Purine Antimetabolites

Question 1

What are the two Anti-Folate drugs?

Answer 1

Methotrexate and Pemetrexed

Question 2

What is the MOA of methotrexate?

Answer 2

inhibits DHFR-> blocks synthesis f thymidine, methionine, and serine.

Question 3

What is the MOA of Pemetrexed?

Answer 3

• multiple sites of action.

- potent inhibitor of thymidylate synthase and GAR transformylase

Question 4

What are the uses of Methotrexate?

Answer 4

Pediatric leukemias, primary CNS lymphoma, NHL

*choriocarcinoma (monotherapy)

Question 5

What are the uses of Pemetrexed?

Answer 5

Malignant pleural mesothelioma

Question 6

What is the High dose MTX used for and what else is given with it?

Answer 6

• CNS prophylaxis in patients with leukemia and lymphoma

- Rescue with Leucovorin

Question 7

What is the intermediate dose of MTX used for?

Answer 7

• choriocarcinoma

- patients usually do not require leucovorin rescue

Question 8

What is low dose MTX given for?

Answer 8

• Intrathecal for CNS prophylaxis; i.v. for bladder and desmoid tumors
• Oral for ALL, APL

Question 9

How does DHF and MTX enter the cell?

Answer 9

through the reduced folate carrier (RFC)

Question 10

By inhibiting DHF my MTX, what enzyme is indirectly effected because of this?

Answer 10

Thymidylate Synthase

Question 11

What does Leucovorin do when administered with MTX?

Answer 11

Helps rescue the patient from the bone marrow suppression that causes the thrombocytopenia and leukopenia

Question 12

What are the toxicities associated with high dose MTX?

Answer 12

Renal toxicity

Question 13

What are the advantages of Pemetrexed?

Answer 13

• Broader spectrum of action

- Circumvents MTX resistance

Question 14

Difference between MTX and Pemetrexed?

Answer 14

Pemetrexed has a negligible effect on DHFR

Question 15

What medication is given with Pemetrexed in the treatment of malignant pleural mesothelioma?

Answer 15

Cisplatin

Question 16

What are the Purine antimetabolite drugs?

Answer 16

6-mercaptopurine
6-thioguanine

Fludarabine
Cladribine

Question 17

What is the MOA of 6-mercaptopurine and 6-thioguanine?

Answer 17

Inhibits purine ring biosynthesis and nucleotide interconversion

Question 18

What is the MOA of Fludarabine?

Answer 18

Tumor cell kinases convert the drug to nucleotide triphosphate which are inserted into DNA and RNA and halt synthesis

Question 19

What is the MOA of Cladribine?

Answer 19

Tumor cell kinases convert the drug into nucleotide analogs which inhibit DNA synthesis and ribonucleotide reductase.

Question 20

What is the therapeutic use of 6-mercaptopurine?

Answer 20

Maintenance of remission in ALL

Question 21

What is the therapeutic use of 6-thioguanine?

Answer 21

Acute non-lymphocytic leukemia (with daunorubicin and cytarabine)

Question 22

What is the therapeutic use of Fludarabine?

Answer 22

CLL,

Question 23

What is the therapeutic use of Cladribine?

Answer 23

Hairy Cell leukemia

Question 24

What are the toxicities of the Purine antimetabolites?

Answer 24

myelosuppression

Question 25

What are the two enzymes that metabolize/inactivate 6-mercaptopurine?

Answer 25

Xanthine oxidase

TP methyltransferase

Question 26

What is the activating enzyme for 6-mercaptopurine that converts it into TIMP?

Answer 26

HPRT-hypoxanthine ribosyltransferase

Question 27

What is the enzyme that converts TIMP—> active metabolites?

Answer 27

IMPDH and TMPT

Question 28

Activation of what enzyme leads to inhibition of de novo purine synthesis?

Answer 28

TMPT

Question 29

What drugs can cause an interaction with 6-mercaptopurine?

Answer 29

Allopurinol and febuxostat

Question 30

What is the difference in TMPTs activity with 6-mercaptopurine and 6-thioguanine?

Answer 30

TMPT in the tissue will activate 6-mercaptopruine

TMPT will inactivate 6-thioguanine