Determinants of response in cancer chemotherapy and modulation of anticancer activity

Abstract

The Symposium on Determinants of Response in Cancer Chemotherapy and Modulation of Anticancer ActiviQ was focused on a discussion of selective biochemical pharmacological and biological parameters which may affect the response of individual patients to drugs and may provide a basis for the design of new treatments. Elucidation of the biochemical and pharmacological determinants of drug action in tumor and normal tissues is a well recognized goal in any attempt to improve the design of chemotherapy. During the last ten years, however, it has become increasingly evident that primary drug action in a cell population is determined by a multiplicity of factors and, in addition, that in many cases a new metabolic equilibrium is established in a target cell as a result of a cascade of effects following the proximal action of a drug. Thus knowledge of the secondary metabolic consequences of a primary effect is essential in developing optimal treatments with a drug alone or in combination with other drugs. The well known heterogeneity of tumor cell populations and the consequences of the relative genetic instability of tumor cells are additional complicating factors in the rational design of cancer chemotherapy (5). The potential utility of stem cell assays and cell kinetics in assessing sensitivity of cell subpopulations to agents and treatments was stressed by Stephens (6) and the difficulties and uncertainties related to clonogenic stem cell assays recognized; it was emphasized, however, that these studies are important in order to clarify fundamental phenomena regulating the biology of neoplastic cell populations. Kinetics of tumor cell repopulation repair of ‘potentially lethal damage’, cloning of human tumors and characterization of drug resistance were particularly emphasized. Studies of the type described are leading to a more detailed understanding of heterogeneous populations of tumour cells. A basic problem in cancer therapy is that tumors that initially are successfully treated have the ability to adapt by generating resistant variants. It is the instability and heterogeneity of tumor cell populations that confers on them the ability to react in this way. A major advantage of cell cloning assays is that they allow one to detect growth from individual tumor cells and to explore their clonal heterogeneity.