The in vivo efficacy of compounds identified to be active in the anti-AIDS and anticancer cell culture screens may be greatly influenced by their pharmaco-kinetics and metabolism. Chemical structural modification of a priority anti-HIV compound, NSC 629243, has been directed by pharmacokinetic and metabolic principles and studies in order to afford a structural analog or congener with greater in vivo efficacy than the original compound identified by the screen. Antitumor compounds selected on the basis of novel or otherwise interesting a strongly distinctive patterns of differential growth inhibition or cytotoxicity are referred by the DTP Screening Data Review Committee to DTP's Biological Evaluation Committee for Cancer for further investigation. Only a very small percentage of the compounds screened have been referred for further consideration. Among the large collection of other compounds, there are certain compounds which show more subtle or moderate activity profiles yet which potentially may have modes of action of interest for new drug discovery. Such structures could serve as the basis for a lead-directed synthetic program which seeks to prepare structural analogues with enhanced activity. Using the Compare pattern-recognition algorithm, new lead synthetic compounds with chemical structures which are not known to be tubulin active have been identified. Molecular modeling has been employed to design potential new tubulin active compounds. GRANTZ01CM07199 Experimental therapeutic models require the availability of sensitive and quantitative methods for assessing tumor burden and response to therapy; conventional approaches typically involve direct macroscopic or microscopic measurement of tumor mass. We are exploring the application of molecular biologic approaches to development of new in vivo metastatic, orthotopic and other xenograft models where more precise quantitative determination of tumor burden is critical. Utilizing probes for repetitive human DNA sequences, we have demonstrated that human tumor DNA can be detected in DNA extracted from whole mouse organs and that this signal can be utilized to characterize the time-course and tissue distribution of metastatic cells. Future work will be directed towards improving methods of dot-blot quantitation, application of the polymerase chain reaction to enhancement of sensitivity for detection of human DNA sequences and application of DNA probe technology to evaluation of therapeutic effects.
