Antimetabolites

Question 1

What are antimetabolites? CCNS or CCS?

Answer 1

• Analogues of folate, pyrimidines or purines that interfere with key enzymes used during DNA synthesis.
• All are CCS - S phase!

Question 2

What is a common mechanism of resistance to antimetabolites?

Answer 2

Modification of the target enzymes!

Question 3

What does methotrexate do?

Answer 3

Potent antineoplastic agent because it blocks BOTH purine and thymidylate synthesis by inhibiting dihydrofolate reductase (DHFR).

Question 4

What does Leucovorin do?

Answer 4

“Leucovorin Rescue”

-It can selectively reduce the MTX toxicity in normal cells, as well as decrease the development of resistance

Question 5

What does 5-FU (5-Fluorouracil) do?

Answer 5

• Inhibits biosynthesis or pyrimidine nucleotides by inhibiting thymidylate synthase, the enzyme that catalyzes the rate limiting step in DNA synthesis.
• This results in a “thymineless death” of rapidly growing cells

Question 6

What do 6-Mercaptopurine and 6-Thioguanine do?

Answer 6

• Must be activated by HGPRT to TIMP and 6-thioGMP.
• T-IMP and 6-thioGMP are poor substrates for guanylyl kinase, therefore IMP and GMP accumulate, causing “pseudo feedback inhibition” of PRPP synthetase (PRPS), guanylyl amidotransferase (GPAT), HGPRT and the enzymes responsible for generation of XMP and adenylsuccinate from IMP!

Question 7

What is tumor lysis syndrome?

Answer 7

Caused by sudden, rapid death of millions of cells – a particular problem in patients with leukemia or lymphoma.
-TLS results from the development of electrolyte and metabolic disturbances that can produce life-threatening complications (esp. hyperuricemia) if not managed properly

Question 8

What does allopurinol do? When is it used?

Answer 8

• Xanthine oxidase inhibitor
• Frequently used during chemotherapy of hematologic cancers to prevent hyperuricemia due to tumor cell lysis - prevent tumor lysis syndrome
• Nephrotoxicity and acute gout produced by excessive uric acid are prevented by co-administration of allopurinol with ANY CHEMOTHERAPEUTIC agent!

Question 9

What happens if you give allopurinol with 6-Mercaptopurine?

Answer 9

BAD!
-Results in excessive mercaptopurine toxicity (because 6-MP is metabolized by xanthine oxidase) unless the dose of 6-MP is reduced to 25-30% of normal.

Question 10

What are the two main mechanisms by which drugs prevent DNA synthesis?

Answer 10

1. Nucleotide synthesis inhibitors (block production)

2. Inhibitors of DNA synthesizing enzymes (inhibit DNA poly)

Question 11

What are four classes to sort drugs that prevent DNA synthesis into?

Answer 11

1. Folic acid analogues
2. Pyrimidine analogues
3. Purine Analogues
4. Misc

Question 12

What are the folic acid analogues?

Answer 12

Methotrexate, Pemetrexed, Pralatrexate, Leucovorin (supporting agent)

Question 13

What are the pyrimidine analogues?

Answer 13

5-Fluorouracil (5-FU), Capecitabine, Cytarabine, Gemcitabine (-abine is a pyrimidine!)

Question 14

What are the purine analogues?

Answer 14

6Mercaptopurine, 6Thioguanine, Allopurinol (supporting agent), Cladarabine, Fludarabine

Question 15

What is the misc. drug that prevents DNA synthesis?

Answer 15

Hydroxyurea

Question 16

What is the mechanism of action of folic acid analogues? What is the difference between MTX and pemetrexed and pralatrexate?

Answer 16

• Competitive Inhibitors of DHFR
• MTX inhibits DHFR more, thymidylate synthase less (rate limiting step for DNA synthesis)
• “P” drugs inhibit DHFR less, thymidylate synthase more

Question 17

What is the resistance mechanisms against folic acid analogues?

Answer 17

1. Change target enzyme –> make it have low affinity for drug
2. Inc. DHFR expression
3. Dec. polyglutamination (drugs don’t stay in cell as well)
4. Dec. accumulation (Dec. transport) - Dec. RFC expression (reduced folate carrier)

Question 18

What is important about the pharmacokinetics of folic acid analogues?

Answer 18

• Must use transport systems of the cell
• -Inc. sensitivity when folate receptor Inc.
• -Inc. resistance when RFC expression Dec.

Question 19

How can MTX be given?

Answer 19

• Orally for non-antineoplastic treatment

- Give IV or intrathecally to cross BBB

Question 20

How is MTX secreted?

Answer 20

• Excreted unchanged in urine
• It Dec. kidney function –> Severe BMS –> side effects
• Administered with HCO3- (bicarbonate) to promote excretion (weak acid)
• Drug interactions: NSAIDs, CISPLATIN, weak acids (ASA)

Question 21

What are the therapeutic uses of MTX?

Answer 21

-BROAD SPECTRUM (extremely) - used in many types of cancers

Question 22

What are the therapeutic uses of Pemetrexed and Pralatrexate?

Answer 22

More selective action (mesothelioma) - NSCLC

Question 23

What are the toxicities of folic acid analogues?

Answer 23

• Cytotoxic
• Pneumonitis
• Hepatic fibrosis
• ABORTIFACENT

Question 24

What is Leucovorin rescue?

Answer 24

MTX + LV –> helps normal tissue recover

• allows use of higher doses of MTX
  1. Dec. toxicity
  2. Dec. likelihood of resistance
• -LV is FATAL if given INTRATHECALLY

Question 25

What are the two pyrimidine analogues?

Answer 25

• 5Fluorouracil

- Capecitabine

Question 26

What does hydroxyurea inhibit?

Answer 26

Ribonucleotide Reductase

-Synchronizes cells in G1, makes then more sensitive to radiation