Introduction

Conventionally dosed chemotherapy regimens are capable of obtaining high rates of response in a wide variety of malignancies. For example, the majority of patients with previously untreated metastatic breast cancer will experience significant tumor shrinkage. This is encouraging because tumor volume regression usually diminishes the symptoms of cancer: if this benefit is not counterbalanced by drug toxicity, the patient's quality of life improves (Coates, Gebski and Bishop, 1987). Nevertheless, complete responses in breast cancer and other diseases are less frequent, and the remissions, when achieved, are rarely durable. The cellular mechanisms by which tumors escape eradication by chemo-therapy are collectively termed drug resistance. Drug resistance is expressed in two forms: biochemical or absolute resistance, by which a cell cannot be killed with any dose level of drug; and relative resistance, by which the cell might require a higher level of drug to be killed. Absolute resistance cannot be overcome by any strategy that manipulates dose or schedule. Relative resistance, in distinction, is amenable to such manipulations, and is a topic of major practical importance in modern oncology. Manipulations of dose, and to some extent schedule, have long been demonstrated to be of value in the treatment of hematological malignancies. Lately, the value of induction and late intensification, a strategy hypothesized on theoretical grounds to be of potential value (Norton and Simon, 1977), has proven to be of benefit in the treatment of some forms of acute leukemia (Zittoun et al., 1995).