Antimetabolites

Question 1

Inhibition of DNA polymerase

Answer 1

Cytarabine
Converted to Ara-CTP which is a competitive inhibitor of DNA polymerase
It can also be incorporated into DNA and inhibit further DNA synthesis

Very good for cancers found in the lining of the brain and spinal cord because in these regions there are lower levels of Cytidine deaminase which converts cytarabine to nontoxic form and with low levels the drug is in active form longer and more effective

Multiple resistance mechanisms
̈ Downregulation of activating enzymes
̈ Upregulation of cytidine deaminase
̈ Downregulation of transporter to move drug into cells

Question 2

interferes with pyrimidine nucleotide synthesis

Answer 2

5-FU - becomes active form FdUMP which mimics dUMP and binds in the active site of thymidylate synthase by binding FdUMP locks thymidylare synthase in a ternary complex thus cannot form DNA
also converted into F-UMP to F-UTP which is incorperated into RNA the fluorine interferes with RNA processing and function

Patients with polymorphisms that result in deficiency of DPD enzyme show increased toxicity to drug as this enzyme metabolizes the drug
Resistance: Downregulation of activating enzymes that convert 5-FU to fd-UMP, Upregulation of thymidylate synthase

Question 3

Blocks synthesis of purine nucleotides

Answer 3

6-Mercaptopurine
formed to active metabolite by HGPRT
Inactivated by TPMT polymorphism common in 10% of children and leads to increase risk of hematologic toxicity
Drug interaction with allopurinol
Resistance – loss of HGPRT, the activating enzyme

Question 4

DHFR inhibition

Answer 4

Methotrexate
inhibition of DHFR reduces the amount of active folate present
Major effects is inhibition of TMP which also inhibits purine and pyrimidine synthesis and, RNA and protien synthesis
Resistance: Amplification of DHFR gene or mutation of DHFR to resistant form of the enzyme, Decreased polyglutamation results in decreased intracellular MTX accumulation

Question 5

Drug rescue for 5-FU (decreases levels)

Answer 5

Thymidine

Question 6

Drug synergy for 5-FU (increases levels)

Answer 6

Leucovorate

Question 7

Drug rescue for Methotrexate

Answer 7

Leucovorin