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Taxol-dependent Transcriptional Activation of IL-8 Expression in a Subset of Human Ovarian Cancer¹

Department of Biology [L-F. L.], University of North Carolina Lineberger Comprehensive Cancer Center [A. K. L., J. P-Y. T., B. K. M., J. S. H.] and Department of Microbiology and Immunology [J. P-Y. T., C. M. W., J. S. H.] and Obstetrics and Gynecology [J. S. H.], University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295; Institute of Physiology [C-C. S-M.], University of Zurich, 8057 Zurich, Switzerland; and Department of Gynecological Oncology [C. v. H-D.], The Royal Hospital for Women, New South Wales 2021, Australia

Taxol is important in the treatment of both primary and drug-resistant ovarian cancer. Although Taxol is known to stabilize microtubules and block cell mitosis, the effectiveness of this drug exceeds that of other antimitotic agents, suggesting it may have an additional mode of action. Stimulated by murine macrophage studies indicating cytokine induction by Taxol, we have investigated proinflammatory cytokine expression in a series of cell lines and recent explants of human ovarian cancer. Taxol induced secretion of interleukin (IL) 8 but not IL-6, IL-1, or IL-1ß in 4 of 10 samples. Induction was dependent on transcriptional activation, and, in contrast to murine macrophage studies, was apparently independent of an active lipopolysaccharide signaling pathway. Confluent cultures secreted as much IL-8 as proliferating cells. Taxol did not induce IL-8 in breast carcinoma, endometrial stromal, or T-lymphocyte or monocyte cultures. We propose that the local expression of this chemokine in vivo may elicit a host response similar in effectiveness to that of cytokine gene therapy. These data are the first to suggest that a chemotherapeutic agent may have a direct effect on transcription of cytokine and/or growth factor genes in ovarian cancer, and that this effect may not be restricted to proliferating tumor cells.

¹ This work is supported by National Cancer Institute grant 48185 and an American Cancer Society Faculty Award to J.P-Y.T. C.M.W. is supported by a Minority Enhancement Supplement to NCI 48185; B.K.M. is supported by an NCI training grant and by an NCI postdoctoral fellowship.

² To whom requests for reprints should be addressed, at Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295. Phone: (919) 966-3098; Fax: (919) 966-3015.

Received 6/15/95. Accepted 1/12/96.

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