Chemotherapy Agents 8/21

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What are the drug classes?

Back 1

Alkylators, Antibiotics, Antimetabolites, Mitotic inhibitors, hormones

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Alkylating agents

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Cell cycle non specific, covalently binds alkyl to DNA, single and double strand breaks
ex. Cyclophosphamide, Ifosfamide, more common with solid tumors (hemorrhagic cystitis is common in both) (also MESNA rescue is used, binds to metabolite acrolein, which causes the bladder irritation)

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Platinum compunds

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-Cisplatin (CDDP), tons of nausea, nephrotoxicity, ototoxicity, aggressive IV hydration with mannitol, Mg supplement, supportive treatment

-Carboplatin, common with brain tumors, some allergic rxns, less nephtox and ototox

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Other alkylating agents

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Busalfan and Temozolomide (brain tumors, sarcomas) are emerging chemtx agents

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Antitumor antibiotics

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Natural products of microbial metabolism, cell cycle non specific, mechanism is intercaltion b/w base pairs and inhibition of topoisomerase II, free radical generation and membrane disruption
-ex. anthracyclines, anthracenidiones, chromomycins

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Anthracyclines

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Doxirubicin (all the -rubicins) extremely broad antitumor spectrum, very cardiotoxic, can use dextrazoxane to bind free radicals formed

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Bleomycin

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another antitumor antibx, used for hodgins diseases, major toxoicity is pulmonary fibrososis

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Antimetabolites

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S phase specific, compete for key enzymes, incorporated into DNA

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Methotrexate (IMPORTANT)

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An antimetabolite, folate antagonist, rescue with leucovorin, used for many cancers in many forms, SE is mucositis may be severe, hepatoxicity, nephrotoxicity. Diagram of the membrane and mechanism.
-gene polymorphisms, MTHFR, homozygotes have 30% enzyme activity, increased sensitivity to methotrexate toxicity

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Purine analogues

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6-mercaptopurine and others

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Pyrimidine Analogues

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Cytarabine (Ara-C) causes flu like syndrome, inflammatory response, high fevers

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Mitotic inhibitors

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Freeze cells in anaphase
-Vinca alkaloids, disrupt microtubule assembly, Vincristine, non-myelosuppressive, broad anti-tumor
-Taxanes, stabilize microtubules (Paclitaxel, Docataxel)

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Topoisomerase inhibtors

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-Topoisomerase I specific, S-phase, Irinotecan = diarrhea
-Topoisomerase II, S-G2 specific, Etoposide/VP-16, can cause secondary leukemia 1-3 yrs later, also allergic rxns

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Hormone Therapy

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-for lymphoblastic leukemias, lymphomas, respond well to corticosteroids (prednisone, dexamthasone), mechanism is not well known, beneficial SE anti-emetic and appetite stimulant/anabolic
-for prostate cancer, androgen deprivaion therapy, surgical (orchioectomy) or medically GnRH agonist, antiandrogens, or even estrogen
-breast cancer, estrogen receptor positive tumors, tamoxifen, raloxifene, which are selective estrogen receptor modulators

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Targeted Therapies

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Tymor cells specific, can mark the tumor cell for attack, deliver specifically to tumor, interfere with critical singinalin via memebrae receptors, exploit differences b/w cancer and normal cells,

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Tyrosine kinase inhibitors

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Tyrosine kinase are critical in cell singlaing, they catalyze phosphoryltation od tyrosine rsidies on various molecules, there are over 90 tyrosine kinases identifies. Receptors are coupled forms with a ligand binindg site whoich results in rearragnements resulting in activyt, nuclear gene expression is affected (there are also cytosloic forms)
--ex Bcr-Abl, KIT, platelet derived growth factor receptor, epidermal growth factor EGFR, and VEGF

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Imatinib Mesylate (Gleevec): Model TKI

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A small molecule tyrosine kinase inhibtor, occupies nucleotide binding cleft of the Bcr-Abl protein tyrosine kinase, preventing ATP to substare, competitively inihibits phosphryltion of downstream molecules
--used for CML and ALL, philadelphia chromosome t(9;22), chimeric Bcr-Abl gene on chrom 22

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Epidermal growth factor receptor (EGFR) signaling interference

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Family of receptor tyrosine kinases, mostly expressed of epithelial and stromal tisues, singaling can be interfered with antibodies that block receptors
---Trastuzumab (herceptin) binds HER2 positive breast cancer

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Differentiation Agents

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-retinoids, vitamin a analogues, all-trans retinoic acid (ATRA) used in acute promylelytic leukemina (APML)
--arsenic used as well

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Immune therapy

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--stimulate immune cells to treat cancer, T and B lymphocytes, we know tumors are immunogenic but there usually is a lack of robust response and there seems to be a tolerance to the self proteins
--tumor vaccines?
--Interferons, immunomodulator, can be a cytostatic agent, or a cytotoxic agent,

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Tumor Vaccines

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???
-Whole cell vaccines, antigen therapy vaccines

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Anti-angiogenesis

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Mediated by VEGF, tumor angiogenesis is usually by upregulation of stimulators and carcinomas have body fluids have high VEGF

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Monoclonal antibodies

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-alter signaling transduction, block ligand receptor interaction, large size limits distibution and tumor penetration
---Rituximab (Rituxan) are anti-CD20, which regulates cell cycle regulation in B cell, used for non-hodgkins lymphoma (NHL)
---Bevacizumab (avastin) targets the VEGF directly, commonly used in metastatic colon cancer, brain tumors, toxicities can be bleeding or HTN

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Clinical correlation: avastin in nude mice

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-reduced neuroblastoma growth without toxicity, 40% reduction in angiogenesis

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Further targeted therapy

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-multikinase inhibtors etc....