Uses Gemcitabine treats a variety of solid tumors very effective in the treatment of pancreatic cancer small cell lung cancer carcinoma of the bladder, breast, kidney, ovary, and head and neck
  • CancerChemotherapy Jillian H. Davis Department of Pharmacology Howard University
  • Plant AlkaloidsVinca Alkaloids Podophyllotoxins Camptothecins Taxanes Vinblastine Etoposide Topotecan Paclitaxel
  • Vinca Alkaloids Vinblastine Vincristine Vinorelbine
  • Vinca AlkaloidsInhibit microtubules(spindle), causingmetaphase cell arrestin M phase. 3 3
  • Vinca Alkaloids Mechanism of Action Binds to the microtubular protein tubulin in a dimeric form The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly Depolymerization of the microtubules occurs Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation CCS agents- M phase
  • Vinblastine Toxicity Nausea Vomiting Marrow depression Alopecia
  • Vinblastine Therapeutic Uses Systemic Hodgkin’s disease Lymphomas
  • Vincristine Toxicity Muscle weakness Peripheral neuritis
  • Vincristine Therapeutic Uses With prednisone for remission of Acute Leukemia
  • Vinorelbine Toxicity Granulocytopenia Therapeutic Uses non-small cell lung cancer
  • Podophyllotoxins Etoposide (VP-16) Teniposide (VM-26) Semi-synthetic derivatives of podophyllotoxin extracted from the root of the mayapple
  • Podophyllotoxins Mechanism of Action Blocks cells in the late S-G2 phase of the cell cycle through inhibition of topoisomerase II Resulting in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme
  • Podophyllotoxins Toxicity Nausea Vomiting Alopecia Hematopoietic and lymphoid toxicity
  • Podophyllotoxins Therapeutic Uses Monocytic Leukemia Testicular cancer Oat cell carcinoma of the lung
  • Camptothecins Topotecan Irinotecan
  • Camptothecins Mechanism of Action Interfere with the activity of Topoisomerase I Resulting in DNA damage Irinotecan- a prodrug that is metabolized to an active Top I inhibitor, SN-38
  • Camptothecins Toxicity Topotecan  Neutropenia, thrombocytopenia, anemia Irinotecan  Severe diarrhea, myelosuppression
  • Camptothecins Therapeutic Uses Topotecan- metastatic ovarian cancer (cisplatin-resistant) Irinotecan- colon and rectal cancer
  • Taxanes Paclitaxel (Taxol) Docetaxel Alkaloid esters derived from the Western and European Yew
  • Taxanes Mechanism of Action Mitotic “spindle poison” through the enhancement of tubulin polymerization
  • Taxanes Toxicity Paclitaxel  Neutropenia, thrombocytopenia  Peripheral neuropathy Docetaxel  Bone marrow suppression  Neurotoxicity  Fluid retention
  • Taxanes Therapeutic Uses Paclitaxel- ovarian and advanced breast cancer Docetaxel- advanced breast cancer
  • Antibiotics Anthracyclines- Doxorubicin & Daunorubicin Dactinomycin Plicamycin Mitomycin Bleomycin
  • Anthracyclines Doxorubicin Daunorubicin
  • Anthracyclines Mechanism of Action High-affinity binding to DNA through intercalation, resulting in blockade of DNA and RNA synthesis DNA strand scission via effects on Top II Binding to membranes altering fluidity Generation of the semiquinone free radical and oxygen radicals
  • Anthracyclines Toxicity Bone marrow depression Total alopecia Cardiac toxicity
  • Anthracyclines Therapeutic Uses Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle, thyroid, and lung, Ewing’s sarcoma, and osteosarcoma Daunorubicin- acute leukemia
  • Dactinomycin Mechanism of Action Binds to double stranded DNA through intercalation between adjacent guanine- cytosine base pairs Inhibits all forms of DNA-dependent RNA synthesis
  • Dactinomycin Toxicity Bone marrow depression Oral ulcers Skin eruptions Immunosuppression
  • Dactinomycin Therapeutic Uses Wilms’ tumors Gestational choriocarinoma with MTX
  • Plicamycin Mechanism of Action Binds to DNA through an antibiotic-Mg2+ complex This interaction interrupts DNA-directed RNA synthesis
  • Plicamycin Toxicity Hypocalcemia Bleeding disorders Liver toxicity
  • Plicamycin Therapeutic Uses Testicular cancer Hypercalcemia
  • Mitomycin Mechanism of Action Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated reduction to generate an alkylating agent that cross- links DNA
  • Mitomycin Toxicity Severe myelosuppression Renal toxicity Interstitial pneumonitis
  • Mitomycin Therapeutic Uses Squamous cell carcinoma of the cervix Adenocarcinomas of the stomach, pancreas, and lung 2nd line in metastatic colon cancer
  • Bleomycin Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations CCS drug that causes accumulation of cells in G2
  • Bleomycin Toxicity Lethal anaphylactoid reactions Blistering Pulmonary fibrosis
  • Bleomycin Therapeutic Uses Testicular cancer Squamous cell carcinomas of the head and neck, cervix, skin, penis, and rectum Lymphomas Intracavitary therapy in ovarian and breast cancers
  • Hormonal AgentsEstrogen & Androgen Gonadotropin-Releasing Aromatase Inhibitors Inhibitors Hormone Agonists Tamoxifen Leuprolide Aminogluthethimide Legend Drug Class Sub-class Prototype Drug
  • Anti-Estrogens Tamoxifen (SERMs) Raloxifene (SERMs) Faslodex
  • Tamoxifen Selective estrogen receptor modulator (SERM), have both estrogenic and antiestrogenic effects on various tissues Binds to estrogen receptors (ER) and induces conformational changes in the receptor Has antiestrogenic effects on breast tissue. The ability to produce both estrogenic and antiestrogenic affects is most likely due to the interaction with other coactivators or corepressors in the tissue and the binding with different estrogen receptors, ERα and ERβ Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes is blocked or altered Resulting in decreased estrogen response. Most of tamoxifen’s affects occur in the G1 phase of the cell cycle
  • Tamoxifen Toxicity Hot flashes Fluid retention nausea
  • Tamoxifen Therapeutic Uses Tamoxifen can be used as primary therapy for metastatic breast cancer in both men and postmenopausal women Patients with estrogen-receptor (ER) positive tumors are more likely to respond to tamoxifen therapy, while the use of tamoxifen in women with ER negative tumors is still investigational When used prophylatically, tamoxifen has been shown to decrease the incidence of breast cancer in women who are at high risk for developing the disease
  • Anti-Androgen Flutamide  Antagonizes androgenic effects  approved for the treatment of prostate cancer
  • Gonadotropoin-Releasing HormoneAgonists Leuprolide Goserelin
  • Gonadotropoin-Releasing HormoneAgonist Mechanism of Action Agents act as GnRH agonist, with paradoxic effects on the pituitary Initially stimulating the release of FSH and LH, followed by inhibition of the release of these hormones Resulting in reduced testicular androgen synthesis
  • Gonadotropoin-Releasing HormoneAgonist Toxicity Gynecomastia Edema thromboembolism
  • Gonadotropoin-Releasing HormoneAgonist Therapeutic Uses Metastatic carcinoma of the prostate Hormone receptor-positive breast cancer
  • Aromatase Inhibitors Aminogluthethimide Anastrozole
  • Aminogluthethimide Mechanism of Action Inhibitor of adrenal steroid synthesis at the first step, conversion of cholesterol of pregnenolone Inhibits the extra-adrenal synthesis of estrone and estradiol Inhibits the enzyme aromatase that converts androstenedione to estrone
  • Aminogluthethimide Toxicity Dizziness Lethargy Visual blurring Rash Therapeutic Uses ER- and PR-positive metastatic breast cancer
  • Anastrozole A new selective nonsteroidal inhibitor of aromatase Treats advanced estrogen and progesterone receptor positive breast cancer that is no longer responsive to tamoxifen
  • Miscellaneous AntiCancer Agents Asparaginase Hydroxurea Mitoxantrone Mitotane Retinoic Acid Derivatives Amifostine
  • Asparaginase An enzyme isolated from bacteria Causes catabolic depletion of serum asparagine to aspartic acid and ammonia Resulting in reduced blood glutamine levels and inhibition of protein synthesis Neoplastic cells require external source of asparagine Treats childhood acute leukemia Can cause anaphylactic shock
  • Hydroxyurea An analog of urea Inhibits the enzyme ribonucleotide reductase Resulting in the depletion of deoxynucleoside triphosphate pools Thereby inhibiting DNA synthesis S-phase specific agent Treats melanoma and chronic myelogenous leukemia
  • Mitoxantrone Structure resembles the anthracyclines Binds to DNA to produce strand breakage Inhibits DNA and RNA synthesis Treats pediatric and adult acute myelogenous leukemia, non-Hodgkin’s lymphomas, and breast cancer Causes cardiac toxicity
  • Mechanisms & Actions of UsefulChemotherapeutic Drugs in NeoplasticDisease