Chemo- Purine/Pyrimidine anti-metabolites

Question 1

MOA of Cytarabine?

Answer 1

Pyrimidine analog–> inhibits DNA polymerase

Question 2

What is the dose-limiting toxicity of capecitabine?

Answer 2

Hand-foot syndrome

Question 3

What is the active metabolite of 5FU? What does it inhibit?

Answer 3

FdUMP inhibits thymidylate synthase

Question 4

What is the oral pro-drug of 5FU?

Answer 4

Capecitabine

Question 5

What cancer is Capecitabine used for?

Answer 5

Colorectal cancer, metastatic breast cancer

Question 6

What cancer is 5FU used for?

Answer 6

Solid tumors- Colorectal, GI, breast, and ovarian carcinomas, and topically for basal cell carcinoma

Question 7

What is the dose-limiting toxicity of 5FU?

Answer 7

Myelosupression

Question 8

What is the dose-limiting toxicity of Ara-C?

Answer 8

Severe myelosupression- granulocytopenia

Question 9

What is the MOA of FdUMP and what drug is it a metabolite of?

Answer 9

Inhibits Thymidylate synthase, prevents dUMP–> dTMP

Active metabolite of 5FU

Question 10

What causes a thymineless death?

Answer 10

Depletion of dTTP by 5FU (FdUMP)

Question 11

What 5FU metabolite inserts into DNA?

Answer 11

FdUTP- causes DNA damage, cell cycle arrest, and death

Question 12

What 5FU metabolite incorporates into RNA?

Answer 12

FUTP- causes RNA damage

Question 13

What are the pyrimidine anti-metabolites?

Answer 13

5FU, gemcitabine, Ara-C, and capecitabine

Question 14

What is the main toxicity of high-dose MTX?

Answer 14

Severe bone marrow suppression, renal toxicity

7-OH-MTX precipitates in kidney –> tubular obstruction

Question 15

What is the MOA of Methotrexate?

Answer 15

Competitive inhibitor of DHF reductase–> DHF accumulation–> inhibits thymidylate synthase

Question 16

What are the anti-folate drugs?

Answer 16

Methotrexate and Pemetrexed

Question 17

What is High Dose MTX used for? What must be given with it?

Answer 17

Used for CNS prophylaxis for high risk leukemia/lymphoma patients. Must be followed with leucovorin for rescue.

Question 18

What is Intermediate dose MTX used for?

Answer 18

Malignant gestational trophoblastic disease (i.e. choriocarcinoma)

Question 19

What is low dose MTX used for?

Answer 19

Intrathecal- CNS prophylaxis
IV- Bladder and desmoid tumors
Oral- ALL, APL

Question 20

What is 6-mercaptopurine used for?

Answer 20

Maintenance of remission in ALL

Question 21

What is 6-Thioguanine used for?

Answer 21

Acute non-lymphocytic leukemia

Question 22

What is Fludarabine used for?

Answer 22

CLL> hairy cell leukemia, indolent NHL

Question 23

What is Cladribine used for?

Answer 23

Hairy Cell Leukemia

Question 24

What is the most common resistance mechanism for 5FU?

Answer 24

Thymidylate synthase alterations

Tumors with high TS levels–> more resistant to 5FU

Question 25

What lab findings would be found in tumor lysis syndrome?

Answer 25

Hyperkalemia, hyperphosphotemia, hypocalcemia, and hyperuricemia

Question 26

What mutation/deficiency will lead to severe 5FU toxicity?

Answer 26

DPYD mutations or DPD deficiency

will have slower clearance, more systemic exposure

Question 27

What makes Capecitabine have selective toxicity?

Answer 27

Tumors have more active thymidine phosphorylase and uridine phosphorylase–> tumor-selective activation to 5FU

Question 28

What are the folate antimetabolites?

Answer 28

Methotrexate and Pemetrexed

Question 29

What can cause 6-MP toxicity?

Answer 29

Gout medications (Allopurinol and febuxostat)
From inhibition of xanthine oxidase

Question 30

What genetic variant effects thiopurine (6-MP, 6-TG) clearance and effectiveness?

Answer 30

TMPT allelic variation
Low levels–> does not inactivate effectively, higher efficacy
High levels–> lower toxicity, high relapse risk

Question 31

How do 6-MP and 6-TG act to treat cancer and in what cell cycle phase?

Answer 31

Inhibit purine ring biosynthesis

S phase