Can anticancer therapy be improved by sequential use of cytotoxic and cytostatic (differentiating or immunomodulating) agents to suppress tumor cell phenotypic diversification?

Abstract

The inherently heterogeneous characteristics of most tumor cells and their abilities to undergo rapid phenotypic change represent two of the most formidable obstacles to effective antineoplastic therapies. Most neoplasms, by the time they are diagnosed, are comprised of heterogeneous cell subpopulations expressing a wide range of different properties [l-4], including many of those once thought to be uniformly expressed among different neoplastic cells [5]. Such heterogeneity (and the possible rapid appearance of tumor cell clones exhibiting significant differences in cellular phenotype) also extends to therapeutic sensitivities and malignant properties. Thus, tumors that exhibit an initial sensitivity to a particular therapeutic agent can become highly resistant to it and to a variety of other agents, including those that act by mechanisms distinct from the initial treatment. Such tumors can also become more malignant. When this occurs, completely successful therapeutic interventions are rare. The dynamic emergence of tumor cells with diverse phenotypes ensures that some cells will arise in the tumor cell population with enhanced metastatic potential and resistance to a variety of physical and chemical agents. Another important aspect of antineoplastic therapy is that the treatments themselves can modify tumor cell phenotype and cellular heterogeneity and the rates at which variant cell subpopulations are generated. This is due partly to the cytotoxic and mutagenic natures of most antineoplastic therapies and the selection of therapy-resistant tumor cell subpopulations, but it is also attributable to nonmutagenic changes, such as gene amplification and recombination [6], and to the high rates of diversification of surviving cells that often possess unstable phenotypes [4,7,8]. In the latter example, in vitro studies with malignant animal tumors have demonstrated that restricting the diversity of tumor cell subpopulations by treatment with cytotoxic agents under conditions that allow some cell survival leads to enhanced generation of new variant tumor cells, including those that are much more metastatic than the original neoplastic cells [9]. In heterogeneous