Antifolates

Question 1

Advantages of Cell Cycle Specific drugs

Answer 1

o No effect on G0 cells
o Don’t need extremely high doses as an S phase drug
o Complete inhibition of DNA/RNA synthesis
o No therapy-related secondary cancers

Question 2

Disadvantages of Cell Cycle Specific drugs

Answer 2

o Fewer target sites

o Little or no effect on slow growing/stem cells (aka G0)

Question 3

Antifolate Drugs

Answer 3

MTX

Pemetrexed

Question 4

Purine Analog Drugs

Answer 4

 6-mercaptopurine

 6-thioguanine

Question 5

Pyrimidien Analog Drugs

Answer 5

 5-FU

 Cytosine arabinoside

Question 6

MOA of Antimetabolites

Answer 6

o Compete with normal intermediates in DNA/RNA synthesis, are substituted for the normal intermediates and then interfere with nucleic acid synthesis

Question 7

Folic Acid Implimentation

Answer 7

o B vitamin (B9) that is a cofactor in DNA synthesis

o Used in the conversion of uracil to thymine (U → T)

Question 8

Folic Acid as a Drug Target

Answer 8

 Inhibit folic acid would cut off the formation of the cofactor and cut down on the nucleotide biosynthesis
 Methotrexate is a substrate for the dihydrofolate reductase (DHR) but you need a lot of this drug to make a difference

Question 9

Folic Acid to thiamine

Answer 9

 After it is taken into our body, it is converted into many different things
 N5-N10 is used in thiamine synthesis
• It is a cofactor added on to dUMP to make thiamine

Question 10

MTX Use

Answer 10

Most widely used anticancer drug

Leukemias

Question 11

MTX: MOA

Answer 11

binds to the DHFR inhibiting DNA synthesis and some RNA components through purine inhibition (specifically thiamine); interferes with synthesis of tetrahydrofolate (THF)
 Polyglutamates are formed by folylpolyglutamyl synthetase (works better)

Question 12

MTX Drug Interactions

Answer 12

 NSAIDs – nyelosuppresion, mucositis

 ASA, penicillins, sulfa – slow MTX elimination

Question 13

MTX SE

Answer 13

 Stomatitis, mucosititis
 Myelosuppression
 Nephrotoxicity
 Hepatotoxicity

Question 14

MTX Resistance

Answer 14

 Transport
 Gene amplification of DHFR
 Altered forms of DHFR
 Polyglutamate synthesis

Question 15

Leucovorin Rescue MOA

Answer 15

In cases where high dose methotrexate is needed, there are typically a lot of side effects associated with the high dose so after 24-36 hours of the high dose therapy, you start giving leucovorin to reduce harmful effects

Question 16

Leucovorin Rescue allows

Answer 16

 Use of high MTX doses
 Reduction of toxic effects
 Provides active folate cofactors

Question 17

Pemetrexed Use and MOA

Answer 17

o Use: Mesothelioma, non-small cell lung cancer
o MOA: Inhibits 3 enzymes used in purine and pyrimidine synthesis (thymidylate synthase, DHFR, glycinamide ribonucleotide formyltransferase- GARFT)