BIOLOGICAL EVALUATION

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Cancer is a recalcitrant disease of enormous socioeconomic importance. Although some improvements in therapy have been realized over the past several years, efficacious drugs are still needed for the systemic treatment of metastatic disease. Plants are one proven source of useful chemotherapeutic agents, and the most focussed method of uncovering such agents is by the process of bioassay-guided fractionation. In the framework of this National Collaborative Natural Product Drug Discovery Group, this project will provide bioassay support. In the previous project period, we have developed a panel of human tumor cell lines comprised of BC1 (breast), Col2 (colon), Lu1 (lung), HT-1080 (sarcoma), Mel 2 (melanoma), KB, multidrug-resistant KB-V1, ZR-75-1 (breast), LNCaP (prostate), and A431 (squamous) cells. KB-V1 cells are evaluated with plant extracts and isolates in the presence and absence of vinblastine to establish the potential of reversing the multidrug-resistance phenotype. In addition, antimitotic potential has been routinely monitored with cultured ASK cells. We have had success with these procedures and the resulting data integrate well with the information obtained with mechanism-based assays performed by other members of the National Collaborative Natural Product Drug Discovery Group. In addition, the activity profile obtained with this panel of cell lines is of value in considering the more advanced development of active isolates. Thus, these cell lines will continue to be employed in the upcoming project period. One additional cell line that has been added to the panel is designated Tax 2-4. Growth of this cell line is dependent on the addition of taxol to the medium, so the presence of taxol-like compounds can be discerned in crude mixtures, and the cell line can be used for the bioassay-directed fractionation of active leads. In addition, since it is clear the some indication of mechanism of action is required in order to properly assess novel plant isolates and to appraise the validity of more advanced development, mechanistic evaluations will be performed as part of this project. These mechanistic studies will be performed to the extent that is warranted on the basis of chemical structure and the in vitro activity profile. As an additional contribution, all isolates obtained by other members of the consortium will be evaluated in the test systems managed by this project, and all resulting data will be entered into a common database. Overall, this project will remained focussed on the provision of a clinically useful cancer chemotherapeutic agent through the consolidated effort of the National Collaborative Natural Product Drug Discovery Group.