Antimetabolites Flashcards
What are antimetabolites?
structural analogs of folic acid
or the purine/pyramidine bases in DNA
Are antimetabolites cell cycle specific or nonspecific?
specific - act on S phase
What are the two drugs that belong to the folate analogs category of antimetabolites?
- methotrexate
2. pemetrexed
What is the mechanism of action of methotexate?
inhibits DHFR
- this normally converts folate to THF
- needed for thymidine and purine synthesis
How is methotrexate administered?
orally or intrathecally
What is methotrexate used to treat?
- childhood ALL
- choriocarcinoma
- combo therapy for burkitts lymphoma
- carcinoma of breast, ovary, H&N, bladder
- meningeal luekemia
- meningeal metastases of tumors
-high dose for osteosarcoma
What are some important toxicities of methotrexate?
- renal toxicity - crystallization in urine at high doses
- hepatotoxicity - long term - fibrosis/cirrhosis
- defective oogenesis or spermatogenesis
- can cause abortion
-BM suppression and GI toxicity
What is the mechanism of action of pemetrexed?
Poly glutamate forms that inhibit THF dependent enzymes (like TS and DGFR)
What is pemetrexed used to treat?
- colon cancer
- mesothelioma
- nonsmall cell lung cancer
- pancreatic cancer
What are three drugs that are pyramidine analogs?
- 5FU
- Cytarabine
- Germcitabine
What is the mech of action of 5FU?
converted into active metabolites:
- 5FDUMP inhibits TS
- 5FdUTP incorporates into RNA - interferes with function
What is 5FU used to treat?
combo therapy for:
- breast
- colorectal
- gastric
- head and neck
- cervical and pancreatic cancer
- topically for basal cell carcinoma
What are some serious side effects of 5FU?
-hand and foot syndrome:
erythema and sensitivity of palms and soles
-cardiac toxicity
What is given to patients to counteract the side effects caused by 5FU?
leucovorin
-must be given IV (GI toxicity and rapid degradation)
What is the mechanism of action of cytarabine?
Ara-C - converted by deoxycitidine kinase –> AraCMP
-Ara CTP terminates DNA synthesis
What is cytarabine used to treat?
AML - MOST effective treatment
- ALL
- Blast phase CML
What is the mechanism of action of gemcitabine?
converted to active metabolites:
-dFdCDP inhibits ribonucleotide reductase
lowers deoxyribonucleotide
-dFdCTP incorporates into DNA - terminates DNA synthesis
What is germcitabine used to treat?
- pancreatic cancer
- non-small cell lung cancer
- ovarian
- bladder
- esophageal
- head and neck
Which is more effective against solid tumors: cytarabine or germcitabine?
Germcitabine
Which drug is a purine analog?
6-Mercaptopurine
What is the mechanism of action of 6-mercaptopurine?
prodrug metabolized by HGPRT to TIMP
- inhbits first step of de novo purine base synthesis and formation of AMP and xanthinylic acid from inosinic acid
- reduces purine levels
-TIMP is converted to thio-guanine ribonucleotides- inhibiting DNA and RNA synthesis
What is 6-mercaptopurine used to treat?
mantain remission in acute ALL
What is an important side effect of 6-mercaptopurine?
hepatotoxicity in prolonged use
What can 6-mercaptopurine interact with causing drug accumulation and toxicity?
allopurinol - used to treat gout
-decrease 6MP dose
