Fitz- Drugs that prevent DNA synthesis

Question 1

What are the anti-metabolite cancer drugs?

Answer 1

5 FU
6 Mercaptopurine
6 Thiguanine
Allopurinol
cladarabine
cytarabine
fludarabine
gemcitabine
leucovorin
methotrexate

Question 2

Where does methotrexate act?

Answer 2

Methotrexate inhibits DHFR and prevents nucleotide synthesis

Question 3

Where does 5FU act?

Answer 3

5 FU affects pyrimidine synthesis by inhibiting thymidylate synthase
ultimately leading to decreased dTMP and decreased DNA synthesis

Question 4

What drugs affect purine synthesis? How?

Answer 4

6-MP
6-TG

These drugs enter via the salvage pathway and must be activated by HGPRT. They are poor substrates for guanyl kinase and ultimately interfere w/ DNA/RNA synthesis.

Question 5

What drug affects the conversion of ribonucleotides to deoxyribonucleotides?

Answer 5

Hydroxy urea inhibits ribonucleotide reductase

Question 6

How do the mechanisms of Methotrexate and premetrexed differ?

Answer 6

MTX- competitive inhibitor of DHFR

Premetrexed- antagonist of thymidalate synthase and purine synthase

Both lead to the inhibition of DNA synthesis, decreased methionine and AA synthesis/metab

Question 7

What mechanisms make cancer cells more susceptible than normal sells to drugs (selective toxicity)?

Answer 7

Some cancer drugs over express the folate receptor.

Question 8

What is a leucovorin rescue?

Answer 8

Leucovorin is used w/ MTX to rescue host tissues from the effects of intense MTX therapy

Leucovorin provides normal tissues w. a way to bypass DHFR so you can use a higher dose of MTX

Question 9

How do the mechanisms of resistance differ between:
MTX
5-FU
6-MP
5-TG

Answer 9

MTX- change target enzyme (DHFR), decreases drug accum

5-FU-change target enzyme (TS), decreases activation of pro-drugs (pyrim mono kinase)

6-MP/5-TG-change target enz (PNP/HGPRT), decrease activation of pro-drug (HGPRT), increase inactivation

Question 10

How are 5-FU and capecitabine activated?

Answer 10

Capecitabine is converted to 5-FU. 5-FU then has to be activated by pyrimidine monophosphate kinase (UMP–UDP)

Question 11

How is the activation of purine analogues unique?

Answer 11

6-MP and 6-TG have to be activated by HGPRT (combining PRPP w/ hypoxanthine/guanine bases)

Question 12

What are the unique SE of MTX?

Answer 12

Bone marrow suppression–> myelosupression

Aborficant

Question 13

What are the unique SE of 5-FU?

Answer 13

LOOOW TI
myelosupression
Acute cerebellar syndrome

Question 14

What are the unique SE of 6-MP?

Answer 14

Bone marrow suppression

Tumor lysis syndrome

Question 15

What is the difference in the MOA of antimetabolite agents that block nucleotide synthesis vs those that act on DNA synthesizing enzymes?

Answer 15

Unlike agents that block nucleotide synthesis, inhibitors of DNA synthesizing enzymes DO NOT inhibit the nucleotide synthesis pathway.

Question 16

What is tumor lysis syndrome?

Answer 16

The sudden rapid death of millions of cells—problem for pts w/ leukemia/lymphoma.

Results from development of electrolyte and metabolic disturbances (esp hyperuricemia) that produce life threatening complications

Question 17

How can you minimize the effects of tumor lysis syndrome?

Answer 17

Allopurinol–used during chemo of hematologic cancers to prevent hyperuricemia d/t tumor cell lysis

Question 18

Why are there concerns over administering allopurinol w/ 6-MP?

Answer 18

It can lead to excessive mercaptopurine toxicity (6-MP is also oxidized by xanthine oxidase) unless the dose of 6-MP is reduced.