Antimetabolites

Question 1

What are antimetabolites?

Answer 1

structural analogs of folic acid

or the purine/pyramidine bases in DNA

Question 2

Are antimetabolites cell cycle specific or nonspecific?

Answer 2

specific - act on S phase

Question 3

What are the two drugs that belong to the folate analogs category of antimetabolites?

Answer 3

1. methotrexate

2. pemetrexed

Question 4

What is the mechanism of action of methotexate?

Answer 4

inhibits DHFR

• this normally converts folate to THF
• needed for thymidine and purine synthesis

Question 5

How is methotrexate administered?

Answer 5

orally or intrathecally

Question 6

What is methotrexate used to treat?

Answer 6

• 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

Question 7

What are some important toxicities of methotrexate?

Answer 7

• 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

Question 8

What is the mechanism of action of pemetrexed?

Answer 8

Poly glutamate forms that inhibit THF dependent enzymes (like TS and DGFR)

Question 9

What is pemetrexed used to treat?

Answer 9

• colon cancer
• mesothelioma
• nonsmall cell lung cancer
• pancreatic cancer

Question 10

What are three drugs that are pyramidine analogs?

Answer 10

1. 5FU
2. Cytarabine
3. Germcitabine

Question 11

What is the mech of action of 5FU?

Answer 11

converted into active metabolites:

• 5FDUMP inhibits TS
• 5FdUTP incorporates into RNA - interferes with function

Question 12

What is 5FU used to treat?

Answer 12

combo therapy for:

• breast
• colorectal
• gastric
• head and neck
• cervical and pancreatic cancer
• topically for basal cell carcinoma

Question 13

What are some serious side effects of 5FU?

Answer 13

-hand and foot syndrome:
erythema and sensitivity of palms and soles
-cardiac toxicity

Question 14

What is given to patients to counteract the side effects caused by 5FU?

Answer 14

leucovorin

-must be given IV (GI toxicity and rapid degradation)

Question 15

What is the mechanism of action of cytarabine?

Answer 15

Ara-C - converted by deoxycitidine kinase –> AraCMP

-Ara CTP terminates DNA synthesis

Question 16

What is cytarabine used to treat?

Answer 16

AML - MOST effective treatment

• ALL
• Blast phase CML

Question 17

What is the mechanism of action of gemcitabine?

Answer 17

converted to active metabolites:

-dFdCDP inhibits ribonucleotide reductase
lowers deoxyribonucleotide

-dFdCTP incorporates into DNA - terminates DNA synthesis

Question 18

What is germcitabine used to treat?

Answer 18

• pancreatic cancer
• non-small cell lung cancer
• ovarian
• bladder
• esophageal
• head and neck

Question 19

Which is more effective against solid tumors: cytarabine or germcitabine?

Answer 19

Germcitabine

Question 20

Which drug is a purine analog?

Answer 20

6-Mercaptopurine

Question 21

What is the mechanism of action of 6-mercaptopurine?

Answer 21

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

Question 22

What is 6-mercaptopurine used to treat?

Answer 22

mantain remission in acute ALL

Question 23

What is an important side effect of 6-mercaptopurine?

Answer 23

hepatotoxicity in prolonged use

Question 24

What can 6-mercaptopurine interact with causing drug accumulation and toxicity?

Answer 24

allopurinol - used to treat gout

-decrease 6MP dose