Purine Antimetabolites Flashcards
What are the two Anti-Folate drugs?
Methotrexate and Pemetrexed
What is the MOA of methotrexate?
inhibits DHFR-> blocks synthesis f thymidine, methionine, and serine.
What is the MOA of Pemetrexed?
- multiple sites of action.
- potent inhibitor of thymidylate synthase and GAR transformylase
What are the uses of Methotrexate?
Pediatric leukemias, primary CNS lymphoma, NHL
*choriocarcinoma (monotherapy)
What are the uses of Pemetrexed?
Malignant pleural mesothelioma
What is the High dose MTX used for and what else is given with it?
- CNS prophylaxis in patients with leukemia and lymphoma
- Rescue with Leucovorin
What is the intermediate dose of MTX used for?
- choriocarcinoma
- patients usually do not require leucovorin rescue
What is low dose MTX given for?
- Intrathecal for CNS prophylaxis; i.v. for bladder and desmoid tumors
- Oral for ALL, APL
How does DHF and MTX enter the cell?
through the reduced folate carrier (RFC)
By inhibiting DHF my MTX, what enzyme is indirectly effected because of this?
Thymidylate Synthase
What does Leucovorin do when administered with MTX?
Helps rescue the patient from the bone marrow suppression that causes the thrombocytopenia and leukopenia
What are the toxicities associated with high dose MTX?
Renal toxicity
What are the advantages of Pemetrexed?
- Broader spectrum of action
- Circumvents MTX resistance
Difference between MTX and Pemetrexed?
Pemetrexed has a negligible effect on DHFR
What medication is given with Pemetrexed in the treatment of malignant pleural mesothelioma?
Cisplatin
What are the Purine antimetabolite drugs?
6-mercaptopurine
6-thioguanine
Fludarabine
Cladribine
What is the MOA of 6-mercaptopurine and 6-thioguanine?
Inhibits purine ring biosynthesis and nucleotide interconversion
What is the MOA of Fludarabine?
Tumor cell kinases convert the drug to nucleotide triphosphate which are inserted into DNA and RNA and halt synthesis
What is the MOA of Cladribine?
Tumor cell kinases convert the drug into nucleotide analogs which inhibit DNA synthesis and ribonucleotide reductase.
What is the therapeutic use of 6-mercaptopurine?
Maintenance of remission in ALL
What is the therapeutic use of 6-thioguanine?
Acute non-lymphocytic leukemia (with daunorubicin and cytarabine)
What is the therapeutic use of Fludarabine?
CLL,
What is the therapeutic use of Cladribine?
Hairy Cell leukemia
What are the toxicities of the Purine antimetabolites?
myelosuppression
What are the two enzymes that metabolize/inactivate 6-mercaptopurine?
Xanthine oxidase
TP methyltransferase
What is the activating enzyme for 6-mercaptopurine that converts it into TIMP?
HPRT-hypoxanthine ribosyltransferase
What is the enzyme that converts TIMP—> active metabolites?
IMPDH and TMPT
Activation of what enzyme leads to inhibition of de novo purine synthesis?
TMPT
What drugs can cause an interaction with 6-mercaptopurine?
Allopurinol and febuxostat
What is the difference in TMPTs activity with 6-mercaptopurine and 6-thioguanine?
TMPT in the tissue will activate 6-mercaptopruine
TMPT will inactivate 6-thioguanine
