Anti-cancer: antimetabolites

Question 1

All the antimetabolites are cell cycle…

Answer 1

specific (CCS)

Question 2

Main MoA - methotrexate

Answer 2

it binds to the active catalytic site of DHFR, inhibiting it and interfering with the synthesis of THF (methotrexate is a folic acid antagonist)

Question 3

Why might there be a prolonged retention of methotrexate in tissues?

Answer 3

it is converted to a series of polyglutamates by the enzyme folylpolyglutamate synthetase in normal and cancer cells

Question 4

Why isn’t polyglutamation a mechanism of resistance?

Answer 4

it actually increases its inhibitory effects dramatically - specifically for the enzymes thymidylate synthase (purine biosynthetic pathway)

Question 5

What are the mechanisms of resistance for methotrexate?

Answer 5

decreased drug transport into the cell, decreased ability to synthesize methotrexate polyglutamates, increased synthesis of DHFR (via altered gene regulation), synthesis of altered DHFR that resists the drug, and active efflux via activation of an MDR-p170 glycoprotein transporter

Question 6

What are the toxicities of methotrexate?

Answer 6

bone marrow depression, leucopenia, thrombocytopenia

Question 7

What are the antidotes for methotrexate?

Answer 7

leucovorin and levoleucovorin

Question 8

How does leucovorin work?

Answer 8

in normal cells only, rescues the biosynthesis of purines and DNA. Does not affect methotrexate in tumor cells

Question 9

What drug could be used to decrease plasma levels of methotrexate?

Answer 9

glucocarpidase

Question 10

What is glucocarpidase?

Answer 10

a recombinant bacterial carboxypeptidase enzyme - it metabolizes methotrexate to inactive metabolites to decrease plasma levels of the drug. This provides a non-renal pathway for elimination, but DOES NOT work intracellularly

Question 11

Glucocarpidase MoA

Answer 11

hydrolyzes the carboxy-terminal glutamate residue from folic acid and its analogs

Question 12

What is important about the two antidotes for methotrexate?

Answer 12

they should be administered two hours apart because glucocarpidase can affect the efficacy of leucovorin

Question 13

What is the other name for mercaptopurine?

Answer 13

6-MP

Question 14

What form must 6-MP be activated to in order to exert its effects?

Answer 14

6-thiosinic acid - this is done by HGPRT

Question 15

What is the main MoA of 6-MP?

Answer 15

it inhibits DNA synthesis by inhibiting enzymes involved in purine nucleotide interconversions

Question 16

6-MP mechanisms of resistance

Answer 16

increased levels of alkaline phosphatase (inhibits the drug), decrease in HGPRT activity

Question 17

toxicities of 6-MP

Answer 17

bone marrow SUPPRESSION, hepatotoxicity

Question 18

Which enzyme converts 6-MP to its inactive form?

Answer 18

xanthine oxidase

Question 19

Which drug can be administered with 6-MP to enhance its activity?

Answer 19

allopurinol - this drug inhibits xanthine oxidase and prevents hyperuricemia (also used for gout)

Question 20

What is the mechanism of resistance for fluorouracil?

Answer 20

none

Question 21

What is the toxicity for fluorouracil?

Answer 21

bone marrow SUPRESSION (myelosuppression), neurotoxicity

Question 22

How does levoleucovorin enhance the effect of 5-FU?

Answer 22

stabilizes the binding of FdUMP to thymidylate synthase - enhances its inhibition

Question 23

5-FU MoA

Answer 23

inhibit thymidylate synthase - this inhibits the synthesis of thymidylate and therefore inhibits DNA synthesis

Question 24

How is 5-FU converted to fDUMP?

Answer 24

it is bioactivated to ribosyl and deoxyribosyl nucleotide metabolites, then is converted to FdUMP. It is also converted to FUTP which interferes with RNA processing