Cancer chemotherapy and Anti-neoplastics 2 Flashcards
Folate anti-metabolite drugs
- Methotrexate
- Pemetrexed
Purine anti-metabolite drugs
- 6-mercaptopurine
- 6-thioguanine
- fludarabine
- cladribine
methotrexate- distinctions
- inhibits DHFR- blocks syn of thymidine, methionine, and serine
- MTX metabolite inhibits GAR and AICAR transformylase- blocks syn of purines
pemetrexed- distinctions
- inhibitor of thymidylate synthase and GAR transformylase
- less potent inhibition of DHFR compared to MTX
- can circumvent MTX resistance
methotrexate- used for?
- choriocarcinomas (monotherapy)!!!
- pediatric leukemias, primary CNS lymphoma, non-Hodgin lymphoma
Pemetrexed- used for?
-malignant pleural mesothelioma! (used with cisplatin)
high dose methotrexate- used for?
- CNS prophylaxis in pts with leukemia and lymphoma
- followed by 2-3 day “rescue” with leucovorin!!
intermediate dose methotrexate- used for?
-choriocarcinoma
low dose methotrexate- used for?
intrathecal for CNS prophylaxis
methotrexate- dose-limiting toxicity
- bone marrow suppression!
- high dose- risks renal crystalluria of MTX and renal failure
- high dose- requires leucovorin rescue!
pemetrexed- dose-limiting toxicity
- bone marrow suppression
- caution in pts with moderate renal insufficiency (co-treatment with NSAIDS!)
methotrexate- moa
- enters cells via RFC (energy dep transport)
- competitive inhibition of DHFR- main moa!!- causes accum of DHF
- accum in cells as MTX(glu)n- inhibits DHFR and AICAR and GAR transformylase
low dose methotrexate- clearance
-80% renal excretion
high dose methotrexate- clearance
- hepatic metabolism
- 7-hydroxy-MTX (inactive, less soluble)
- renal elimination- crystalluria tubular obstruction!!!!
Pemetrexed- moa
- competitive inhibition of TS and GAR transformylase- main moa!!!
- accum in cells as a polyglutamate- inhibits TS and GAR transformylase
- has a negligible effect of DHFR, compared to MTX’s effect!!!!
Pemetrexed- clinical significance
-survival benefit with cisplatin in malignant pleural mesothelioma!!!!
6-Mercaptopurine- distinctions, therapeutic uses, dose limiting toxicity
- inhibits purine ring biosyn and nucleotide interconversion- disrupts DNA and RNA integrity
- maintenance of remission in ALL (acute lymphocytic leukemia)!!
- myelosuppression!!; dose adjustment with allopurinol or febuxostat (xanthine oxidase inhibitor)
6-Thioguanine- distinctions, therapeutic uses, dose limiting toxicity
- inhibits purine ring biosyn and nucleotide interconversion- disrupts DNA and RNA integrity
- acute-NON-lymphocytic leukemia
- myelosuppression
Fludarabine- distinctions, therapeutic uses, dose limiting toxicity
- tumor cell kinases convert to nucleotide triphosphates- inserted into DNA, RNA, and disrupt DNA/RNA syn
- CLL (chronic lymphocytic leukemia!!
- myelosuppression
Cladribine- distinctions, therapeutic uses, dose limiting toxicity
- tumor cell kinases convert it to nucleotide analogs; inhibits DNA syn; inhibitor of ribonucleotide reductase
- hairy cell leukemia!!!
- myelosuppression
6-Mercaptopurine- hepatic inactivation
- hepatic inactivation via TPMT and XO (xanthine oxidase)
- TPMT–> Methyl-6-MP (inactive)
- XO–> 6-Thiouric acid (inactive)
6-Mercaptopurine- bioactivation
- HPRT-> TIMP
- -TPMT–> active
- -IMPDH–> active
clinical significance of HPRT bioactivation
-converts 6-MP to active metabolites- inhibits purine biosyn!!
Toxicological significance of hepatic metabolism
- low bioavailability- XO metabolizes 80% of 6-MP!
- excess exposure (drug interactions)- inhibition of xanthine oxidase by gout medications
6-Mercaptopurine- drug interactions
-inhibition of xanthine oxidase by gout medications!- allopurinol, febuxostat!!
Thioguanine- moa
-bypasses the XO inactivation step! (no drug interactions with XO inhibitors)
Fludarabine and Cladribine- moa
(chemical analogs of adenosine)- 2’ position of sugar
-inside tumor cells, kinase enzymes convert them to nucleotide tri-phosphates- these active metabolites inhibit DNA polymerase and can incorporate into DNA and RNA
Pyrimidine, Folate, Purine Antimetabolites- what part of cell cycle are the tumor cells vulnerable?
-S cycle!!
-S cycle!!
-G1 and G2- Gap phases- cell Grows and prepares to divide
-S- Synthesis phase (cell duplicates DNA)
-M- Mitotic phase (divides into 2 daughter cells)
-Go- resting state- cells not actively dividing
(G1, S, G2, M, Go)
