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Heme & Lymph-Unit 1 (Pharm) > Folate Anti-Metabolites and Purine Anti-Metabolite Drugs (Fitz) > Flashcards

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

1
Q

List folate anti-metabolite drugs

A

Methotrexate

Pemetrexed

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2
Q

List purine anti-metabolite drugs

A

6-mercaptopurine
6-thioguanine
Fludarabine
Cladribine

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3
Q

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

A

Methotrexate

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4
Q

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

A

Pemetrexed

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

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5
Q

Therapeutic uses of MTX?

A

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

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6
Q

Therapeutic uses of Pemetrexed?

A

Malignant pleural mesothelioma in combo with Cisplatin

Also used in refractory non-small cell lung cancer

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7
Q

Therapeutic uses for high dose MTX?

A

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

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8
Q

Therapeutic uses of intm dose MTX?

A

Malignant gestational trophoblastic disease -e.g., choriocarcinoma

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9
Q

Therapeutic uses of Low dose MTX?

A

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

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10
Q

Dose limiting toxicity of methotrexate?

A

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

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11
Q

Dose limiting toxicity of pemetrexed?

A

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

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12
Q

MOA of MTX?

A

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.

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13
Q

Clearnace and metabolism of intm dose MTX? HDMTX?

A

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

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14
Q

What should you give if MTX BM suppression/toxicity?

A

Leucovorin rescue

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15
Q

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

A

7-OH-MTX

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16
Q

Pemetrexed MOA?

A

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

17
Q

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

A

Cisplatin

Increase survival by about 3 months

18
Q

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

A

6-mercaptopurine and 6-thioguanine

19
Q

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

A

Fludarabine (2-F-araA)

20
Q

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

A

Cladribine

21
Q

Therapeutic use of 6-mercaptopurine? 6-thioguanine?

A

6-mercaptopurine: Maintenance of remission in ALL

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

22
Q

Therapeutic use of Fludarabine?

A

CLL

Also effective against hairy-cell leukemia, indolent NHL

23
Q

Therapeutic use of Cladribine?

A

Hairy cell leukemia
Also effective against NHL
CLL

24
Q

Dose-limiting toxicity of purine antimetabolites?

A

Myelosuppression

25
Q

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

A

Fludarabine

26
Q

Which hepatic enzymes inactive 6-mercaptopurine?

A

XO

TPMT

27
Q

Which hepatic enzymes bioactivate 6-mercaptopurine?

A

HPRT creates active metabolite TIMP

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

28
Q

__ initiates conversion of 6-MP to active metabolites

A

HPRT

29
Q

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 ___

A

De novo purine biosynthesis

DNA and RNA production

30
Q

Toxicological significance of hepatic metabolism of 6-MP?

A
  • 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
31
Q

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

A

XO

Allopurinol and febuxostat are XO inhibitors

32
Q

6-TG is activated by __ and inactivated by ___

A

HPRT

TPMT

33
Q

Fludarabine and Cladribine are chemical analogs of ___

A

Adenosine

34
Q

MOA of Fludarabine and Cladribine?

A

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

35
Q

List the S-phase active pyrimidine antimetabolites

A

5-FU
Capecitabine
Cytarabine-AraC
Gemcitabine

36
Q

List the S-phase active Folate antimetabolites

A

MTX

Pemetrexed

37
Q

List the S phase active purine antimetabolites

A

Thiopurines-6MP and 6TG

Cladribine, Fludarabine

38
Q

Why does the cell cycle matter for cancer drug efficacy?

A

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

Heme & Lymph-Unit 1 (Pharm) (5 decks)

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