книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Learning Objectives

Define the mechanisms of anti-cancer drugs

Demonstrate an understanding of the toxicity of anticancer drugs

PRINCIPLES AND DEFINITIONS

Log-Kill Hypothesis

Cytotoxic actions of anticancer drugs follow first-order kinetics: They kill a fixed percentage of tumor cells, not a fixed number → one rationale for drug combinations.

Growth Fraction

Cytotoxic drugs are more effective against tumors that have a high growth fraction (large percentage actively dividing). Normal cells with high growth fraction (e.g., bone marrow) are also more sensitive to anticancer drugs.

Cell-Cycle Specificity

λDrugs that act specifically on phases of the cell cycle are called cell-cycle specific (CCS) and are more effective in tumors with high-growth fraction (leukemias, lymphomas).

λDrugs that are cell-cycle nonspecific (many bind to and damage DNA) can be used in tumors with low-growth fraction, as well as tumors with high-growth fraction.

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Section IX λ Anticancer Drugs

Table IX-1-2. Targeted Anticancer Drugs

TOXICITY OF ANTICANCER DRUGS

Table IX-1-3. Other Dose-Limiting or Distinctive Toxicities

λRapidly proliferating cells, such as the bone marrow, gastrointestinal tract mucosa, hair follicles, and gonads are the most sensitive to cytotoxic drugs.

λMost often bone marrow suppression (BMS) is dose limiting.

λAnticancer drug dosage is usually carefully titrated to avoid excessive neutropenia (granulocytes <500/mm3) and thrombocytopenia (platelets <20,000/mm3).

λColony-stimulating factors, erythropoietin, and thrombopoietin can be supportive →↓ infections and need for antibiotics (see table below).

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Chapter 1 λ Anticancer Drugs

Table IX-1-4. Clinical Uses of Cytokines

Chapter Summary

λThe “log-kill” hypothesis states that cytotoxic anticancer agents kill a certain percentage, not a fixed number, of cells.

λCytotoxic drugs are most effective against rapidly dividing cells.

λDrugs that act on proliferating cells are cell-cycle specific and are usually also cycle-phase specific. Figure IX-1-1 illustrates the cell cycle and the drugs acting in each cycle phase.

λDrugs that act on nonproliferating cells are dose-dependent and cell-cycle– independent.

λRationales for combination drug usage are that each drug will independently kill a fixed percentage and that one drug will still kill a cancer cell that has developed resistance to a different drug in the cocktail.

λRapidly proliferating normal cells are more sensitive to cytotoxic drugs.

Bone marrow suppression often determines the upper limit of tolerable chemotherapy. Table IX-1-1 lists mechanisms of action, selected clinical uses, and side effects of major anticancer drugs. Table IX-1-3 shows the doselimiting and distinctive toxicities of anticancer drugs.

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1.Which of the following chemotherapeutic drugs inhibits the polymerization of microtubules but is not associated with causing bone marrow suppression?

A.Cyclophosphamide

B.Cisplatin

C.5-Fluorouracil

D.Vinblastine

E.Vincristine

2.A patient with non-Hodgkin lymphoma is to be started on the CHOP regimen, which consists of cyclophosphamide, doxorubicin, vincristine, and prednisone. Which one of the following agents is most likely to be protective against the toxicity of doxorubicin?

A.Amifostine

B.Dexrazoxane

C.Leucovorin

D.Mesna

E.Vitamin C

3.A drug used in a chemotherapy regimen works by complexing with iron and oxygen to promote DNA strand breaks. While on this drug the patient must be monitored closely due to pulmonary side effects. In what phase of the cell cycle does this drug work?

A.G1

B.S

C.G2

D.M

E.This drug is not cell-cycle dependent.

4.Resistance to which anticancer drug, used in leukemias, lymphomas, and breast cancer, is associated with increased production of dihydrofolate reductase?

A.Doxorubicin

B.Vinblastine

C.6-MP

D.Cytarabine

E.Methotrexate

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Section IX λ Anticancer Drugs

5.A patient undergoing cancer chemotherapy has an increase in urinary frequency with much discomfort. No specific findings are apparent on physical examination. Laboratory results include hematuria and mild leukopenia, but no bacteria or crystalluria. If the symptoms experienced by the patient are drug related, what is the most likely cause?

A.Cyclophosphamide

B.5-FU

C.Methotrexate

D.Prednisone

E.Tamoxifen

Answers

1.Answer: E. Only two of the drugs listed do not cause bone marrow suppression: cisplatin and vincristine. Only two of the drugs listed inhibit microtubule plymerization: vinblastine and vincristine. The drug that fits both categories is vincristine. Patients on vincristine should be monitored for neurotoxicity, especially peripheral neuropathies.

2.Answer: B. Dexrazoxane is an iron-chelating agent that prevents the formation of free radicals and reduces the cardiotoxicity of anthracyclines such as doxorubicin. Amifostine is protective of nephrotoxicity caused by cisplatin. Folinic acid (leucovorin) reduces the toxicity of methotrexate because it provides an active form of folate to normal (nonneoplastic) cells, resulting in “leucovorin rescue.” Mesna, which inactivates acrolein, is available for protection against hemorrhagic cystitis in patients treated with cyclophosphamide.

3.Answer: C. It helps to know which anticancer drugs are cell-cycle specific and which have characteristic toxicities. Bleomycin forms a complex with iron and oxygen and promotes DNA strand breaks. Its major side effects are pulmonary

toxicities including pneumonitis and fibrosis. It acts acting mainly in the G2 phase of the cell-cycle.

4.Answer: E. Methotrexate is a widely-used chemotherapy drug that is also commonly used in moderate to severe rheumatoid arthritis. It inhibits the enzyme dihydrofolate reductase (DHFR) thereby reducing the synthesis of tetrahydrofolate and thus inhibiting DNA synthesis. Resistance occurs when cancer cells upregulate DHFR or alter the binding of methotrexate to DHFR.

5.Answer: A. These symptoms are those of a mild case of hemorrhagic cystitis. Bladder irritation with hematuria is a fairly common complaint of patients treated with cyclophosphamide. It appears to be due to acrolein, a product formed when cyclophosphamide is bioactivated by liver P450 to form cytotoxic metabolites. Mesna is the antidote used to detoxify acrolein and protect against hemorrhagic cystitis.

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SECTION X

Immunopharmacology