Anticancer Drugs Flashcards
most important efflux pump responsible for multidrug resistance
p-glycoprotein aka multidrug resistant protein 1 (MDR1)
cell cycle specific agents
B-AMEC
Bleomycin Antimetabolites Microtubule inhibitors Epipodophyllotoxins Camptothecins
what are the cell cycle non specific agents
Alkylating Agents
Platinum coordination complexes
Antitumor antibiotics (minus Bleomycin)
what are the antimetabolites
Folate analogues: Methotrexate
Purine analogues: 6-mercaptopurine and 6-thioguanine
Pyrimidine analogues: Fluoropyrimidines (5-fluorouracil and capecitabine) and Deoxycytidine analogues (cytarabine and gemcitabine)
what inhibits the renal excretion of methotrexate
CANP
Cephalosporin
Aspirin
NSAIDs
Penicillin
mechanism of action of methotrexate
catalyzed by folylpolyglutamate synthetase to MTX polyglutamate –> inhibits dihydrofolate reductase –> no THF –> needed for deoxythymidylate nucleotides and purine nucleotides
what drug is used in conjunction with MTX and why
Leucovorin, derivative of THF, to rescue normal cells from toxicity and overcome accidental drug overdose
adverse effects of MTX
a lot can be resolved with leucovorin
Myelosuppression
Pulmonary Fibrosis
mechanism of 6-mercaptopurine
converted to 6-MP ribose phosphate (or thio-inosinic acid or TIMP) by HGPRT –> inhibits phosphoribosyl pyrophosphate amidotransferase –> needed for de novo purine synthesis
what drugs/deficiency can make 6-mercaptopurine toxic
- it is metabolized by xanthine oxidase so if given with allopurinol which inhibits the enzyme then 6-MP will reach toxic level if dose not reduced
- also metabolized by TPMT (thiopurine methyltransferase) so if deficiency in allele, 6-MP can reach toxic levels if dose not reduced
mechanism of thioguanine
converted to nucleotide thioguanosine monophosphate (TGMP) by HGPRT
- inhibits PRPP amidotransferase which inhibits purine synthesis
- inhibits Guanylate kinase so can’t go from GMP to GDP
- can be converted to TGTP and dTGTP which can be incorporated into RNA and DNA respectively
what can make a normal dose of thioguanine toxic
TPMT (thiopurine methyltransferase) deficiency hence thioguanine dose must be reduced
it is inactivated by deamination (not oxidation) so xanthine oxidase (allopurinol) does not play a role here
when treating adult acute leukemia, what drug is thioguanine used synergistically with
Cytarabine
first line drug for colorectal cancer
5-fluorouracil
mechanism of 5-fluorouracil
converted to FdUMP which forms a tertiary complex with thymidylate synthase and reduced folate (N5, N10, and methylene THF) –> inhibition of DNA synthesis
what potentiates the activity of 5-fluorouracil
increasing level of the reduced folate - N5, N10, and methylene THF
what can cause a normal dose of 5-fluorouracil to become toxic
deficiency of dihydropyrimidine dehydrogenase (DPD), the enzyme that metabolized it
adverse effects of 5-fluorouracil
hand foot syndrome (also seen in capecitabine)
what catalyzes capecitabine
thymidine phosphorylase
the enzyme thymidine phosphorylase is high in what cancers (name drug metabolized by enzyme)
breast and colorectal cancer
capecitabine
mechanism of cytarabine
converted to cytosine arabinoside triphosphate
- inhibits DNA pol alpha (DNA synthesis)
- inhibits DNA pol beta (DNA repair)
- incorporated into chain –> termination
how is cytarabine inactivated
by deamination in the intestinal mucosa
mechanism of gemcitabine
- converted to gemcitabine diphosphate which inhibits ribonucleotide reductase –> reduces nucleotide needed for DNA synthesis
- converted to gemcitabine triphosphate which incorporates into chain and causes termination
how is gemcitabine eliminated
deaminated to difluorodeoxyuridine which is excreted in urine
adverse effect of gemcitabine
renal microangiopathy syndromes like HUS (hemolytic uremic syndrome) and TTP (thrombotic thrombocytopenic purpura)
what are the anticancer microtubule inhibitors and what does inhibiting microtubules do
Vinca Alkaloids: Vinblastine and Vincristine
Taxanes: Docetaxel and Paclitaxel
inhibits formation of mitotic spindles needed for cell division to daughter cells and also microtubules are needed for cellular functions such as movements, phagocytosis, and axonal transport
mechanism of vinca alkaloids (name them)
Vinblastine and Vincristine
they bind to beta-tubulin and stops it from polymerizing with alpha-tubulin to form microtubules
adverse of vincristine
Paralytic Ileus
Peripheral Neuropathy
Optic Atrophy
SIADH
mechanism of Taxanes (name them)
Docetaxel and Paclitaxel
they bind to beta-tubulin (different site from vinca alkaloids) –> promote microtubule polymerization and inhibit depolymerization –> arrest cells in mitosis –> apoptosis
condition requiring reduced dose of taxanes (name them)
Docetaxel and Paclitaxel
liver dysfunction
adverse effect seen in Paclitaxel and how it is avoided
hypersensitivity reactions
avoided with premedication with dexamethasone, diphenhydramine, and H2 blocker
what is Abraxane and its importance
albumin bound Paclitaxel formulation approved for metastatic cancer that is not associated with hypersensitivity reactions hence no need for premedication with dexamethasone, diphenhydramine, and H2 blocker
what are the Epipodophyllotoxins
Etoposide
Teniposide
mechanism of action of epipodophyllotoxins (name them)
Etoposide and Teniposide
inhibits topoisomerase II –> DNA damage through strand breakage
what are the Camptothecins
Irinotecan
Topotecan
mechanism of Camptothecins (name them)
Irinotecan and Topotecan
inhibits topoisomerase I –> needed for cutting religating single DNA strands
what is the more potent form of Irinotecan and how are they eliminated
SN-38 (converted in the liver)
both eliminated in bile and feces
adverse effects of Irinotecan
diarrhea with two forms
- 1st: within 24 hours and due to cholinergic activity so stop with atropine
- 2nd: within 2 to 10 days and can lead to electrolyte imbalance and dehydration
what are the antitumor antibiotics
BADD
Bleomycin
Anthracyclines: Daunorubicin and Doxorubicin
mechanism of bleomycin
binds to DNA –> free radical formation via Fe dependent process–> single and double strand breaks –> inhibition of DNA biosynthesis
adverse effect of bleomycin
pulmonary fibrosis
mechanism of anthracyclines (name them)
Daunorubicin and Doxorubicin
inhibits topoisomerase II
adverse effects of anthracyclines (name them)
Daunorubicin and Doxorubicin
Cardiotoxicity: 2 form
- acute: 2-3 days and is usually transient and asymptomatic
- chronic: due to increased free radicals within the myocardium and is treated/prevented with iron chelating agent dexrazoxane
