Antineoplastic: Natural Products

Question 1

Vincristine

Answer 1

• mechanism: microtubule inhibitor (blocks ability of tubulin to polymerize; blocks mitosis in metaphase)
• kinetics: IV injection can cause hyperuricemia; modify dose with impaired hepatic function or biliary obstruction
• clinical: acute lymphoblastic leukemia, Wilms tumor, Ewing sarcoma, and Hodgkin and non Hodgkin lymphomas; also has mild bone suppressing ability
• toxicity/interactions: nausea, vomiting diarrhea, and alopecia; peripheral neuropathy; constipation (can cause inappropriate ADH secretion; anticonvulsants (phenytoin, phenobarbital, and carbamazepine) can accelerate its metabolism and azole antifungal drugs can slow its metabolism
• misc: trade name is ONCOVIN; is the “o” in the POMP regimen for leukemia and the MOPP regimen for Hodgkin lymphoma

Question 2

Vinblastine

Answer 2

• mechanism: microtubule inhibitor (blocks ability of tubulin to polymerize; blocks mitosis in metaphase)
• kinetics: IV injection can cause hyperuricemia; modify dose with impaired hepatic function or biliary obstruction
• clinical: systemic Hodgkin and non Hodgkin lymphomas, advanced non small cell lung cancer, administered with bleomycin and cisplatin for metastatic testicular carcinoma
• toxicity/interactions: nausea, vomiting, diarrhea, and alopecia; more potent myelosuppresant than vincristine; granulocytopenia is dose limiting

Question 3

Actinomycin D

Answer 3

• mechanism: antibiotic (interferes with DNA dependent RNA polymerase, hinders DNA synthesis at higher doses, and causes single strand breaks)
• kinetics: IV, doesn’t enter CSF
• clinical: used with surgery and vincristine for Wilms tumor, used with methotrexate for gestational choriocarcinoma, soft tissue sarcomas can also respond
• toxicity/interactions: bone marrow depression (dose limiting toxicity); nausea, vomiting, diarrhea, stomatitis, and alopecia; sensitizes to radiation and inflammation at prior sites of radiation therapy may occur

Question 4

Daunorubicin

Answer 4

• mechanism: anthracycline antibiotic (several mechanisms, including membrane lipid perxoidation, DNA strand scission, and direct oxidation of purine and pyrimidine bases by free radicals)
• kinetics: IV (inactivated in GI tract), doesn’t penetrate blood brain barrier or testes, dose needs to be modified with impaired hepatic function
• clinical: acute leukemias
• toxicity/interactions: irreversible, dose dependent cardiotoxicity; transient bone marrow suppression, stomatitis, GI tract disturbances, increased skin pigmentation, alopecia
• misc: occurrence of multi drug resistance is common

Question 5

Doxorubicin

Answer 5

• mechanism: anthracycline antibiotic (several mechanisms, including membrane lipid perxoidation, DNA strand scission, and direct oxidation of purine and pyrimidine bases by free radicals)
• kinetics: IV (inactivated in GI tract), doesn’t penetrate blood brain barrier or testes, dose needs to be modified with impaired hepatic function
• clinical: variety of sarcomas and carcinomas (including breast and lung), acute lymphocytic leukemia and lymphomas
• toxicity/interactions: irreversible, dose dependent cardiotoxicity; transient bone marrow suppression, stomatitis, GI tract disturbances, increased skin pigmentation, alopecia; treatment with trastuzumab increases congestive heart failure
• misc: occurrence of multi drug resistance is common

Question 6

Bleomycin

Answer 6

• mechanism: antibiotic (causes strand breakage in DNA and chromosomal aberrations by an oxidative process)
• kinetics: subcutaneous, IV, intramuscular, and intracavitary; need dose adjustment with renal failure
• clinical: testicular cancers (administered with vinblastine or etoposide, higher response rate with cisplatin as well); effective but not curative for squamous cell carcinomas and lyphomas
• toxicity/interactions: pulmonary toxicity (rales, cough, and infiltrate to potentially fatal fibrosis), mucocutaneous reactions and alopecia, hypertrophic skin changes and hyperpigmentation of the hands are prevalent, high incidence of fever and chills and low incidence of serious anaphylactoid reactions; myelosuppresion is rare)

Question 7

Paclitaxel

Answer 7

• mechanism: microtubule inhibitor (produce overly stable microtubules that are nonfunctional)
• kinetics: has a large volume of distribution; doesn’t enter the CNS; dose modification is not required for renal impairment but doses should be reduced for hepatic dysfunction
• clinical: advanced ovarian cancer, metastatic breast cancer, administered with cisplatin for non small cell lung cancer
• toxicity/interactions: neutropenia (dose limiting toxicity), peripheral neuropathy, transient bradycardia, alopecia
• misc: premedicated with dexamethasone and diphenhydramine as well as an H2 blocker due to serious hypersensitivity reactions

Question 8

Etoposide

Answer 8

• mechanism: topoisomerase II inhibitor, leads to irreversible double strand breaks in DNA
• kinetics: IV and oral; enter CSF poorly
• clinical: oat cell carcinoma of the lung; administered with bleomycin and cisplatin for testicular carcinoma
• toxicity/interactions: myelosuppresion (dose limiting, primarily leukopenia), leukemia; alopecia, anaphylactic reactions, nausea, and vomiting

Question 9

Camptothecins (topotecan and irinotecan)

Answer 9

• mechanism: inhibits topoisomerase I (prevents religation of single strand breaks)
• kinetics: IV; dose needs to be modified for impaired kidney function
• clinical: topotecan (metastatic ovarian cancer and small cell lung cancer); irinotecan (used with leucovorin and 5-fluorouracil for colon or rectal carcinoma)
• toxicity/interactions: thrombocytopenia and anemia, diarrhea, nausea, vomiting, alopecia, and headache; topotecan (bone marrow suppression esp neutropenia is dose limiting); irinotecan (myelosuppression)