Folate Anti-Metabolites and Purine Anti-Metabolite Drugs (Fitz)

Question 1

List folate anti-metabolite drugs

Answer 1

Methotrexate

Pemetrexed

Question 2

List purine anti-metabolite drugs

Answer 2

6-mercaptopurine
6-thioguanine
Fludarabine
Cladribine

Question 3

This anti-folate drug inhibits DHFR –> blocks synthesis of Thymidine, Methinonine, and Serine. Its metabolite inhibits GAR and AICAR transformylase –> blocks synthesis of purines

Answer 3

Methotrexate

Question 4

This anti-folate drug has multiple sites of action: potent inhibitor of TS and GAR transformylase.

Answer 4

Pemetrexed

1000x less potent inhibition of DHFR compared to MTX. Can circumvent MTX resistance

Question 5

Therapeutic uses of MTX?

Answer 5

Pediatric leukemia (acute lymphoblastic anemia)
Primary CNS lymphoma
NHL
Choriocarcinoma (monotherapy)
Component of therapy in colon, GI, breast, Head and Neck

Question 6

Therapeutic uses of Pemetrexed?

Answer 6

Malignant pleural mesothelioma in combo with Cisplatin

Also used in refractory non-small cell lung cancer

Question 7

Therapeutic uses for high dose MTX?

Answer 7

CNS prophylaxis in pts w/leukemia and high-risk lymphoma
Dose of MTX must be followed by 2-3 days RESCUE WITH LEUCOVORIN
Rescue depends on rapid clearance of MTX by kidneys

Question 8

Therapeutic uses of intm dose MTX?

Answer 8

Malignant gestational trophoblastic disease -e.g., choriocarcinoma

Question 9

Therapeutic uses of Low dose MTX?

Answer 9

Intrathecal for CNS prophylaxis
IV for bladder, desmoid tumors
Oral for ALL, APL

Question 10

Dose limiting toxicity of methotrexate?

Answer 10

Pregnancy Category D
BM suppression (thrombocytopenia, neutropenia)
Mucositis
Toxicity profile varies with dose –> HDMTX high dose regimen risks renal crystalluria of MTX and renal failure and HDMTX requires leucovorin rescue

Question 11

Dose limiting toxicity of pemetrexed?

Answer 11

Pregnancy category D
BM suppression
Caution in pts w/even mild, moderate renal insufficiency

Question 12

MOA of MTX?

Answer 12

Competitive inhibition of DHFR is the main MOA for MTX. Inhibition of DHFR causes accumulation of DHF. DHF(glu)n inhibits TS and AICAR transformylase

MTX(glu)n accumulation which inhibits DHFR and AICAR transformylase and GAR transformylase.

Question 13

Clearnace and metabolism of intm dose MTX? HDMTX?

Answer 13

Intm dose/low dose MTX –> renal excretion of 80-90% MTX

HDMTX –> Hepatic metabolism to 7-hydroxy-MTX (inactive, less soluble) –> Renal elimination –> Can get crystalluria tubular obstruction

Question 14

What should you give if MTX BM suppression/toxicity?

Answer 14

Leucovorin rescue

Question 15

In renal toxicity of High dose MTX, it precipitates in the kidney as this metabolite:

Answer 15

7-OH-MTX

Question 16

Pemetrexed MOA?

Answer 16

Competitive inhibition of TS and GAR transformylase is the main MOA for Pemetrexed

Accumulate in cells as polyglutamate-Pemetrexed(glu)n which inhibits TS and GAR transformylase

Has a negligible effect on DHFR, compared to MTX

Has broader spectrum of activity and circumvents MTX resistance

Question 17

What is given with Pemetrexed to increase survival in malignant pleural mesothelioma?

Answer 17

Cisplatin

Increase survival by about 3 months

Question 18

These purine antimetabolites inhibit purine ring biosynthesis and nucleotide interconversion –> disrupts DNA and RNA integrity

Answer 18

6-mercaptopurine and 6-thioguanine

Question 19

This purine anti-metabolite requires tumor cell kinases to convert the drug to nucleotide triphosphates –> inserted into DNA, RNA and disrupt DNA and RNA synthesis

Answer 19

Fludarabine (2-F-araA)

Question 20

Tumor cell kinases convert this purine antimetabolite to nucleotide analogs; inhibits DNA synthesis; also potent inhibitor of ribonucleotide reductase

Answer 20

Cladribine

Question 21

Therapeutic use of 6-mercaptopurine? 6-thioguanine?

Answer 21

6-mercaptopurine: Maintenance of remission in ALL

6-thioguanine: acute non-lymphocytic leukemia (with daunorubicin and cytarabine)

Question 22

Therapeutic use of Fludarabine?

Answer 22

CLL

Also effective against hairy-cell leukemia, indolent NHL

Question 23

Therapeutic use of Cladribine?

Answer 23

Hairy cell leukemia
Also effective against NHL
CLL

Question 24

Dose-limiting toxicity of purine antimetabolites?

Answer 24

Myelosuppression

Question 25

This purine antimetabolite is only given IV to avoid intestinal bacteria generating toxic fluoroadenine

Answer 25

Fludarabine

Question 26

Which hepatic enzymes inactive 6-mercaptopurine?

Answer 26

XO | TPMT

Question 27

Which hepatic enzymes bioactivate 6-mercaptopurine?

Answer 27

HPRT creates active metabolite TIMP IMPDH and TPMT convert TIMP into active nucleotide metabolites that are anti-neoplastic

Question 28

__ initiates conversion of 6-MP to active metabolites

Answer 28

HPRT

Question 29

The conversion of TIMP ( from 6-MP) to 6-methyl TIMP ribonucleotides by TPMT inhibits production of ___ The conversion of TIMP (from 6-MP) to TXMP 6-thioxanthine monoP by IMPDH and eventual production to 6-thio-dGTP and 6-thio-GTP causes inhibition of ___

Answer 29

De novo purine biosynthesis DNA and RNA production

Question 30

Toxicological significance of hepatic metabolism of 6-MP?

Answer 30

- Low bioavailability: 1st pass effect, 6-MP overexposure d/t inhibition of XO by gout meds - Excess exposure: risk of excess exposure d/t inhibition of XO --> Allopurinol and Febuxostat drug interactions

Question 31

6-thioguanine bypasses this enzyme inactivation step and has no drug interaction with drugs such as allopurinol or febuxostat

Answer 31

XO Allopurinol and febuxostat are XO inhibitors

Question 32

6-TG is activated by __ and inactivated by ___

Answer 32

HPRT TPMT

Question 33

Fludarabine and Cladribine are chemical analogs of ___

Answer 33

Adenosine

Question 34

MOA of Fludarabine and Cladribine?

Answer 34

Enter tumor cells by active transport --> in tumor cells, various kinases convert them to nucleotide mono-, di-, and tri-Phosphates and deoxynucleotide di-, triphosphates --> These active metabolites inhibit DNA polymerase and they can incorporate into DNA and RNA Cladribine deoxynucleotide metabolites also inhibit ribonucleotide reductase and deplete cellular pools of dNTP needed for DNA synthesis

Question 35

List the S-phase active pyrimidine antimetabolites

Answer 35

5-FU Capecitabine Cytarabine-AraC Gemcitabine

Question 36

List the S-phase active Folate antimetabolites

Answer 36

MTX | Pemetrexed

Question 37

List the S phase active purine antimetabolites

Answer 37

Thiopurines-6MP and 6TG | Cladribine, Fludarabine

Question 38

Why does the cell cycle matter for cancer drug efficacy?

Answer 38

Cell cycle specific drugs are SCHEDULE-DEPENDENT. The DURATION AND TIMING OF DRUG ADMINISTRATION AFFECT EFFICACY MORE THAN THE DOSE