Design of Adjuvant Chemotherapy Based on Target Cell Determinants of Drug Action: Possibilities and Limitations

Abstract

The traditional approach to surgical adjuvant chemotherapy is to select a drug or combination of drugs that have been shown to be effective against advanced disease of the tumor type being treated and to use them in a prospective randomized clinical trial. Such trials frequently involve a large number of patients treated over several years. Another conceptual approach is discussed herein, namely attempting to predict at the time of surgery the specific sensitivity of the tumor and to treat each patient with chemotherapy designed for that individual. Such an approach is in its infancy and may finally prove logistically impracticable, but its conceptual appeal is such that at this time it must be pursued so that its validity may be verified. At the present state of knowledge it seems reasonable to assume that the selective toxicity of anticancer drugs depends on a multiplicity of factors [3]. Indeed, the action of a drug in target cells may be determined by such factors as (1) binding to, and transport through, the plasma membrane(2) activation inside the cell or a cell compartment, (3) regulatory mechanisms at the proximal site of action potentially leading to adaptation of repair, (4) the cascade of changes that take place as a result of the perturbation of a network of enzymes within a close metabolic pathway and the influence on these changes exerted by intracellular or extracellular factors through modifications in metabolite pools, (5) the rate of decrease of active drug concentration in the cell, (6) the metabolic requirements of the target cell as related to cell function or kinetics, and (7) the effects of agents administered concurrently. In addition to determinants that operate primarily in the target cell population, drug kinetics and metabolic disposition in the whole body may affect cellular toxicity inasmuch as they determine drug or active metabolite availability to target cells as a function of time. Homeostatic mechanisms such as hormonal influences may also modify the metabolism of target cells and thus affect their sensitivity to a drug. It is, therefore, not surprising that a great deal of individual variability in response to a drug is commonly observed among patients with the same histopathologic and clinical type of tumor.

Article

The data from this Center discussed were obtained in studies supported in part by USPHS Grants CA-13038, CA-18420, CA-21071, CA-5834 and CA-18499.