Cancer chemotherapy and Anti-neoplastics 1 Flashcards
pyrimidine anti-metabolite drugs
- 5 Fluorouracil
- Capecitabine
- Cytarabine
- Gemcitabine
pyrimidine antimetabolites- moa
-inhibit dTMP synthesis and DNA synthesis
5-Fluorouracil- distinction, therapeutic uses, dose-limiting toxicity
- active metabolites- FdUMP inhibits thymidylate synthase
- solid tumors!!- colorectal and other GI, breast, ovarian carcinomas; topical for basal cell carcinoma!!!
- GI intolerance, mucositis, myelosuppression
Capecitabine- distinction, therapeutic uses, dose-limiting toxicity
- oral pro-drug of 5-Fluorouracil
- colorectal cancer!, breast cancer
- similar to 5GU toxicity, plus hand-foot syndrome!
Gemcitabine- distinction, therapeutic uses, dose-limiting toxicity
- kinases convert it to nucleotide analongs- inhibits DNA syn
- pancreatic cancer!
- myelosuppression
Cytarabine- distinction, therapeutic uses, dose-limiting toxicity
- kinases convert it to AraCTP- inhibits DNA synthesis
- acute myelogenous leukemia!
- myelosuppression
5-fluorouracil- clinical significance
- colorectal cancer!
- other solid tumors!
5-fluorouracil- activated via?
(analog of the pyrimidines, uracil and thymidine)
- enzyme activation inside tumor cells!!- convert 5FU to fdUMP, FdUTP, FUTP
- thymidine phosphorylase- 5FU–> 5FUdR
- thymidine kinase- 5FUdR–> 5FdUMP
5-fluorouracil- moa
-activated inside tumor cells! the metabolite FdUMP: -inhibits thymidylate synthase- blocks conversion of dUMP into dTMP -depletes dTMP -distorts dNTP pools -causes thymineless death!
5-fluorouracil- contributing mechanisms
- FdUTP (metabolite)- incorporates into and causes DNA damage
- FUTP (metabolite)- incorporates into RNA, causes RNA damage
5-fluorouracil- mechanism of resistance?
- alterations in thymidylate synthase
- tumors with higher levels of TS are more resistant- due to TS gene amplification
5-fluorouracil- efficacy and toxicity- depends on?
-rates of activation in tumor cells vs inactivation by liver!
5-fluorouracil- clearance?
inactivation by liver!!
- hepatic Dihydropyrimidine dehydrogenase (DPD)- converts F5U to DHFU (inactive metabolite)
- liver eliminates up to 80% of 5FU
5-fluorouracil- pharmacogenomics- allelic variation?
- DPD gene (DPYD mutation)- slows 5FU clearance and aggravate its systemic toxicity
- DPD deficiency- recessive trait
- causes neuro sxs!!
Capecitabine- moa
(orally bioavailable)
Activation in liver:
-carboxyesterase 1A1/2- convert it to 5-DFCR
-cytidine deaminase- convert to 5-DFUR
Tumors overexpress:
-thymidine phosphorylase- converts 5-DFUR to 5FU
Capecitabine- clinical significance
- used for colon cancer! (orally)
- also breast cancer!- slows cancer progression
Capecitabine- toxicities
- diarrhea
- hand and foot syndrome!!- dose-limiting toxicity
- myelosuppression
Cytarabine and Gemcitabine- are what?
chemical analogs of cytidine
-both pro-drugs
Cytarabine (Ara-C)- moa
- enters tumor cells via hENT1 (equilibrative nucleoside transporter 1)
- Ara-C is phosphorylated by DCK (deoxycytidine kinase)–> Ara-CMP
- CMPK (deoxycytidylate kinase)–> Ara-CDP
- NDKs (nucleoside diphosphate kinases)–> Ara-CTP
- Ara-CTP (active) competes with CTP (cytidine triphosphate) in DNA polymerase
what happens to ARA-CTP in a tumor cell AML)?
- Ara-CTP blends with cellular nucleotides
- AML tumor cells perceive Ara-CTP as CTP
- Ara-CTP binds to DNA polymerase and inhibits DNA syn!!!
- Ara-CTP is incorporated into DNA and terminates further DNA strand elongation!! (cannot form a 3-5 phosphodiester bond)
Cytarabine- AML response depends on?
- rate of activation by DCK vs its rate of inact by PN (pyrimidine nucleotidase) and CDA (cytidine deaminase)!!!
- liver and spleen contain high levels of CDA!!- sanctuary for leukemic cells
cytarabine vs gemcitabine
comparable!!
Cytarabine- distinctions
-treat Acute myelogenous leukemia
Gemcitabine- distinctions
- inhibits ribonucleotide reductase
- treats pancreatic cancer!!
