CASE 50

A 60-year-old woman presents to her oncologist for follow-up of her metastatic ovarian cancer. She was diagnosed approximately a year ago. Initial treatment included surgery and a cisplatin-based chemotherapy regimen. Unfortunately, she was recently diagnosed with recurrent disease. She currently takes only promethazine as needed for nausea and a combination of hydrocodone and acetaminophen as needed for pain. On examination she appears comfortable. She has a thin growth of hair on her scalp. Her abdomen has a well-healed surgical scar but is otherwise unremarkable. The remainder of her examination is normal. She is diagnosed with recurrent metastatic ovarian cancer and placed on a chemotherapeutic regimen that includes paclitaxel.

What is the mechanism of action of paclitaxel?

What are the common adverse reactions seen with paclitaxel?

ANSWERS TO CASE 50:

Plant Anticancer Alkaloids

Summary: A 60-year-old woman with recurrent metastatic ovarian cancer is being treated with combination chemotherapy including paclitaxel.

Mechanism of action of paclitaxel: Promotes formation and inhibits disassembly of stable microtubules, resulting in inhibition of mitosis.

Adverse effects of paclitaxel: Myelosuppression, peripheral neuropathy, GI side effects.

CLINICAL CORRELATION

Paclitaxel is a chemical derived from bark of the Pacific yew tree. Its chemotherapeutic effect is based on its ability to inhibit mitosis. Its mechanism of action is to promote the formation of and inhibit the disassembly of stable microtubules in the M phase of cell division. Paclitaxel is used for the treatment of metastatic ovarian, breast, and small cell lung cancers. It is metabolized in the liver and excreted in the bile. Myelosuppression and peripheral neuropathy are often dose-limiting toxicities, and hypersensitivity reaction, GI side effects, and hair loss are common.

APPROACH TO:

Pharmacology of Plant Anticancer Alkaloids

OBJECTIVES

1. List the plant alkaloids used as cancer chemotherapeutic agents and describe their mechanisms of action, therapeutic uses, and adverse effects.

DEFINITIONS

Microtubules: Structures composed of tubulin polymers that are critical components of the cell cytoskeleton and the mitotic spindle.

Topoisomerases (I and II): Nuclear enzymes that cleave and unwind DNA to relieve torsional stress. They are necessary for DNA replication and RNA transcription. Topoisomerase II is also necessary for mitosis.

DISCUSSION

Class

Table 50–1 describes selected anticancer drugs. See also Case 49.

TABLE 50–1 • SELECTED ANTICANCER DRUGS DERIVED FROM NATURAL PRODUCTS (MAY BE COMBINED WITH OTHER ANTICANCER AGENTS)

Structure

Vinblastine and vincristine are derived from the periwinkle plant (Vinca rosea).

Vinorelbine is a semisynthetic vinca alkaloid.

Paclitaxel is a complex diterpene derived from the Western and European yew (Taxus brevifolia and Taxus baccata).

Etoposide is a semisynthetic podophyllotoxin, an extract from the Mandrake root (Mandragora officinarum) or May apple root (Podophyllum peltatum).

Mechanism of Action

Vinca alkaloids (vinblastine, vincristine, vinorelbine): Bind tubulin to terminate microtubule assembly and cause cell arrest in metaphase (M) by blocking mitosis and chromosomal aggregation and causing mitotic spindle dissolution.

Taxanes (paclitaxel): Bind to microtubules resulting in their stabilization and in an enhancement of aberrant tubulin polymerization that result in cytotoxicity, including mitotic arrest.

Epipodophyllotoxins (etoposide): Reversibly complex with the enzyme topoisomerase II that results in double-stranded DNA strand breakage.

Administration

Hypersensitivity to paclitaxel can be reduced by premedication with dexamethasone and histamine H₁- and H₂-receptor blockers.

Pharmacokinetics

Abraxane is a formulation of paclitaxel bound to albumin, approved for treatment of breast cancer, that does not cause hypersensitivity reactions, and is less likely to result in severe neurotoxicity or myelosuppression.

Vinca alkaloid hepatic metabolism is decreased by L-asparaginase.

Paclitaxel is metabolized extensively by hepatic P450 enzymes (CYP450 3A4) with potential, therefore, of drug-drug interactions. Dose reduction is necessary for patients with liver dysfunction.

Etoposide is 95 percent plasma protein bound. Dose reduction is necessary for patients with renal dysfunction.

COMPREHENSION QUESTIONS

50.1 Which of the following classes of cancer chemotherapeutic agents bind tubulin and cause arrest of cells in metaphase?

A. Alkylating agents

B. Antimetabolites

C. Taxanes

D. Vinca alkaloids

50.2 Abraxane is often used to reduce hypersensitivity to which of the following drugs?

A. Etoposide

B. Paclitaxel

C. Vinblastine

D. Vincristine

50.3 Neurotoxicity is dose-limiting for which of the following drugs?

A. Etoposide

B. Methotrexate

C. Paclitaxel

D. Vincristine

ANSWERS

50.1 D. Vinca alkaloids (vinblastine, vincristine, vinorelbine) bind tubulin to terminate microtubule assembly and cause cell arrest in metaphase (M) by blocking mitosis and chromosomal aggregation and causing mitotic spindle dissolution. Alkylating agents form covalent bonds with adjacent guanine residues and inhibit DNA replication and transcription. Antimetabolites compete with naturally occurring compounds for binding sites on enzymes or else become incorporated into DNA or RNA to interfere with cell growth and division. Taxane (paclitaxel) binds to microtubules resulting in their stabilization and in an enhancement of aberrant tubulin polymerization that result in cytotoxicity, including mitotic arrest.

50.2 B. Hypersensitivity to paclitaxel can be reduced by abraxane, a formulation of paclitaxel bound to albumin.

50.3 D. Neurotoxicity is dose limiting for vincristine. Myelosuppression is dose limiting for paclitaxel, etoposide, and methotrexate.

PHARMACOLOGY PEARLS

The plant anticancer alkaloids act on the microtubules, during the mitosis (M) phase of the cell cycle.

The vinca alkaloids cause sensory and motor toxicities with the following order of activity: vincristine is greater than vinblastine, which is greater than vinorelbine.

Neurotoxicity is dose limiting for vincristine, whereas myelosuppression is dose limiting for paclitaxel, etoposide, and methotrexate.

REFERENCES

Abal M, Andreu JM, Barasoain I. Taxanes: microtubules and centrosome targets, and cell cycle dependent mechanism of action. Curr Cancer Drug Targets. 2003;3(3):193–203.

Gradishar WJ. Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother 2006;7(8):1041–53.