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Anticancer Drugs

Anticancer Drugs. Felix Hernandez, M.D. Alkylating Agents. The first anticancer agents developed Chemically related to mustard gas used in WW1 Are more effective in treating slow-growing tumors because they are cell-cycle nonspecific

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Anticancer Drugs

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  1. Anticancer Drugs Felix Hernandez, M.D.

  2. Alkylating Agents • The first anticancer agents developed • Chemically related to mustard gas used in WW1 • Are more effective in treating slow-growing tumors because they are cell-cycle nonspecific • Alkylating agent induced damage to cancer cells accumulates even during non-active portions of the cell cycle. • All alkylating agents are toxic to hematologic cells, therefore myelosuppression is a predictable side effect • The drugs used to treat CNS cancers are used because they cross the BBB not because they are better agents

  3. Alkylating Agents • Chlorambucil • Phase: non specific • MOA: crosslinks DNA by binding to both strands • Resistance: decreased cellular uptake and increased repair of drug induced DNA damage • Side Effects: bone marrow suppression, drug is carcinogenic and may be teratogenic • Indications: Chronic Lymphocytic Leukemia (CLL), Ovarian Carcinoma • Cyclophosphamide • Phase: non specfic • MOA: metabolized to phosphoramide mustard which is a DNA alkylating agent • Resistance: same • Side Effects: hemorrhagic cystitis, BM suppression, cardiotoxicity • Administer Mensa to prevent hemorrhagic cystitis (binds to the toxic metabolite) • Indications: breast, testicular and other solid tumors, leukemia, lymphoma, neuroblastoma and immunosuppression

  4. Alkylating Agents • Carmustine • Phase: non specific • MOA: inhibit DNA synthesis by DNA alkylation and protein carbamoylation • Resistance: Same • Side Effects: bone marrow suppression, pulmonary toxicity • Indications: CNS tumors, lymphomas, Hodgkin’s, melanoma • Cisplastin • Phase: non specific • MOA: crosslinks DNA • Resistance: Same • Side Effects: renal toxicity, BM suppression, ototoxicity • Use Amifostine to bind the toxic metabolites and decrease the nephrotoxicity • Indications: testicular, ovarian, lung, bladder cancer, neuroblastoma, brain tumors, and osteosarcoma

  5. Antimetabolites • Are cell cycle specific agents • Prevent the synthesis of nucleotides or inhibit enzymes by mimicking nucleotides • Methotrexate • Mercaptopurine • 5-Fluorouracil (5-FU)

  6. Antimetabolites • Methotrexate • Phase: S-phase. It also arrests some cells in G1 phase and stop them from entering S-phase • MOA: blocks folate reduction by inhibiting dihydrofolatereductase. • Resistance: decreased uptake, increased production of dihydrofolatereductase, altered forms of DHFR • Side Effects: BM suppression, GI ulcers, nephrotoxicity, hepatotoxicity • Give leucovorin with it to rescue folate in noncancerous cells • Indications: Acute Lymphocytic Leukemia (ALL), osteogenic sarcoma, breast, head neck, small cell lung, psoriasis, and RA

  7. Antimetabolites • Mercaptopurine • Phase: S-phase • MOA: metabolized to 6-mercaptopurine ribose phosphate (6MPRP), a false negative feedback inhibitor • Resistance: increased alkaline phosphatase which degrades 6MPRP, decreased sensitivity to feedback inhibition • Side Effects: BM suppression, hepatotoxicity • Indications: Acute leukemia

  8. Antimetabolites • 5-Fluorouracil (5-FU) • Phase: S/G1 phase-specific • MOA: metabolized to fluoro-UMP which incorporates into RNA. Is also metabolized to fluoro-dUMP which inhibits thymidylatesynthetase • Prodrugs are Floxuridine and Capecitabine • Resistance: decreased phosphorylation of the prodrug to active form, increased or altered target enzyme • Side Effects: anorexia, ulcers, BM suppression, dermatitis, photo-sensitivity • Indications: Many solid tumors, topically for superficial tumors of the skin, Floxuridine for GI adenocarcinoma and Capecitabine for breast CA

  9. Antibiotic Cancer Agents • Are isolated from the fungal species Streptomyces • Dactinomycin • Phase: S-phase • MOA: intercalates between guanine bases of DNA. Also decreases RNA synthesis by blocking DNA-dependent RNA synthesis • Resistance: Decreased drug uptake • Side Effects: hypersensitivity, BM suppression, ulcers, acne, injection site necrosis • Indications: Wilm’s tumor, Ewing Sarcoma, testicular tumors

  10. Antibiotic Cancer Agents • Doxorubicin (Adriamycin), Daunorubicin (Daunomycin) • Phase: S-phase • MOA: Intercalates into DNA and decreases DNA and RNA synthesis, causes single and double strand breaks • Resistance: decreased drug uptake, increased drug efflux • Side Effects: irreversible cardiomyopathy which leads to CHF, ECG changes (benign), leukopenia • Give Dexrazone to reduce the cardiomyopathy • Indications: Doxorubicin  sarcomas, multiple myeloma, acute leukemias, testicular, breast, gastric, bladder, and throat CA. Daunorubicin  Acute leukemias

  11. Antibiotic Cancer Agents • Bleomycin • Phase: G2/M-Phase-Specific • MOA: Bithiazole rings intercalate into DNA strands. The drugs also oxidizes iron creating free radicals which damage DNA • Side Effects: pulmonary fibrosis, pneumonitis, ulceration, increased skin pigmentation • Indications: testicular cancer, lymphomas, SCC of the head, neck, skin and genitalia. • Is also used as a sclerosing agent for malignant pleural effusion

  12. Mitosis Inhibitors • Vincristine, Vinblastine • Phase: M-phase • MOA: binds tubulin and depolymerizes microtubules • Resistance: decreased drug uptake and retention • Side Effects: autonomic, peripheral and motor neuropathy, no BM Suppression • Indications: • Vincrsitine: ALL, Hodgkin’s • Vinblastine: Lymphomas • Isolated from the periwinkle plant

  13. Mitosis Inhibitors • Paclitaxel • Phase: M-phase specific • MOA: stabalizes microtubules and prevents the depolymerize microtubules which is essential for mitosis • Side Effects: peripheral neuropathy, BM suppression, myalgias • Indications: metastatic ovarian carcinoma, breast CA • Isolated from the bark of western yew • Etoposide • Phase: G2-phase-specific • MOA: interferes with topoisomerase which causes DNA strand breaks • Side Effects: BM suppression • Indications: testicular and lung cancers

  14. Others • Hydroxyurea • Phase: S-phase-specific • MOA: inhibits ribonucleotidereductasestherefor blocking deoxyribonucleotide formation (DNA nucleotides) • Side Effects: BM suppression • Indications: chronic granulocytic leukemia • Topotecan • Phase: Non specific • MOA: interacts with topoisomerase I and results in DNA breaks during replication • Side Effects: BM suppression, severe diarrhea • Indications: lung and ovarian CA

  15. Monoclonal Antibodies • Rituxamab • MOA: binds CD20 antigen on B-cells found in B-cell lymphomas and it exerts its cytotoxicity • Side Effects: chills, rigors (infusion related) • Indications: B-cell lymphomas • Trastuzumab • MOA: binds to HER2 protein and inhibits the growth of tumor cells • HER2 is overexpressed in 20-30% of breast CA • Side Effects: same as Rituxamab • Indications: Breast CA

  16. Hormones • Tamoxifen • MOA: Estrogen receptor antagonist that prevents endogenous estrogens from stimulating tumor growth • Indications: estrogen-receptor positive breast CA in postmenopausal women • Side Effects: increased risk of uterine CA in treated women • Aromatase Inhibitor • MOA: inhibits aromatase, the enzyme responsible for estrogen production in the ovaries • Indications: advanced breast CA • Flutamide • MOA: testosterone receptors antagonist • Indications: to inhibit the transient side effects caused by initial Leuprolide induced LH and FSH secretion

  17. Hormones • Leuprolide • MOA: GNRH analog which desensitizes GNRH receptors in the pituitary causing a decreased release of gonadotropin. Results in a decrease in sex hormone release • Indications: advanced prostate CA • Side Effects: initially stimulates a transient release of FSH and LH

  18. Immune Mediators • Interferon • MOA: enhances the activity of cytotoxic-T, NK cells, and macrophages. Inhibits the proliferation of tumor cells. • Indications: Hairy cell leukemia, Kaposi’s Sarcoma • Misc. • Tretinoin • MOA: analog of retinoic acid (vitamin A) and induces maturation in acute promyelocytic leukemia cells and neuroblastoma. • Side Effects: retinoic acid syndrome (fever, dyspnea, pulmonary infiltrates and effusions, fluid retention)

  19. Hematopoetic Agents • Epoetin Alpha (Epogen) • MOA: recombinant human erythropoetin that stimulates erythropoiesis • Indications: anemia associated with CRF, correcting AZT (Zidovudine) induced anemia, and chemotherapy induced anemia • Requires several weeks of therapy before a change in H/H is seen. It doesn’t replace transfusion for acute treatments • Contraindicated in patients with uncontrolled HTN because it can exacerbate the HTN with the rise in hematocrit

  20. Hematopoetic Agents • Filgrastim (G-CSF) • MOA: recombinant granulocyte colony stimulating factor which induces the synthesis of neutrophils • Indications: replenishment of neutrophils in patients treated with myelosuppressive drugs • Side Effects: medullary bone pain due to rapid cell proliferation in the BM • Sargramostim (GM-CSF) • MOA: recombinant granulocyte-macrophage colony stimulating factor. Induces the maturation granulocytes and macrophages but nor erythrocytes or megakaryocytes, • Indications: accelerate BM replenishment following BM transplantation • Side Effects: Medullary bone pain

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