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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
Therapeutic use of Fludarabine
Chronic lympocytic leukemia (CLL)* | -also effective against hair-cell leukemia, indolent Non-Hodgkin's lymphoma
26
Therapeutic use of Cladribine
Hair cell leukemia* | -also effective against non-hodgkin's lymphoma; -chronic lymphocytic leukemia (CLL)
27
6-Mercaptopurine toxicity
Meylosuppression
28
6-Thioguanine toxicity
Myelosuppression; hepatotoxicity with long term use
29
Fludarabine Toxicity
Myelosupression; opportunistic infections | -IV only to avoid intestinal bacteria generating toxic fluoroadenine
30
Cladribine toxicity
Myelosuppression; drug fever
31
How is 6-MP inactivated?
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
How is 6-MP activated then?
- 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
What is the clinical significance of HPRT bioactivation?
Hypoxanthine ribosyl transferase intitiates conversion of 6-MP to active metabolites
34
what do the 6-methyl TIMP ribonucleotides do?
inhibit denovo purine biosynthesis
35
What do the TXMP 6-thioxanthine monophosphate things do?
Get converted to 6-thio-dGTP or 6-thio-GTP and get incorporated into DNA or RNA..... stops everything
36
Why is the liver so important for 6-MP?
The XO enzyme in it significantly reduces the bioavailability
37
What do we have to worry about that inhibits Xanthine oxidase?
gout medications.... | -it will give us over exposure to 6-MP
38
What drugs will inhibit XO?
Allopurinol | febuxostat
39
Which drug will by-pass the XO inactivation step?
6-thioguanine -this one is cool because then it won't have that goofy drug interaction with the XO inhibitors Allopurinal or fubuxostat
40
So how is 6-TG metabolized then?
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
What are Fludarabine and Cladribine analogues of?
Adenosine
42
MOA of Fludarabine and Cladribine?
- enter tumor cells via active transport - get converted to nucleotides - inhibit DNA polymerase and can incorporate into DNA and RNA
43
Which drugs are active during the S-phase of the cell cycle?
- Pyrimidine antimetabolites: 5FU, Capecitabine, AraC, Gemcitabine - Folate Antimetabolites: MXT, Pemetrexed - Purine Antimetabolites: Thiopurines- 6MP, 6TG, Cladribine, fludarabine
44
What are the 4 phases of the cell cycle?
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
If a cell isn't growing very much, will these S-phase drugs work very well on it?
No...
46
Why is it so important to catch a tumor early so we can treat it?
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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