Cancer chemotherapy 1.0

Question 1

What is the log-kill hypothesis?

Answer 1

Chemotherapuetics kill a constant fraction (1st order kinetics) of cells with each dose given.

NOTE: Disseminated cancers have high growth fraction so respond well to chemotherapeutics, while solid cancer tumors are opposite.

Question 2

How do you appropriately choose drugs to combat cancer?

Answer 2

1. Each drug should be active when used alone
2. Each drug should have different mechanisms of action
3. Cross-resistance between drugs should be minimal
4. Drugs should have different toxic effects
5. Optimum scheduling

Question 3

What is the main mechanism of resistance?

Answer 3

Increased expression of Multiple Drug Resistance (MDR-1) gene to cell surface p-glycoprotein; used in drug efflux

Question 4

What does MDR pump out?

Answer 4

Natural drug products:

1. Anthracyclines (doxorubicin, daunorubicin)
2. Plant alkaloids (vinblastin, vincristine, etopside, topotecan, placitaxel)
3. Imantinib

Question 5

What drugs inhibit MDR?

Answer 5

Verapamil, quinidine, cyclosporine

Question 6

What are the six steps of resistance?

Answer 6

1. Increased expression of MDR-1 gene to cell surface p-glycoprotein.
2. Altered drug metabolism (increase cytochrome p450, etc.)
3. Altered drug target
4. Increased repair of drug-induced damage.
5. Increased trapping agents (think thiols)
6. Compartmentalization (Acidic drugs are trapped in basic environments, etc.)

Question 7

Use of Aldesleukin (IL-2) in bone marrow depression?

Answer 7

Increased lymphocyte differentiation and NKs, used in renal cell carcinoma and melanoma

Question 8

Use of Interleukin 11 in bone marrow depression?

Answer 8

Increased platelet formation

Question 9

Use of Filgrastim (G-CSF) in bone marrow depression?

Answer 9

Increased granulocytes

Question 10

Use of Sargramostim in bone marrow depression?

Answer 10

Increased granulocytes and macrophages

Question 11

Use of Erythropoetin in bone marrow depression?

Answer 11

Increased RBCs

Question 12

Use of Thrombopoetin in bone marrow depression?

Answer 12

Increased platelets

Question 13

Drug to treat early induced chemotherapy induced vomiting?

Answer 13

Odansetron; 5-HT3 antagonist (can also use Granisetron)

Question 14

Drug to treat delayed induced chemotherapy induced vomiting?

Answer 14

Aprepitant; NK-1 antagonist (used after 24 hours)

Question 15

What drugs are used in combination to treat chemotherapy induced vomiting?

Answer 15

Odansetron, Aprepitant, and Dexamethasone

Question 16

Drugs that act on S-phase (DNA synthesis) of cell cycle?

Answer 16

Cytarabine, 6-mecaptopurine, 6-thioguanine, Methotrexate, Hydroxyurea, 5-FU

(NOTE: anything we saw in Biochem)

Question 17

Drugs that act on M-phase (mitosis) of cell cycle?

Answer 17

Vinblastine, Vincristine, Paclitaxel

Question 18

Drugs that act on G2-phase (synthesis of cell components for mitosis) of cell cycle?

Answer 18

Bleomycin

Question 19

Drugs that act on G0-phase (resting phase) of cell cycle?

Answer 19

Alkylating Agents, and Anti-tumor Antibiotics

Question 20

Where does etopside act?

Answer 20

On the S-G2 entry, the S check point.

Question 21

What MOA do 6-thioguanine, Methotrexate, and 6-mecaptopurine have in DNA synthesis?

Answer 21

Inhibit purine ring synthesis, so no purines/pyramidines can be formed.

Question 22

What MOA does Hydroxyurea have in DNA synthesis?

Answer 22

Inhibit ribonucleotide reductase, so deoxyribonucleotides can’t be formed.

Question 23

What MOA do Methotrexate and 5-Flourouracil share in DNA synthesis?

Answer 23

Inhibit dTMP synthesis, so deoxyribonucleotides can’t be formed.