chemo lecture 2 Flashcards
What are the folate anti metabolite drugs
- Methotrexate
- Pemetrexed
what are the purine anti metabolite drugs
- 6 mercaptopurine
- 6-Thioguanine
- Fludarabine
- Cladribine
What enzyme does methotrexate inhibit?
This blocks what?
DHFR: dihydrofolate reductase
-blocks synthesis of thymidine, methionine and serine
What does pemetrexed inhibit
thymidylate synthase and GAR transformylase
-1000x LESS potent inhibitor of DHFR compared to methotrexate
therapeutic uses of methotrexate
- pediatric leukemias
- Primary CNS lymphoma
- NHL
- choriocarcinoma (MONOTHERAPY)
Therapeutic use of pemetrexed
-malignant pleural mesothelioma
High dose of Methotrexate in treatment of leukemia and high risk lymphoma must be followed by what?
“rescue” with leucovorin
explain the metabolism and toxicity of High dose methotrexate
- hepatic rather than renal like lower doses
- converted to 7-Hydroxy-MTX
- causes Crystalluria tubular obstruction
GI toxicities of MTX
- mucositis
- small bowel ulcers and bleeding
- Diarrhea- discontinue to prevent perforation of gut
toxicities with intrathecal injection of MTX
neurotoxicity: stiff neck, seizures, encephalopathy, paraplegia
clinical significance of pemetrexed
survival benefit with cisplatin in malignant pleural mesothelioma
What is 6-Mercaptopurine used for
maintenance of remission in ALL
What is Fludarabine used for
CLL
what is Cladribine used for
Hairy Cell Leukemia
route of administration of fludarabine and why?
ONLY IV to avoid intestinal bacteria generating toxic fluoroadenine
explain metabolism of 6-MP IN LIVER
goes to the liver then
- TPMT to methyl-6-MP
- XO to 6-Thiouric acid
- both of the above are inactive metabolites
- the rest goes to other cells
explain metablism of 6-MP after the Liver in other cells
- HPRT to TIMP
- then TPMT takes TIMP to 6-methyl-TIMP ribonucleotides (Most clinically relevant pathway)
- IMPDH also takes TIMP to TXMP
- All of the above are active metabolites
explain role of TPMT in liver vs. other cells
responsible for activation in other cells but inactivation in Liver
explain toxicity of 6-MP due to gout meds
-gout meds inhibit xanthine oxidase so you get overexposure
What are the gout meds to watch out for when giving 6-MP
- Allopurinol
- Febuxostat
Explain the role of TPMT in 6-TG metabolism compared to 6-MP
TPMT inactivates 6-TG in liver and other cells whereas 6-MP gets activated by TPMT in other cells
Xanthine Oxidase and 6-TG
6-TG bypasses the XO inactivation so no drug interaction
What 2 drugs are chemical analogs of Adenosine that inhibit DNA polymerase
- Fludarabine
- Cladribine
What phase of the cell cycle do Folate and Purine antimetabolites inhibit
S phase
