Anticancer Drugs

PRINCIPLES AND DEFINITIONS

Log-Kill Hypothesis

Cytotoxic actions ofanticancer drugs follow first-orderkinetics: Theykilla fixed percentage oftumor cells, not a fixed number one rationale for drug combi­ nations.

Growth Fraction

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

Cell-Cycle Specificity

•Drugs that act specifically on phases ofthe cell cycle are called cell-cycle specific (CCS) and are more effective in tumors with high-growth frac­ tion (leukemias, lymphomas).

•Drugs 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.

G2 phase

Bleomycin

Figure IX-1 -1 . Cell-Cycle Specificity of Anticancer Drugs

Section IX • Anticancer Drugs

Definition ofabbreviations: BMS, bone marrow suppression; CCS, cell-cycle specific; CHF, congestive heart failure; GI, gastrointestinal.

Clinical Correlate

Thymineless Death of Cells

Flucytosine (FC) and 5-fluorouracil (5-FU) are bioactivated to 5-fluorodeoxyuridine (5-FdUMP), which inhibits thymidylate synthetase "thymineless death" of fungal cells (FC) or neoplastic cells (5-FU).

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Chapter 1 • Anticancer Drugs

TOXICITY OF ANTICANCER DRUGS

Table IX-1-2. Other Dose-Limiting or Distinctive Toxicities

*Less BMS-"marrow sparing"

•Rapidly proliferating cells, such as the bone marrow, gastrointestinal tract mucosa, hair follicles, and gonads are the most sensitive to cyto­ toxic drugs.

•Most often bone marrow suppression (BMS) is dose limiting.

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

•Colony-stimulating factors, erythropoietin, and thrombopoietin can be supportive ---infections7J, and need for antibiotics (see table below).

Table IX-1-3. Clinical Uses of Cytokines

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Section IX • Anticancer Drugs

RESISTANCE TO ANTICANCER DRUGS

Another rationale for combination drug regimens in cancer is to prevent or delay the emergence ofresistance.

Table IX-1-4. Modes of Resistance to Anticancer Drugs

Chapter Summary

•The "log-kill" hypothesis states that cytotoxic anticancer agents kill a certain percentage, not a fixed number, of cells.

•Cytotoxic drugs are most effective against rapidly dividing cells.

•Drugs 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.

•Drugs that act on nonproliferating cells are dose-dependent and cell-cycle­ independent.

•Rationales forcombination 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.

•Rapidly proliferating normal cells are more sensitive to cytotoxic drugs.

Bone marrow suppression often determines the upper limit oftolerable chemotherapy. Table IX-1-1 lists mechanisms of action, selected clinical uses, and side effects of major anticancer drugs. Table IX-1-2 shows the dose-limiting and distinctive toxicities of anticancer drugs.

•Table IX-1-4 summarizes the modes of resistance developed by cancers toward specific anticancer drugs.

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1 . Which o f the following chemotherapeutic drugs inhibits the polymeriza­ tion of microtubules but is not associated with causing bone marrow sup­ pression?

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 ofthe following agents is most likely to be protective against the toxicity of doxorubicin?

A.Amifostine

B.Dexrazoxane

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.Gz

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 • 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 leu­ kopenia, but no bacteria or crystalluria. Ifthe symptoms experienced by the patient are drug related, what is the most likely cause?

A. Cyclophosphamide

D.Prednisone

E.Tamoxifen

Answers

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 ofthe cell-cycle.

4.Answer:E. Methotrexate is a widely-used chemotherapydrug that is also com­ monly used in moderate to severe rheumatoid arthritis. It inhibits the enzyme dihydrofolate reductase (DHFR) thereby reducing the synthesis of tetrahydro­ folate 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 byliver P450 to form cytotoxic metabolites. Mesna is the antidote used to detoxify acrolein and protect against hemorrhagic cystitis.

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