Chemo lecture 1

Question 1

what are the PYRIMIDINE anti-metabolite drugs that inhibit DNA synthesis?

Answer 1

• 5 Fluorouracil
• Capecitabine
• Cytarabine (Ara-C)
• Gemcitabine

Question 2

Given AFTER the tumor is removed by surgery?

Answer 2

Adjuvant chemo

Question 3

What is the goal of adjuvant chemo

Answer 3

prevent cancer reoccurance

Question 4

Given PRIOR to surgery to remove tumor

Answer 4

Neoadjuvant chemo

Question 5

What is the goal of Neoadjuvant chemo

Answer 5

shrink the tumor so that the surgery is less extensive

Question 6

Given specifically to address symptom management without expecting to significantly reduce the cancer

Answer 6

Palliative therapy

Question 7

What is the active metabolite of 5-FU that inhibits thymidylate synthase and therefore inhibits dTMP synthesis?

Answer 7

FdUMP

Question 8

What is the active metabolite of 5-FU that damages DNA?

Answer 8

FdUTP

Question 9

What is the active metabolite of 5-FU that damages RNA?

Answer 9

FUTP

Question 10

what is the ORAL pro drug of 5FU

Answer 10

Capecitabine

Question 11

What drug gets converted by kinases to nucleotide analogs and inhibits DNA synthesis

Answer 11

Gemcitabine

Question 12

What drug gets converted by kinases to AraCTP and inhibits DNA synthesis

Answer 12

Cytarabine (Ara C)

Question 13

What cancers do you used 5FU for?

What is the topical use

Answer 13

Solid tumors: colorectal and other GI
Breast, ovarian carcinomas

-topical for Basal cell carcinoma

Question 14

what cancers do you use Capecitabine for?

Answer 14

• Colorectal

- metastatic breast cancer that is resistant to paclitaxel and anthracycline)

Question 15

cancer for Gemcitabine

Answer 15

pancreatic

Question 16

cancer for Cytarabine (Ara C) and what do you use this with

Answer 16

• Acute myelogenous leukemia

- used with 6-thioguanine and daunorubicin

Question 17

Dose limiting toxicity of 5FU

Answer 17

• Severe GI intolerance
• Mucositis
• Myelosuppression

Question 18

Dose limiting toxicity of Capecitabine?

Answer 18

similar to 5FU plus hand-foot syndrome

Question 19

Dose limiting toxicity of Gemcitabine

Answer 19

myelosuppression - neutropenia

Question 20

Dose limiting toxicity of Cytarabine (Ara C)

Answer 20

Severe myelosuppression - granulocytopenia

Question 21

Clinical use of 5FU

Answer 21

treat advanced colorectal cancer and adjuvant therapy of early stage colon cancer
-also other solid tumors (esophageal, gastric, pancreatic, colorectal, anal, and hepatocellular)

Question 22

What is 5-FU usually used in combo with

Answer 22

folate antagonists and other chemo drugs, radiation, and surgery

Question 23

5FU is an analog of what

Answer 23

uracil and thymidine (pyrimidines)

Question 24

Tumor cells activate 5FU through what enzymes

Answer 24

Thymidine phosphorylase –>5FUdR and then

Thymidine Kinase –> 5FdUMP

Question 25

What does the 5FU metabolite FdUMP do?

Answer 25

- inhibits thymidylate synthase - Depletes dTMP (and dTTP downstream) - Distorts dNTP pools - CAUSES THYMINELESS DEATH

Question 26

Pyrimidine antimetabolite drugs target what phase of the cell cycle

Answer 26

S phase

Question 27

Co treatment of 5FU with what 2 things can increase the anticancer activity?

Answer 27

Leucovorin and methotrexate

Question 28

explain the selective toxicity of 5FU in tumors

Answer 28

thymidine and uracil phosphorylase activity in tumor tissue is greater than in normal tissue

Question 29

what is the most common mechanism of resistance to 5FU

Answer 29

alterations in thymidylate synthase -tumors with higher levels of thymidylate synthase are relatively more resistant to 5FU

Question 30

what enzyme in the liver metabolizes 5FU? | What does it turn into?

Answer 30

dihydropyrimidine dehydrogenase | -DHFU

Question 31

What allelic variation can slow 5FU clearance and aggrevate its systemic toxicity

Answer 31

DPYD gene . . .DPD deficiency | -hereditary thymine-uraciluria or familial pyrimidinemia

Question 32

what are the symptoms of DPD deficiency

Answer 32

none . . to seizures | -also 5FU toxicity

Question 33

What are the symptoms of the 5FU toxicity from those with DPD deficiency

Answer 33

- cerebellar ataxia | - neurologic symptoms

Question 34

what is on Capecitabine that makes it orally bioavailable

Answer 34

carbamate appendage

Question 35

what are the 2 enzymes in order that activate capecitabine in the LIVER to produce 5'-DFUR

Answer 35

- Carboxyesterase 1A1 and 2 | - Cytidine deaminase

Question 36

what enzyme in TUMORS convert 5'-DFUR to 5FU?

Answer 36

thymidine phosphorylase

Question 37

Clinical uses for Capecitabine

Answer 37

- advanced metastatic colon cancer | - advanced breast cancer . .slows progression

Question 38

Ara-C and Gemcitabine are chemical analogs of what

Answer 38

Cytidine

Question 39

how do Ara-C and Gemcitabine enter tumors cells?

Answer 39

hENT1: equilibrative nucleoside transporter 1

Question 40

what are the 3 enzymes that turn Ara-C and Gemcitabine into triphosphates theat then inhibit DNA polymerase?

Answer 40

- Deoxycytidine kinase - deoxycytidylate kinase - nucleoside diphosphate kinase

Question 41

mechanism of resistance to Ara-C

Answer 41

inactivation by pyrimidine nucleotidase and cytidine deaminase in tumor cells

Question 42

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

Answer 42

Spleen and Liver

Question 43

Differences b/t Ara-C and Gemcitabine

Answer 43

- 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