52: Miscellaneous Chemotherapeutics

INTRODUCTION

The anthracyclines,^24,120 nitrogen mustards,^{1,38,55,60,90,130} and platinum-based complexes^{32,35,59,64,68,83,108,111,124} are discussed in this chapter because of their increased likelihood for overdose based on past reports and current clinical use.

ANTHRACYCLINES

Daunorubicin and doxorubicin share many common indications for cancer therapy, but they differ in that doxorubicin is used in solid tumors such as breast carcinoma, and daunorubicin is used in hematogenous malignancies, such as acute myelogenous leukemia and acute lymphocytic leukemia. The clinical toxicity of the older anthracyclines is limited by the use of less toxic structural analogs (eg, epirubicin, idarubicin) and liposome-encapsulated formulations (pegylated liposomal doxorubicin).

Pharmacology

The chemotherapeutics derived from the bacterium Streptomyces are dactinomycin, daunorubicin, doxorubicin, bleomycin, mitomycin, and plicamycin. Only plicamycin crosses the blood–brain barrier. Doxorubicin has a protein binding of 75% to 80%, a volume of distribution of 28.0 ± 3.3 L/kg, and a terminal elimination half-life of approximately 30 hours.⁴³ The liposome encapsulated formulation of doxorubicin has a prolonged terminal half-life of 50 hours because of a slower clearance compared with the nonencapsulated formulation. Doxorubicin and daunorubicin are both eliminated by the liver, and their dosages are decreased in patients with hepatic insufficiency. Delayed drug elimination contributes to increased area under the concentration versus time curve and peak concentration, both of which are associated with myelosuppression and cardiac toxicity, respectively.⁶⁶ The mechanism of therapeutic action of the anthracyclines is attributed to DNA intercalation¹⁰¹ and inactivation of topoisomerase II.¹¹⁷ These xenobiotics are metabolized to active metabolites, which have lesser degrees of activity than their parent compounds. The liposomal-encapsulated formulation of doxorubicin has limited selective activity at the tumor compared to nontumor sites in the body, such as the heart and bone marrow because of its particle size (100 A°).^86,98 A typical dose schedule for daunorubicin is 30 to 60 mg/m² daily for 3 days; for doxorubicin, 45 to 60 mg/m² every 18 to 21 days; and for pegylated liposomal doxorubicin, 50 mg/m² every 28 days.

Pathophysiology

The red anthracycline antibiotics—dactinomycin and doxorubicin—are associated with cardiotoxicity, which limits their therapeutic use. The associated toxicity is caused by a different mechanism than the therapeutic effects.¹¹⁷ The purported mechanism of cardiac toxicity is from the formation of free radicals and impaired intracellular calcium.^84,91 Doxorubicin and dactinomycin are quinone derivatives and can be reduced to free radicals. These metabolites are extremely cytotoxic through the promotion of lipid peroxidation in a manner similar to paraquat and bleomycin. The limited efficacy of free radical scavengers (α-tocopherol, N-acetylcysteine) for anthracycline cardiotoxicity led to an understanding of the importance of iron as a cofactor for these free ...