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Heme and Lymph Midterm > Fitzy 1: Pyrimidine anti-metabolite drugs that inhibit DNA synthesis > Flashcards

Fitzy 1: Pyrimidine anti-metabolite drugs that inhibit DNA synthesis Flashcards

1
Q

What are the 4 drugs that are pyrimidines?

A

5 Fluorouracil (5FU)
Capecitbabine
Cytarabine (Ara-C)
Gemcitabine

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2
Q

What is adjuvant therapy?

A

given after the tumor is removed by surgery…. prevent cancer reoccurrence

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3
Q

What is neoadjuvant chemotherapy?

A

given prior to surgery to remove a tumor

goal is to shrink the tumor

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4
Q

What does 5FU do?

A

FdUMP inhibits thymidylate synthase (stops dTMP synthesis)

FdUTP and FUTP damage DNA and RNA respectively

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5
Q

What is Capecitabine?

A

and oral pro drug of 5FU

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6
Q

What happens with Gemcitabine?

A

Kinases convert gemcitabine to nucleotide analogs… inhibits DNA synthesis

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7
Q

What happens with Cyatarabine (Ara-C)?

A

Kinases convert Ara-C to AraCTP…. that inhibits DNA synth

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8
Q

Therapeutic use of 5FU?

A

Solid tumorsl colorectal and other GI , breast, ovarian carcinomas
-Topica- basal cell carcinoma

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9
Q

Therapeutic use for Capecitabine

A

Colorectal cancer (start with C); metastatic breast cancer

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10
Q

Therapuetic use for Gemcitabine?

A

Pancreatic cancer

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11
Q

Therapeutic use for Cytarabine?

A

Acute Myelogenous leukemia (AML)

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12
Q

Toxicity for 5FU?

A

Severe GI intolerance, mucositis, myelosuppression

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13
Q

Toxicity for Capecitabine?

A

like 5FU, but with that goofy hand and foot syndrome

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14
Q

Toxicity for Gemcitabine?

A

Myelosuppression- neutropenia

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15
Q

Toxicity for Cyarabine (Ara C)

A

Severe myelosuppression- granulocytopenia

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16
Q

MOA of 5FU?

A
  • analogue of pyrimidines (Uracil and thymidine)
  • enzymatic activation of 5FU INSIDE THE TUMOR CELLS is required for clinical effects *
  • gets converted to FdUMP, FdUTP, and FUTP
  • given parenterally (injected)
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17
Q

What does the 5FU metabolite FdUMP do?

A
  • inhibits thymidylate synthase
  • depletes dTMP
  • distorts dNTP pools
  • causes Thymineless death*
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18
Q

At what part of the cell cycle does 5FU act at?

A

S-Phase

-that means synthesis phase…. the only time when having screwed up DNA would really suck

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19
Q

What is the result of thymidylate synthase inhibition by 5FU?

A

dUMP gets converted into dUTP instead… that accumulates… dNTP pool distortiong
-thymineless death

20
Q

What reaction does thymidylate synthase handle?

A
  • converts dUMP to dTMP

- the dTMP can eventually get worked into DNA 2 phosphates down the road :)

21
Q

What is so bad about FdUTP? (metabolite of 5FU)

A

incorporates into and causes DNA damage, cell cycle arrest, and death

22
Q

What is bad about FUTP (metbaolite of 5FU)?

A

incorporates into RNA and causes RNA damage…. makes sense because it’s not “deoxy” anything..

23
Q

What is actually the thing that inhibits thymidylate synthase?

A

FdUMP… from the 5FU

24
Q

What can we give along with 5FU to increase the anticancer activity?

A

leucovorin and methotrexate

25
Q

Why is this drug 5FU selective for tumor cells?

A

the T/U phosphorylase that breaks it down is more active in tumor tissue

26
Q

What kinds of tumors are more resistant to 5FU?

A

the ones with higher levels of Thymidylate synthase (TS)

-so, we want tumors with lower TS activity becuase we can kill them with 5FU

27
Q

Where does 5FU get inactivated? what organ?

A

the liver

28
Q

What is the inactive metabolite of 5FU and what is the Half life of 5FU?

A

DHFU

10 minutes

29
Q

What enzyme in the liver inactivates 5FU?

A

Dihypropyrimidine dehydrogenase (DPD)

  • converts 5FU to DHFU
  • this happens to like 80% of the 5FU administered
  • so allelic variation in DPD gene (DPYD) can slow 5FU clearance and aggravate its systemic toxicity
30
Q

What is DPD?

A

an enzyme that breaks down thymine and uracil

*also inactivates 5FU

31
Q

What happens if someone has an inherited DPD deficiency and they get 5FU?

A

severe 5FU toxicity

-much slower 5FU clearance

32
Q

Capecitabine MOA?

A
  • given orally
  • activated in liver: carboxyesterase 1A1 and 2 convert it to 5’-DFCR
  • then, Cytidine deaminase converts that to 5’-DFUR
  • tumors overexpress thymidine phosphorylase which converts 5’DUFR to 5FU… then it’s the same thing
33
Q

What is Capecitabine used for again?

A

advanced COLON cancer

-has less side effects and it’s more convenient to take

34
Q

Capecitabine toxicities?

A
  • diarrhea
  • hand-foot syndrome*
  • the myelosuppression, mucositis, alopecia, and nausea is more of a 5FU thing….
35
Q

What is Hand-foot syndrome?

A

a toxicity of Capecitabine

-they get really nasty looking red hands and feet

36
Q

What are Gemcitabine and Cytarabine (AraC) chemical anologues of?

A

Cytidine

37
Q

Cytarabine (AraC) MOA?

A
  • enters tumor cells via hENT-1
  • P’ed by dCK to Ara-CMP
  • P’ed to Ara-CDP by CPMK
  • Ara-CTP by NDKs…. this competes with CTP in DNA polymerase
  • Ara-CTP incorporated into DNA causes “chain termination” and cell death
  • Gemcitabine is analogous to this!*
38
Q

So, what enzyme ends up picking up Ara-CTP?

A

DNA polymerase

  • it thinks that it’s Cysteine!
  • competitively inhibits DNA synthesis
39
Q

What are we depending on for an AML response to Ara-C?

A

-the RATE of activation by doxycytidine kinase vs. the RATE of inactivation by pyrimidine nucleotidase and cytidine deaminase (CDA) in tumor cells

40
Q

What does Pyrimidine nucleotidase do?

A

turns Ara-CMP into Ara-C

41
Q

What does Cytidine deaminase (CDA) do?

A

turns the C into a U in both Ara-C and Ara-CMP

*remember that the RATE is the most important thing

42
Q

What organ has a high level of CDA?

A

Liver and spleen

*so, these things are sanctuary for leukemic cells because these mother fuckers keep deaminating Ara-C

43
Q

How are Gemcitabine and Ara-C administered?

A

IV

-poor bioavailability in because of high levels of cytosine deaminase in gut and liver

44
Q

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

A

myelosuppression

45
Q

So, what are the main differences between Gemcitabine and Ara-C?

A

Ara-C: Tx of AML
Gemcitabine: Tx of pancreatic cancer, non small cell lung cancer…. this one also has the drug induced fever and flu-like syndrome. Also, Gem-diphosphate inhibits ribonucleotide reductase (depletes cellular dNTPs)

Heme and Lymph Midterm (11 decks)

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