Chemo lecture 1 Flashcards
what are the PYRIMIDINE anti-metabolite drugs that inhibit DNA synthesis?
- 5 Fluorouracil
- Capecitabine
- Cytarabine (Ara-C)
- Gemcitabine
Given AFTER the tumor is removed by surgery?
Adjuvant chemo
What is the goal of adjuvant chemo
prevent cancer reoccurance
Given PRIOR to surgery to remove tumor
Neoadjuvant chemo
What is the goal of Neoadjuvant chemo
shrink the tumor so that the surgery is less extensive
Given specifically to address symptom management without expecting to significantly reduce the cancer
Palliative therapy
What is the active metabolite of 5-FU that inhibits thymidylate synthase and therefore inhibits dTMP synthesis?
FdUMP
What is the active metabolite of 5-FU that damages DNA?
FdUTP
What is the active metabolite of 5-FU that damages RNA?
FUTP
what is the ORAL pro drug of 5FU
Capecitabine
What drug gets converted by kinases to nucleotide analogs and inhibits DNA synthesis
Gemcitabine
What drug gets converted by kinases to AraCTP and inhibits DNA synthesis
Cytarabine (Ara C)
What cancers do you used 5FU for?
What is the topical use
Solid tumors: colorectal and other GI
Breast, ovarian carcinomas
-topical for Basal cell carcinoma
what cancers do you use Capecitabine for?
- Colorectal
- metastatic breast cancer that is resistant to paclitaxel and anthracycline)
cancer for Gemcitabine
pancreatic
cancer for Cytarabine (Ara C) and what do you use this with
- Acute myelogenous leukemia
- used with 6-thioguanine and daunorubicin
Dose limiting toxicity of 5FU
- Severe GI intolerance
- Mucositis
- Myelosuppression
Dose limiting toxicity of Capecitabine?
similar to 5FU plus hand-foot syndrome
Dose limiting toxicity of Gemcitabine
myelosuppression - neutropenia
Dose limiting toxicity of Cytarabine (Ara C)
Severe myelosuppression - granulocytopenia
Clinical use of 5FU
treat advanced colorectal cancer and adjuvant therapy of early stage colon cancer
-also other solid tumors (esophageal, gastric, pancreatic, colorectal, anal, and hepatocellular)
What is 5-FU usually used in combo with
folate antagonists and other chemo drugs, radiation, and surgery
5FU is an analog of what
uracil and thymidine (pyrimidines)
Tumor cells activate 5FU through what enzymes
Thymidine phosphorylase –>5FUdR and then
Thymidine Kinase –> 5FdUMP
What does the 5FU metabolite FdUMP do?
- inhibits thymidylate synthase
- Depletes dTMP (and dTTP downstream)
- Distorts dNTP pools
- CAUSES THYMINELESS DEATH
Pyrimidine antimetabolite drugs target what phase of the cell cycle
S phase
Co treatment of 5FU with what 2 things can increase the anticancer activity?
Leucovorin and methotrexate
explain the selective toxicity of 5FU in tumors
thymidine and uracil phosphorylase activity in tumor tissue is greater than in normal tissue
what is the most common mechanism of resistance to 5FU
alterations in thymidylate synthase
-tumors with higher levels of thymidylate synthase are relatively more resistant to 5FU
what enzyme in the liver metabolizes 5FU?
What does it turn into?
dihydropyrimidine dehydrogenase
-DHFU
What allelic variation can slow 5FU clearance and aggrevate its systemic toxicity
DPYD gene . . .DPD deficiency
-hereditary thymine-uraciluria or familial pyrimidinemia
what are the symptoms of DPD deficiency
none . . to seizures
-also 5FU toxicity
What are the symptoms of the 5FU toxicity from those with DPD deficiency
- cerebellar ataxia
- neurologic symptoms
what is on Capecitabine that makes it orally bioavailable
carbamate appendage
what are the 2 enzymes in order that activate capecitabine in the LIVER to produce 5’-DFUR
- Carboxyesterase 1A1 and 2
- Cytidine deaminase
what enzyme in TUMORS convert 5’-DFUR to 5FU?
thymidine phosphorylase
Clinical uses for Capecitabine
- advanced metastatic colon cancer
- advanced breast cancer . .slows progression
Ara-C and Gemcitabine are chemical analogs of what
Cytidine
how do Ara-C and Gemcitabine enter tumors cells?
hENT1: equilibrative nucleoside transporter 1
what are the 3 enzymes that turn Ara-C and Gemcitabine into triphosphates theat then inhibit DNA polymerase?
- Deoxycytidine kinase
- deoxycytidylate kinase
- nucleoside diphosphate kinase
mechanism of resistance to Ara-C
inactivation by pyrimidine nucleotidase and cytidine deaminase in tumor cells
what organs have very high levels of cytidine deaminase and are a biochemical sanctuary for leukemic cells because they inactivate Ara-C to Ara-U
Spleen and Liver
Differences b/t Ara-C and Gemcitabine
- Gem-diphosphate inhibits ribonucleotide reductase and depletes cellular dNTPs
- Ara-C is for acute myelogenous leukemia while Gem iss for pancreatic and non-small cell lung cancer
- Gem causes Drug induced fever and flu like syndrome
