Residual drug damage compromising the ability of tissues to mount a compensatory proliferative response to subsequent insults initiated long after drug treatment has been found in both the intestinal and renal epithelium, and in the hematopoietic tissues. Preliminary investigations have demonstrated that the subsequent insult may be cytotoxic (i.e. drug or radiotherapy) or biological (i.e. experimentally induced anemia). In addition, the growth of tumors in drug treated animals (a condition simulating the clinical presentation of recurrent disease) has also been found to compromise normal host tissue function. At least for the hematopoietic system, residual drug damage has been postulated to result from a lesion to either the stromal (micro-environmental) or stem cell population. However, both have not been investigated simultaneously. We propose a series of studies in mice that will investigate the long-term effects of a number of drugs (representing alkylating, intercalating, cycle phase specific, and pan-cytotoxic drugs) on the potential of both hematopoietic response to a subsequent stress to the hematopoietic system. Both experimentally induced anemia and the growth of the Lewis lung tumor will be used as a stress subsequent to drug treatment. Initially, emphasis will be placed on screening the selected drugs for residual hematopoietic damage at or near the mean tolerated dose (MTD). These studies will be followed by experiments designed to establish (a) threshold, (b) fractionation, and (c) additivity effects of drug dose. Finally, emphasis will focus on the assessment of animal age as a determinant of the magnitute of long-term damage produced by specific drugs. Ultimately, the results from these studies will offer information as to which drugs result in residual damage, the magnitude of that damage, and the mechanism(s) involved. Those answers can then be applied to the formulation of basic principles upon which more efficacious long-term (or adjuvant) chemotherapeutic regimes can be designed.
