- 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)

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

What are the 4 drugs that are pyrimidines?

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

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What is adjuvant therapy?

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

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What is neoadjuvant chemotherapy?

given prior to surgery to remove a tumor

goal is to shrink the tumor

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What does 5FU do?

FdUMP inhibits thymidylate synthase (stops dTMP synthesis)

FdUTP and FUTP damage DNA and RNA respectively

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What is Capecitabine?

and oral pro drug of 5FU

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What happens with Gemcitabine?

Kinases convert gemcitabine to nucleotide analogs… inhibits DNA synthesis

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What happens with Cyatarabine (Ara-C)?

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

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Therapeutic use of 5FU?

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

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Therapeutic use for Capecitabine

Colorectal cancer (start with C); metastatic breast cancer

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Therapuetic use for Gemcitabine?

Pancreatic cancer

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Therapeutic use for Cytarabine?

Acute Myelogenous leukemia (AML)

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Toxicity for 5FU?

Severe GI intolerance, mucositis, myelosuppression

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Toxicity for Capecitabine?

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

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Toxicity for Gemcitabine?

Myelosuppression- neutropenia

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Toxicity for Cyarabine (Ara C)

Severe myelosuppression- granulocytopenia

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MOA of 5FU?

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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What does the 5FU metabolite FdUMP do?

inhibits thymidylate synthase
depletes dTMP
distorts dNTP pools
causes Thymineless death*

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

S-Phase

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

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

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

What reaction does thymidylate synthase handle?

converts dUMP to dTMP

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

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

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

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

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

What is actually the thing that inhibits thymidylate synthase?

FdUMP… from the 5FU

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

leucovorin and methotrexate

Why is this drug 5FU selective for tumor cells?

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

What kinds of tumors are more resistant to 5FU?

the ones with higher levels of Thymidylate synthase (TS) | -so, we want tumors with lower TS activity becuase we can kill them with 5FU

Where does 5FU get inactivated? what organ?

the liver

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

DHFU | 10 minutes

What enzyme in the liver inactivates 5FU?

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

What is DPD?

an enzyme that breaks down thymine and uracil *also inactivates 5FU

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

severe 5FU toxicity | -much slower 5FU clearance

Capecitabine MOA?

- 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

What is Capecitabine used for again?

advanced COLON cancer | -has less side effects and it's more convenient to take

Capecitabine toxicities?

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

What is Hand-foot syndrome?

a toxicity of Capecitabine | -they get really nasty looking red hands and feet

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

Cytidine

Cytarabine (AraC) MOA?

- 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!*

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

DNA polymerase - it thinks that it's Cysteine! - competitively inhibits DNA synthesis

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

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

What does Pyrimidine nucleotidase do?

turns Ara-CMP into Ara-C

What does Cytidine deaminase (CDA) do?

turns the C into a U in both Ara-C and Ara-CMP | *remember that the RATE is the most important thing

What organ has a high level of CDA?

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

How are Gemcitabine and Ara-C administered?

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

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

myelosuppression

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

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)