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LHT1 > Cancer chemotherapy and Anti-neoplastics 1 > Flashcards

Cancer chemotherapy and Anti-neoplastics 1 Flashcards

1
Q

pyrimidine anti-metabolite drugs

A
  • 5 Fluorouracil
  • Capecitabine
  • Cytarabine
  • Gemcitabine
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2
Q

pyrimidine antimetabolites- moa

A

-inhibit dTMP synthesis and DNA synthesis

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3
Q

5-Fluorouracil- distinction, therapeutic uses, dose-limiting toxicity

A
  • active metabolites- FdUMP inhibits thymidylate synthase
  • solid tumors!!- colorectal and other GI, breast, ovarian carcinomas; topical for basal cell carcinoma!!!
  • GI intolerance, mucositis, myelosuppression
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4
Q

Capecitabine- distinction, therapeutic uses, dose-limiting toxicity

A
  • oral pro-drug of 5-Fluorouracil
  • colorectal cancer!, breast cancer
  • similar to 5GU toxicity, plus hand-foot syndrome!
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5
Q

Gemcitabine- distinction, therapeutic uses, dose-limiting toxicity

A
  • kinases convert it to nucleotide analongs- inhibits DNA syn
  • pancreatic cancer!
  • myelosuppression
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6
Q

Cytarabine- distinction, therapeutic uses, dose-limiting toxicity

A
  • kinases convert it to AraCTP- inhibits DNA synthesis
  • acute myelogenous leukemia!
  • myelosuppression
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7
Q

5-fluorouracil- clinical significance

A
  • colorectal cancer!

- other solid tumors!

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8
Q

5-fluorouracil- activated via?

A

(analog of the pyrimidines, uracil and thymidine)

  • enzyme activation inside tumor cells!!- convert 5FU to fdUMP, FdUTP, FUTP
  • thymidine phosphorylase- 5FU–> 5FUdR
  • thymidine kinase- 5FUdR–> 5FdUMP
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9
Q

5-fluorouracil- moa

A 
-activated inside tumor cells!
the metabolite FdUMP:
-inhibits thymidylate synthase- blocks conversion of dUMP into dTMP
-depletes dTMP
-distorts dNTP pools
-causes thymineless death!
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10
Q

5-fluorouracil- contributing mechanisms

A
  • FdUTP (metabolite)- incorporates into and causes DNA damage
  • FUTP (metabolite)- incorporates into RNA, causes RNA damage
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11
Q

5-fluorouracil- mechanism of resistance?

A
  • alterations in thymidylate synthase

- tumors with higher levels of TS are more resistant- due to TS gene amplification

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12
Q

5-fluorouracil- efficacy and toxicity- depends on?

A

-rates of activation in tumor cells vs inactivation by liver!

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13
Q

5-fluorouracil- clearance?

A

inactivation by liver!!

  • hepatic Dihydropyrimidine dehydrogenase (DPD)- converts F5U to DHFU (inactive metabolite)
  • liver eliminates up to 80% of 5FU
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14
Q

5-fluorouracil- pharmacogenomics- allelic variation?

A
  • DPD gene (DPYD mutation)- slows 5FU clearance and aggravate its systemic toxicity
  • DPD deficiency- recessive trait
  • causes neuro sxs!!
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15
Q

Capecitabine- moa

A

(orally bioavailable)
Activation in liver:
-carboxyesterase 1A1/2- convert it to 5-DFCR
-cytidine deaminase- convert to 5-DFUR
Tumors overexpress:
-thymidine phosphorylase- converts 5-DFUR to 5FU

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16
Q

Capecitabine- clinical significance

A
  • used for colon cancer! (orally)

- also breast cancer!- slows cancer progression

17
Q

Capecitabine- toxicities

A
  • diarrhea
  • hand and foot syndrome!!- dose-limiting toxicity
  • myelosuppression
18
Q

Cytarabine and Gemcitabine- are what?

A

chemical analogs of cytidine

-both pro-drugs

19
Q

Cytarabine (Ara-C)- moa

A
  • enters tumor cells via hENT1 (equilibrative nucleoside transporter 1)
  • Ara-C is phosphorylated by DCK (deoxycytidine kinase)–> Ara-CMP
  • CMPK (deoxycytidylate kinase)–> Ara-CDP
  • NDKs (nucleoside diphosphate kinases)–> Ara-CTP
  • Ara-CTP (active) competes with CTP (cytidine triphosphate) in DNA polymerase
20
Q

what happens to ARA-CTP in a tumor cell AML)?

A
  • Ara-CTP blends with cellular nucleotides
  • AML tumor cells perceive Ara-CTP as CTP
  • Ara-CTP binds to DNA polymerase and inhibits DNA syn!!!
  • Ara-CTP is incorporated into DNA and terminates further DNA strand elongation!! (cannot form a 3-5 phosphodiester bond)
21
Q

Cytarabine- AML response depends on?

A
  • rate of activation by DCK vs its rate of inact by PN (pyrimidine nucleotidase) and CDA (cytidine deaminase)!!!
  • liver and spleen contain high levels of CDA!!- sanctuary for leukemic cells
22
Q

cytarabine vs gemcitabine

A

comparable!!

23
Q

Cytarabine- distinctions

A

-treat Acute myelogenous leukemia

24
Q

Gemcitabine- distinctions

A
  • inhibits ribonucleotide reductase

- treats pancreatic cancer!!

LHT1 (6 decks)

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