Therapeutic Index and the Cancer Stem Cell Paradigm

Abstract

The therapeutic index of antineoplastic therapies has traditionally been driven by the concepts of maximally tolerated dose and treatment response. When the tumor is viewed as homogeneous with respect to response, and response is defined by tumor regression, there are many effective antineoplastic regimens. However, the persistent problem of cancer recurrence in the face of apparently successful therapy, and the recognition that tumors are at least as heterogeneous as normal tissue, necessitates a reevaluation of the concept of therapeutic index from the standpoint of the most therapy resistant cells within the tumor vs. the maximal disruption that critical tissues can withstand. The cancer stem cell paradigm helps explain some of the heterogeneity within tumors and posits that therapy resistance originates with the strategies by which normal tissue stem cells protect themselves from toxic insults. The recognition that at any given time, self-renewing (tumorigenic) tumor cells are protected by mechanisms, such as multiple drug resistance (MDR) transporters, detoxifying enzymes, a resting state, and niche effects, ensures that a proportion of tumor cells will have toxicity profiles similar to normal tissue stem cells. The problem of therapeutic index is compounded by the fact that clonogenic cancer cells have merely to survive and reactivate to perpetuate the neoplasm, whereas vital organ functions cannot be compromised for long without lethal consequences. In this chapter, we review the evolving concepts of therapeutic index, maximal tolerated dose, and tumor heterogeneity in the context of the cancer stem cell paradigm. Primary clinical isolates are used to provide examples of heterogeneity within the tumorigenic compartment, within cells that resist therapy, and within cells protected by MDR transporters.