Due to the high failure rates, drug development is a very expensive and inefficient process. Few of the millions of compounds generated by chemists are suitable for human use because of their toxicity. There is a major need to reduce the number of animals used in research while increasing the efficiency, safety and reducing the costs of clinical trials. This proposal will support the development and validation of murine stem cell biology used in combination with gene and protein array technologies as a more predictive and cost effective in vitro test for toxic drugs and compounds. Known anti-cancer drugs will be evaluated for their effects on the in vitro growth and development of the stem cell-derived tissues (liver, heart, & nervous systems). Developing and validating the combination of broad clinically relevant biology represented during the in vitro differentiation of stem cells with in-depth protein and gene profiling should enable the development of a powerful test system for a better understanding of inter-species differences and will enable the identification and recognition of important surrogate markers of human toxicity. The result of this development work will be a commercial screening system to identify at a early preclinical stage toxic drug candidates that will increase the efficiency and reduce the costs of drug development. The NCI has begun to use human bone marrow cells for assessing drugs for hematopoietic toxicities, and to help establish MTD levels for phase 1 clinical trials. Although this approach is proving very useful, it has significant limitations. The three major limitations are, access to necessary fresh human bone marrow, both donor and biological variability of the sample, and the approach assesses only hematopoietic toxicities. The stem cell system proposed in this application eliminates or dramatically reduces these drawbacks.
