Drugs that Prevent DNA Synthesis Flashcards
By mechanism, what are the two types of drugs that prevent DNA synthesis?
- nucleotide synthesis inhibitors
2. inhibitors of DNA synthesizing enzymes
What are the three sets of structural analogs that prevent DNA synthesis?
- folic acid analogues
- pyrimidine analogues
- purine analogues
For the folate analogues, how do some cancer cells have selective toxicity? Primary resistance?
those have overexpress the folate receptor will have selective toxicity
those that underexpress the reduced folate carrier will have primary resistance
What does methotrexate inhibit?
competitive inhibitor of DHFR
What are the toxic effects of the folate analogues?
- primarily toxic effects on bone marrow and GI epithelium
- pneumonitis
- hepatic fibrosis
- alopecia, dermatitis
- MTX is an abortifacaent
What drug is administered after high dose methotrexate as a “folate rescue”. Why does it work?
leucovorin - a reduced form of folinic acid
it works because the high dose MTX forces the cell to take it up via the folate receptor. then leucovorin enters the cell via the RFC, which is mutated in the cancer cells. So the normal cells get the folate they need, but cancer cells don’t
What adminstration route can you NOT use for leucovorin?
intrathecal - you’ll die
What are the two pyrimidine analogues we know?
5-fluorouracil
capecetabine
What’s the mechanism of action for the pyrimidine analogues? AKA, wat enzyme do they inhibit? h
they decrease biosynthesis of pyrimidine nucleotides by inhibitin thymidulate synthase, which is the rate limiting step in DNA synthesis - so you get a “thymineless death” of rapidly growing cells
How does resistance generally develop against the pyrimidine analogues?
increased expression of thymidylate synthase
decreased activiation of prodrugs by decreased pyrimidine monphosphate kinase activity
Although pyrimidine analogues can enter the pyrimidine synthesis pathway at 3 different places, which is the key entry point?
the conversion of UMP to UDP which is catalyzed by pyrimidine monophosphate kinase
Why must 5-FU be given IV?
Because it has limited oral bioavailability because gut mucos has high concentrations of diydropyrimidine dehydrogenase
Significant metabolic degradation ocurs for 5-FU. How is it eliminated?
80% hepatic
20% rena;
Inherited deficiency of what will lead to a greatly increased drug sensitivity?
dihydropyrimidine dehydrogenase - because it doesn’t get degraded
How is capecitabine related to 5-FU?
Capecitabine is converted to 5-FU thorugh a 3 step process
Why does capecitabine have higher selective toxicity than 5-FU?
Because the last step in the conversion of capecitabine to 5-FU is though thymidine phosphorylase, which is overexpressed in many tumours
5-FU and capecitabine tend not to be particularly effective when given alone, so what are they combined with?
methotrexate
Does 5-FU have a relatively high or low therapeutic index?
low - even for an antineoplastic
What are the primary toxic effects of 5-FU?Which one is specific to 5-FU?
Primary effects are on bone marrow (myelosuppression reaches mas at 9-14 days) and GI epithelium
Also alopecia, dermatitis and hand-foot syndrome
the specific one is acute cerebellar syndrome
What are the two purine analogs we learned?
6-mercaptopurine and 6-thioguanine
Where to 6-MP and 6-TG enter the salvage pathway? AKA…which enzyme activates them?
Where PRPP reacts with hypoxanthine or guanine bases to form IMP or GMP respectively - catalyzed by HGPRT
What enzyme is then inhibited by 6-MP and 6-TG?
guanylyl kinase (which converts GMP to GDP)
As the IMP and GMP buildup because of the block on guanylyl kinase, what three enzymes experience “pseudofeedback inhibition?”
the enzymes earlier on in the pathway: PRPP synthetase (PRPS), guanylyl amidotransferase (GPAT), and HGPRT
Azathioprine is converted to 6-mercaptopurine, but what is it used for primarily?
immunosuppression, no antineoplastic
What are the two metabolic pathways in the liver for 6-mercaptopurine?
- xanthine oxidase oxidizes it to an inactive form
2. methylatin and subsequent oxidation
Why is allopurinol often given during chemotherapy of hematologic cancers?
To prevent hyperuricemia due to tumor cell lysis
What is tumor lysis syndrome?
It’s caused by the sudden rapid deaht of millions of cells - leads to development of electrolyte and metabolic disturbances that can produce life-threatening complications like hyperuricemia
Specifically, what is prevented by the co-administration of allopurinol?
it prevents the nephrotoxicity and acute gout that would be produced by the excessive uric acid
Which purine analog can you give with allopurinol and which one do you have to be really careful with?
6-TG is gine, but you have to be careuful with 6-MT because it is metabolized by xanthine oxidase, which is inhibited by allopurinol
you have to reduce the 6-MP dose to 25% of normal
What are the 4 antimetabolites that inhibit DNA synthesizing enzymes? WHat’st he 5th that’s not an antimetabolite?
cladarabine, cytarabine, fludaraine, gemcitabine…hydroxyurea
