Lecture 16: Antineoplastic Agents

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1.

5-fluorouracil (Adrucil)

Class: Antimetabolite, anticancer, Pyrimidine analog (Thymine). Use: Solid, slow growing tumors, breast, colon, ovarian, pancreatic, and gastric carcinomas. used topically for premalignant skin lesions and for basal cell carcinoma. Mech: Converted to deoxyribonucleotide and ribonucleotide to inhibit DNA and RNA synthesis. principle Effect is to inhibit Thymidylate synthetase needed to make thymidylic acid. Side Effect: nerve and GI toxicity, bone marrow suppression.

4.

Cisplatin (Platinol)

Class: Anti neoplastic (cell cycle non specific) Use: Curative for testicular tumors, small cell lung, head and neck tumors, bladder and ovarian cancer. Mech: Forms heavy metal complex that has antitumor activity. it inhibits new DNA and RNA synthesis and forms DNA cross links. Toxicity: GI stress, neurotoxicity (peripheral neuritis), acoustic nerve damage.

5.

Cyclophosphamide (cytoxan)

Class: Alkylating immunosuppressant, anticancer agent. use: Cancer chemotherapy, nephrotic syndrome, intractable rheumatoid arthritis. Mech: Pro-drug, has to be activated by P450 (hepatic) to form phosphoramide mustard. Phosphoramide alkylates DNA leading to cytotoxicity to dividing cells. Absorption: Oral or IV Toxicity: Bone marrow depression, hemorrhagic cystitis, alopecia, amenorrhea, testicular atrophy, sterility, possible secondary malignancy years later.

2.

6Mercaptopurine (Purinethol)

Class: Antineoplastic, antimetabolite (cell cycle specific) Use: Maintenance of remission for all cancers. Mech: Converted in cell to a nucleotide, which acts as an inhibitor of purine synthesis. The conversion of inactive drug to active metabolite is called lethal synthesis. Prevents formation of adenylic and guanylic acid. Distribution: given orally, distributed widely in body. Penetrates blood brain barrier, filtered via the kidney. Toxicity: Bone Marrow depression.

3.

Bleomycin (Blenoxane)

Class: Antitumor antibiotic, Cell cycle specific G2 Use: Curative when used in combination for testicular cancer (vinblastine + cisplatin). Used for Hodgkin and NonHodgkin's lymphoma, head and neck tumors, squamous cell cancers. Mech: Binds DNA to copper or iron, which generates ROS, leading to DNA strand breaks, and inhibition of DNA synthesis. Side Effect: Pulmonary fibrosis, nerve and Skin toxicity, rarely causes myelosuppression.

6.

Cytarabine (Cytosar-U)

Class: Antimetabolite, anti-cancer, cell cycle specific, Cytosine Pyrimidine analog. Use: AML, CML (acute phase) Mech: Modified sugar moiety in ribonucleoside, rather than the pyrimidine base. it needs to be converted to 5' triphosphate of cytosine arabinoside (araCTP). Drug can be deaminated by extracellular kinases. Drug competitively inhibits DNA polymerase + , resulting in block of DNA synthesis. It also incorporates into RNA, blocking chain elongation and ligation of fragments of newly synthesized DNA. Side Effect: GI toxicity, nerve, bow marrow suppression.

9.

Etoposide (Vepesid)

Class: Natural product anticancer drug. Epipodophyllotoxins, cell cycle specific. Use: testicular and ovarian CA, lymphomas, Small cell lung CA, Acute myelogenous and lymphoblastic leukemia. Mech: Binds topoisomerase II-DNA complex. This leads to single strand breaks, increase succeptibility to irreversible double strand breaks. This inhibits DNA repair process. Side Effect: bone marrow suppression, nerve toxicity.

10.

Gemcitabine

Class: Antimetabolite, anticancer, pyrimidine analog. Fluorine substituted deoxycytidine analog. Use: Pancreatic Cancer, non small cell lung CA, bladder CA, and non-Hodgkin's Lymphoma. Mech: Converted to active Di and Triphosphate nucleotide, which inhibits ribonucleotide reductase, decrease pool of deoxyribonucleoside triphosphate required for DNA synthesis. Gemcitabine can be incorporated into DNA, where it causes chain termination. Side Effect: Bone marrow suppression, mostly neutropenia.

7.

Docetaxel

Class: Taxane, a natural product anticancer drug. Cell cycle specific (metaphase). Use: Solid cancers like breast, ovarian lung, prostate, bladder, gastroesophageal, head and neck. Mech: Binds to -tubulin and prevents the dissasembly of polymerized microtubules, which causes dysfunctional tubules during metaphase and leads to death of cell. Distribution/Elim: Give via IV. Side effect: Neurotoxicity and bone marrow depression. Irinotecan

11.

Class: Camptothecin analog, a natural product anticancer drug. S-phase specific Use: metastatic colorectal cancer Mech: inhibitor of topoisomerase I, damages DNA by inhibiting enzyme that cuts and religates DNA single strands during repair process. Distribution/Elim: Pro-drug that has to be converted in liver to active drug SN-38. irinotecan and its metabolites are eliminated in bile and feces. Toxicity: Myelosuppression and diarrhea.

8.

Doxorubicin (Adriamycin)

Class: Antitumor antibiotic, cell-cycle non specific, Anthracycline Use: One of the most useful cancer drugs. used for soft tissue tumors, osteogenic and other sarcomas. Small cell Lung CA, Hodgkin and Non-Hodgkin's lymphomas, acute leukemias and more. Mech: Binds tightly to DNA by intercalation, which leads to stabilization of topoisomerase II to DNA cleavage complex, thus leads to DNA breaks. Quinone structure reduced by P450 creating ROS, which leads to more DNA strand breaks. Side Effect: Myelosuppression, cardiotoxicity.

12.

Methotrexate

Class: Antimetabolite, anticancer drug, cell specific (S-phase) Use: Curative for choriocarcinoma and osteogenic sarcoma. Maintenance for other cancers, breast cancer. Mech: binds to dihydrofolate reductase, preventing folate from doing so. This reduces ability to synthesize thymidine and purines. T 1/2: Methotrexate has long half-life and stays bound to dihydrofolate reductase due to glutamate tails attached to it. N5 formyl tetrahydrofolate (citrovorum factor) (Leucovorin) can undergo one-carbon transfers and bypass the need of dihydrofolate reductase, used to spare bone marrow (reverse effects of methotrexate). Toxicity: Bone marrow Suppression

15.

Vinblastine (Velban)

Class: Vinca alkaloid, a natural product anti cancer drug. Blocks mitosis in Metaphase Use: Hodgkin's disease, neuroblastoma, testicular cancer with bleomycin and cisplatin. Mech: Binds tubulin, prevents polymerization, prevents microtubule formation, blocks mitosis in metaphase. Distribution/Metab: IV, Metab is hepatic, less than 5% appear in urine. Toxicity: Bone marrow suppression, alopecia, GI distress. Note: Differ from vincristine only in their methyl (vinblastine) or formyl (vincristine) side chains.

16.

Vincristine (oncovin)

Class: Vinca alkaloid, a natural product anticancer drug. Cell cycle specific (metaphase) Use: Acute leukemia, Wilms' tumor, Hodgkin's lymphoma, and other lymphomas, Ewing's soft tissue sarcomas. Mech: Binds tubulin heterodimer, inhibiting microtubule polymerization and the formation of a normal mitotic apparatus. Blocks mitosis in metaphase. Distribution/ Metab: IV, metabolized mostly hepatic, less than 5% appears in urine. Toxicity: Neurologic, bone marrow suppression.

13.

Paclitaxel (Taxol)

Class: Taxane, a natural product anticancer drug. Cell cycle specific (metaphase) Use: Solid tumors like breast, ovarian, lung, gastroesophageal, prostate, bladder, head and neck cancers. Mech: Binds to -tubulin, prevents dissembly of polymerized microtubules by stabilizing it. This leads to dysfunctional tubules, cell locked in metaphase and death. Distribution: Given Via IV Side Effect: Neutropenia, peripheral neuropathy, hypersensitivity reactions during infusion. Occasional vomiting and diarrhea.

14.

Topotecan

Class: Camptothecin analog, a natural product anticancer drug. S phase specific. Use: 2nd line therapy for advance ovarian CA and small cell lung CA. Mech: Inhibiting topoisomerase I, it damages DNA by inhibiting the enzyme that cuts and re-ligates single DNA strands during normal repair processes. They are S-phase specific drugs. Distribution/Elim: Eliminated via Kidney. Side Effect: Bone Marrow suppression, diarrhea.