Introduction

The use of cytotoxic drugs is a relatively recent advance in the treatment of cancer. Prior to the 20th century, essentially the only treatment for cancer was surgical removal of the tumor. Not until the discovery of the mustards in the 1940s did the use of chemicals become promising in the treatment of cancer (Marshall, 1964; DeVita, 1978). Over the past five decades new cytotoxic agents have been developed, either by isolating chemicals from natural products, such as the vinca alkaloids, or by synthesizing novel compounds, such as folic acid antagonists. In spite of the discovery of almost a hundred new compounds that are used in the clinic today, most cancers that have spread from the original site of origin are considered incurable. Many of these drugs are capable of inducing remissions in numerous types of cancers; however, these remissions are usually not permanent and the patient ultimately dies of drug-resistant disease. The development of drug-resistant cancers is considered to be the most significant obstacle to the cure of cancer today.

One of the most well-documented causes of drug resistance is the multidrug resistant phenotype (MDR) (Gerlach et al., 1986; Dalton and Miller, 1991). This phenotype is due to the overexpression of P-glycoprotein (Pgp) the protein encoded by the human MDR1 gene (Gros et al., 1986; Ueda et al., 1987). The MDR1 gene is a member of the ATP-binding cassette superfamily of genes.