Flashcards in Fitzpatrick - Anti-Neoplastic Drugs Deck (27)
5FU requires activation in what location for clinical effects?
Conversion to activated metabolites occurs INSIDE the tumor cell.
What is the active metabolite of 5FU?
What four actions does 5FdUMP do?
1. Inhibits thymidylate synthase...
2. ...blocking conversion of dUMP into dTMP. Eventual depletion of dTTP.
3. Accumulation of dUTP distorts "dNTP" pools...
4. ...causing "Thymineless" Death bc dTTP is essential for DNA synthesis.
Classify the specificity of 5FU
A cell cycle specific drug acting in S-phase
What metabolite of 5FU incorporates into the tumor DNA and causes DNA damage, cell cycle arrest, and death?
What metabolite of 5FU incorporates into RNA to cause RNA damage?
TS is associated with MoR to ___ in what way?
Tumors with higher levels of TS protein are more resistant to 5FU. TS gene amplification
5FU clearance occurs how?
Metabolic inactivation of 5FU by the liver.
Clinical efficacy and toxicity of 5FU is dependent upon rate of metabolic activation in the tumor or its metabolic inactivation in the liver?
its metabolic inactivation in the liver
What is the inactive metabolite of 5FU? How does this occur?
-Inactive metabolite: DHFU
-Hepatic enzyme: Dihydropyrimidine dehydrogenase (DPD) eliminates up to 80% of 5FU.
A person with AR DPD mutation/deficiency is at risk for what?
(called familial pyrimidineamia or hereditary thymine-uraciluria)
Symptoms of 5FU toxicity
stomatitis, leukpenia, thrombocytopenia, hair loss, diarrhea, fever, cerebellar ataxia, neurologic symptoms
Metabolic activation of capecitabine.
2. Activation in the LIVER and TUMORS
What is capecitabine?
A pro-drug of 5FU
Name the two enzymes in liver activation of capecitabine.
capecitabine +(CARBOXYESTERASE) --> 5'-DFCR + (CYTIDINE DEAMINASE) --> 5'-DFUR
Name the three enzymes in tumor activation of capecitabine.
capecitabine +(CARBOXYESTERASE) --> 5'-DFCR + (CYTIDINE DEAMINASE) --> 5'-DFUR + (T/U PHOSPHORYLASE) --> 5FU
Capecitabine therapeutic uses (two).
1. Colorectal cancer
2. Metastatic brest cancer
Hand-Foot Syndrome - a chronic dose limiting toxicity.
What two pyrimidine anti-metabolie drugs are analgous pro-drugs?
Gemcitabine and Ara-C
Activated form of Ara-C in tumors is called?
What happens to Ara-CTP in tumor cells?
- It binds to DNA polymerase, inhibiting/stalling DNA synthesis.
- Incorporated into DNA and terminates DNA strand elongation.
How does Ara-CTP terminate DNA strand elongation when incorporated into DNA?
Arabinose cannot form 3'-5' phosphodiester bond
Although Ara-C and gemcitabine are similar pro-drugs, what
cancer is Ara-C used for v. Cancer that gemcitabine is used for.
Ara-C = AML
Gemcitabine = pancreatic cancer
What two organs contain high levels of cytidine deaminase (CDA), which deaminate/inactivate Ara-C - resulting in residual AML in these two organs.
Spleen and liver.
Comparable aspects of gemcitabine and Ara-C
1. *Metabolic activation
2. *Metabolic inactivation
4. inhibit DNA polymerase via chain termination
5. IV administration
6. Dose limiting toxicities
Co-treat 5-FU with what atwo other drugs?
Leucovorin and MTX.