Cancer Chemotherapeutic Agents
P- glycoprote in is an ATde pe nde nt me mbrane (e fflux) transporte r that is re sponsible for what?
Pumping drugs out of cells (responsible for multidrug resistance of chemotherapeutic agents)
Give e xample s of cance r che mothe rape utic age nts that are commonly associate d with e ach of the following adve rse e ffe cts:
C ardiotoxicity; dilate d cardiomyopathy Doxorubicin
Pulmonary fibrosis; pne umonitis Bleomycin
Stomatitis; e sophagitis
Methotrexate; 5-fluorouracil; dactinomycin He morrhagic cystitis
Cyclophosphamide; ifosfamide He morrhagic diathe sis
Pe riphe ral ne uropathy; ne urotoxicity Plicamycin
Ne phrotoxicity Vincristine Alle rgic re actions Cisplatin
He patotoxicity Etoposide; L-asparaginase Pancre atitis
6-Mercaptopurine; busulfan; Cyclophosphamide C utane ous toxicity (hand-foot syndrome ) L-Asparaginase
5-Fluorouracil
Disulfiram-type re actions Procarbazine
W hat is the name of the antidote that binds to and inactivate s the toxic me tabolite s re sponsible for cisplatin-induce d ne phrotoxicity?
Amifostine
W hat is the name of the cyclophosphamide and ifosfamide urotoxic me tabolite that is re sponsible for causing he morrhagic cystitis?
Acrolein
W hat is the name of the antidote that binds to and inactivate s acrole in, the re by pre ve nting he morrhagic cystitis in patie nts re ce iving cyclophosphamide or ifosfamide che mothe rapy?
Mesna
W hich iron che lating age nt is use d to de cre ase the incide nce and se ve rity of doxorubicin-induce d cardiomyopathy in patie nts with me tastatic bre ast cance r who have re ce ive d a life time cumulative doxorubicin dose (300 mg/m2)?
Dexrazoxane
Give e xample s of antime tabolite cance r che mothe rape utic age nts:
Methotrexate; 5-fluorouracil; cytarabine; fludarabine; 6-thioguanine; 6-mercaptopurine Are the antime tabolite cance r che mothe rape utic age nts C C S?
Yes (S phase)
W hat is the me chanism of action of me thotre xate ? Inhibits dihydrofolate reductase (DHFR)
W hat re action doe s DHFR catalyz e ?
Conversion of folic acid to tetrahydrofolic acid (active form)
W hat drug is use d as a “re scue me dication” in patie nts taking me thotre xate ?
Leucovorin, which acts as an active form of folic acid (replenishing the folate pool) that has bypassed the inhibited DHFR and is more readily taken up by normal cells than by malignant cells
W hat are the adve rse e ffe cts of me thotre xate ?
Stomatitis; bone marrow suppression (BMS); urticaria; alopecia; nausea; vomiting; diarrhea; nephrotoxicity; hepatotoxicity; pulmonary toxicity; neurotoxicity W hat is the me chanism of action of 5-fluorouracil?
Pyrimidine analog that is converted to active 5-FdUMP which inhibits thymidylate synthetase, thereby decreasing the amount of cellular thymidine and subsequent DNA
W hat is the me chanism of action of cytarabine ? Pyrimidine antagonist
W hat is the me chanism of action of both 6-me rcaptopurine and 6-thioguanine ? Purine antagonists
W hat immunosuppre ssive drug be come s active only afte r be ing conve rte d to 6-me rcaptopurine ? Azathioprine
Be cause 6-me rcaptopurine is me taboliz e d by xanthine oxidase , its se rum le ve ls may be significantly incre ase d whe n give n concomitantly with what othe r me dication?
Allopurinol (xanthine oxidase inhibitor)
W hat e nz yme activate s 6-me rcaptopurine to its corre sponding nucle otide form by adding a ribose phosphate to its structure ? Hypoxanthine-guanine phosphoribosyl transferase (HGPRT )
W hat are the major adve rse e ffe cts of 6-me rcaptopurine ? Nausea; vomiting; diarrhea; hepatotoxicity; BMS
Give e xample s of antitumor antibiotics:
Doxorubicin; daunorubicin; dactinomycin; plicamycin; bleomycin; idarubicin Are the antitumor antibiotics C C S?
Yes (S-phase)
Name thre e anthracycline antitumor antibiotics:
1. Doxorubicin 2. Daunorubicin 3. Idarubicin
W hat is the me chanism of action of the anthracycline antibiotics?
Inhibition of DNA topoisomerase II; formation of free radicals (leading to DNA strand scission); DNA intercalation; inhibition of DNA and RNA synthesis Name thre e non-anthracycline antitumor antibiotics:
1. Dactinomycin 2. Bleomycin 3. Mitomycin
W hat is the me chanism of action of ble omycin?
Complexes with iron and reacts with oxygen which in turn leads to DNA strand scission W hich phase of the ce ll cycle is ble omycin spe cific for?
G2
Give e xample s of anticance r alkylating age nts:
Cyclophosphamide; ifosfamide; mechlorethamine; nitrosoureas (carmustine, lomustine, streptozotocin); cisplatin; carboplatin Are the anticance r alkylating che mothe rape utic age nts C C S?
No
W hat is the me chanism of action of anticance r alkylating age nts?
Covalently bind (alkylation) to DNA leading to cross-linked and dysfunctional DNA strands Give e xample s of anticance r mitotic inhibitors:
Paclitaxel; docetaxel; vincristine; vinblastine; vinorelbine Are the anticance r mitotic inhibitors C C S?
Yes (M phase)
W hat is the me chanism of action of vincristine and vinblastine ?
T hey are vinca alkaloids that inhibits the ability of tubulin to polymerize, thereby preventing formation of the microtubule structures needed during mitosis.
W hat adve rse e ffe cts do vincristine and vinblastine have in common?
Nausea; vomiting; diarrhea; alopecia; phlebitis; cellulites Are vincristine and vinblastine ve sicants?
Yes, they are strong vesicants.
W hich adve rse e ffe ct is unique to vincristine ? Peripheral neuropathy
W hich adve rse e ffe ct is unique to vinblastine ? BMS
W hat plant are the vinca alkaloids de rive d from?
Periwinkle plant
W hich plant is paclitaxe l a de rivative of?
Needles of the Western or Pacific yew tree W hat is the me chanism of action of paclitaxe l?
Binds to tubulin and increases polymerization and stabilization of the microtubule structure, thereby preventing depolymerization W hat are the adve rse e ffe cts of paclitaxe l?
Neutropenia; alopecia; hypersensitivity reactions
How are hype rse nsitivity re actions pre ve nte d in patie nts re ce iving paclitaxe l cance r che mothe rapy?
Pretreatment with diphenhydramine and dexamethasone
Give two e xample s of e pipodophyllotoxin cance r che mothe rape utic age nts:
1. Etoposide 2. T eniposide
W hat is the me chanism of action of the e pipodophyllotoxin cance r che mothe rape utic age nts?
Inhibition of DNA topoisomerase II
Give two e xample s of cance r che mothe rape utic age nts that inhibit DNA topoisome rase I:
1. T opotecan 2. Irinotecan
W hat is the me chanism of action of L-asparaginase ?
Hydrolyzes asparagine to aspartic acid and ammonia, thereby depriving tumor cells of asparagine required for protein synthesis
T his short chapter is meant as an overview of basic concepts of cancer chemotherapy. Clinical pharmacological therapies for specific cancer subtypes are discussed later in the text in relevant chapters.