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Heme and Lymph Midterm > Fitz 2: Purine metabolites > Flashcards

Fitz 2: Purine metabolites Flashcards

1
Q

What are the 2 folate anti-metabloite drugs?

A

Methotrexate and pemetrexed

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2
Q

What are the 4 purine anti metabolite drugs?

A

6-mercaptopurine
6-Thioguanine
Fludarabine
Cladribine

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3
Q

What does Methotrexate (MTX) do?

A
  • inhibits DHFR which blocks synth of thymidine, methionine, and serine
  • metabolite MTX (glu)n inhibits GAR and AICAR transformylase which blocks the synthesis of purines
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4
Q

What does Pemetrexed do?

A
  • potent inhibitor of thymidylate synthase and GAR transformylase
  • 1000x LESS potent inhibition of DHFR compared to MTX
  • can circumvent MTX resistance
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5
Q

Therapeutic use of MTX?

A
  • pediatric leukemias
  • Choriocarcinoma
  • primary CNS lymphoma
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6
Q

Therapeutic use of pemetrexed?

A

Malignant pleural mesothelioma

  • a rare cancer associated with asbestos exposure… combo with cisplatin
  • also used in refractory non-small cell lung cancer (NSCLC)
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7
Q

Therapeutic use of High Dose MTX (HDMTX)?

A

-CNS prophylaxis in pts with leukemia and high-risk lymphoma
-must be followed by 2-3 day rescue with leucovorin
-

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8
Q

Therapeutic uses of Intermediate dose MTX?

A

MAlignant gestational trophoblastic disease (GTD)- e.g. choriocarcinoma.
-pts seldom require aggressive hydration, urinary alkalinization, or leucovorin rescue

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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

Toxicity for MTX?

A
  • bone marrow suppression
  • leucovorin rescue required
  • crystalluria tubular obstruction
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11
Q

Toxicity for Pemetrexed?

A
  • bone marrow suppression

- Caution in pats with renal insufficiency

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12
Q

MTX MOA?

A
  • enters cell through RFC (reduced folate carrier)
  • competitively inhibits DHF reductase
  • so DHF(Glu)n builds up and inhibits Thymidylate synthase
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13
Q

How is intermediate or low dose MTX cleared from the body?

A

Renal Excretion

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14
Q

How is high dose MTX cleared?

A

Hepatic metabolism and renal elmination

-can get crytalluria tubular obstruction

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15
Q

Toxicity of MTX?

A
  • GI: mucositis, small bowel ulcers and bleeding, diarrhea (discontinue to prevent perforation of gut)
  • Bone marrow suppression: thormbocytopenia and leukopenia, Madirs 7-10 days after Rx, recovery 14-21 days Leucovorin rescue
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16
Q

What metabolite precipates in the kidney with high dose MTX?

A

7-OH-MTX

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17
Q

Pemetrexed MOA?

A
  • enteres cell via energy dependent tranport RFC
  • inhibits TS, GAR-FT (transformylase)
  • *neglible effect on DHFR
  • like MTX, it accumulates as a polyglutamate
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18
Q

What is the clinical significance of Pemetrexed?

A

survival benefit in malignant pleural mesothelioma

-use with cisplatin

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19
Q

What dot he Purine Antimetabolites do?

A

inhibit purine ring biosynthesis, nucleotide interconversions, and impair DNA/RNA

20
Q

What do 6-Mercaptopurine and 6-Thioguanine do?

A

inhibit purine ring biosynth and nucleotide interconversion…. disrupts DNA and RNA integrity

21
Q

What does Fludarabine (2-F-araA) do?

A

Tumor cell kinases convert 2-F-araA to nucleotide triphosphates… inserted into DNA, RnA and distrupt DNA and RNA synth

22
Q

What does Cladribine, 2-Cl-deoxyadenosine do?

A

Tumor cell kinases conert it to nucleotide analogs; inhibits DNA synth; also potent inhibitor of ribonucleotide reductase

23
Q

Therapeutic use of 6-Mercaptopurine

A

Maintenance of remission in acute lymphocytic leukemia (ALL)

24
Q

Therapeutic uses of 6-Thioguanine?

A

Acute non-lymphocytic leukemia

-with daunorubicin and cytarabine

25
Q

Therapeutic use of Fludarabine

A

Chronic lympocytic leukemia (CLL)*

-also effective against hair-cell leukemia, indolent Non-Hodgkin’s lymphoma

26
Q

Therapeutic use of Cladribine

A

Hair cell leukemia*

-also effective against non-hodgkin’s lymphoma; -chronic lymphocytic leukemia (CLL)

27
Q

6-Mercaptopurine toxicity

A

Meylosuppression

28
Q

6-Thioguanine toxicity

A

Myelosuppression; hepatotoxicity with long term use

29
Q

Fludarabine Toxicity

A

Myelosupression; opportunistic infections

-IV only to avoid intestinal bacteria generating toxic fluoroadenine

30
Q

Cladribine toxicity

A

Myelosuppression; drug fever

31
Q

How is 6-MP inactivated?

A

in the liver, TPMT and XO change it into MEthyl-6-MP and 6-Thiouric acid respectively

  • these are inactive metabolites
  • the active drug goes on to affect all other cells in the body
32
Q

How is 6-MP activated then?

A
  • exits the liver
  • gets converted to TIMP by HPRT enzyme in cells
  • TIMP gets converted to 6-methyl-TIMP ribonucleotides and TXMP 6-thioxanthine monophosphate by TPMT and IMPDH respectively
  • these metabolites are antineoplastic
33
Q

What is the clinical significance of HPRT bioactivation?

A

Hypoxanthine ribosyl transferase intitiates conversion of 6-MP to active metabolites

34
Q

what do the 6-methyl TIMP ribonucleotides do?

A

inhibit denovo purine biosynthesis

35
Q

What do the TXMP 6-thioxanthine monophosphate things do?

A

Get converted to 6-thio-dGTP or 6-thio-GTP and get incorporated into DNA or RNA….. stops everything

36
Q

Why is the liver so important for 6-MP?

A

The XO enzyme in it significantly reduces the bioavailability

37
Q

What do we have to worry about that inhibits Xanthine oxidase?

A

gout medications….

-it will give us over exposure to 6-MP

38
Q

What drugs will inhibit XO?

A

Allopurinol

febuxostat

39
Q

Which drug will by-pass the XO inactivation step?

A

6-thioguanine
-this one is cool because then it won’t have that goofy drug interaction with the XO inhibitors Allopurinal or fubuxostat

40
Q

So how is 6-TG metabolized then?

A

just the two top arms work

  • TPMT inactivates it
  • HPRT activates it
  • it gets made into nucleotides and taken up… stops DNA and RNA synth
41
Q

What are Fludarabine and Cladribine analogues of?

A

Adenosine

42
Q

MOA of Fludarabine and Cladribine?

A
  • enter tumor cells via active transport
  • get converted to nucleotides
  • inhibit DNA polymerase and can incorporate into DNA and RNA
43
Q

Which drugs are active during the S-phase of the cell cycle?

A
  • Pyrimidine antimetabolites: 5FU, Capecitabine, AraC, Gemcitabine
  • Folate Antimetabolites: MXT, Pemetrexed
  • Purine Antimetabolites: Thiopurines- 6MP, 6TG, Cladribine, fludarabine
44
Q

What are the 4 phases of the cell cycle?

A

G1, S, G2, M

  • G1 and 2 are “gap” phases: cell grows and continues to divide
  • S is “synthesis” phase: cell duplicates DNA
  • M is “mitotic” phase: cell aligns chromosomes and divides into two daughter cells
  • cells not actively dividing are in a resting state (G0)
45
Q

If a cell isn’t growing very much, will these S-phase drugs work very well on it?

A

No…

46
Q

Why is it so important to catch a tumor early so we can treat it?

A

early in tumor growth, the cells are dividing rapidly, so these drugs will work well on them
-later, the rate of division curtails…. and we die

Heme and Lymph Midterm (11 decks)

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