IDENTIFICATION OF THE STRUCTURAL REGION OF TAXOL THAT MAY BE RESPONSIBLE FOR CYTOKINE GENE INDUCTION AND CYTOTOXICITY IN HUMAN OVARIAN-CANCER CELLS

Purpose: Interleukin-8 (IL-8) is a pleiotropic chemokine with both che moattractant and angiogenic properties. In addition to its cytotoxic e ffects on ovarian cancer cells, taxol can transcriptionally activate g enes such as IL-8 that may play a role in tumorigenesis. Utilizing IL- 8 as a prototypic marker of tumor-derived modulators of growth, we und ertook a systematic study of taxol and 11 structurally modified taxol analogs to identify the region of the taxane skeleton responsible for IL-8 gene induction. Methods: The human ovarian cancer cell line OVCA- 420 was exposed to taxol or taxol analogs. IL-8 gene induction was ass essed by Northern blot analysis after 6 h and cytotoxicity after 72 h. Results: Changes in the southern hemisphere (C-1 to C-4) of the taxan e skeleton had greater effects on IL-8 induction than changes in the n orthern hemisphere (C-7 to C-11). Some of the taxol analogs modified a t positions C-1 and/or C-2 with increased hydrophobicity induced IL-8 expression more than three-fold over that induced by taxol or taxotere and more than 20-fold over control cells. Cells that failed to induce IL-8 gene expression in response to taxol were only marginally respon sive to the analogs unless first primed with IL-1 beta Modifications t o the northern hemisphere did not alter taxol's effect on IL-8 express ion in human cells, but did influence TNF alpha expression in murine m acrophage cells, suggesting species and/or gene specificity. We found a direct correlation between IL-8 induction and cytotoxicity, in that analogs that dramatically upregulated IL-8 expression proved to be the most cytotoxic, inhibiting cell survival by >90%. Conclusion: Taken t ogether our results demonstrate that changes in the southern hemispher e of the taxane skeleton influence bath the gene induction and cytotox ic potential of taxol in human ovarian cancer cells.