Therapeutic Index and the Cancer Stem Cell Paradigm
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.
Key Words:Cancer stem cells Multiple drug resistance transporters (MDR) Therapeutic index Maximal tolerated dose Lung cancer Breast cancer Flow cytometry CD90 CD117 CD133 Side population (SP) Minimal residual disease (MRD)
This work was supported by grants BC032981 and BC044784 from the Department of Defense, the Hillman Foundation and the Glimmer of Hope Foundation. Vera Donnenberg is a CDMRP Era of Hope Scholar. The authors thank Ms. Darlene Monlish, Ms. Melanie Pfeifer, Mr. E. Michael Meyer, and Mr. Ludovic Zimmerlin for their expert technical assistance, and Drs. Rodney Landreneau and Shannon Puhalla for providing samples and clinical expertise. We also thank Mr. Peter Nobes and Mr. David Roberts of Applied Cytometry for the opportunity to collaborate on the development of software specifically designed for multiparameter rare event analysis on large datafiles.
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