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Abrogation of Taxol-induced G₂-M Arrest and Apoptosis in Human Ovarian Cancer Cells Grown as Multicellular Tumor Spheroids¹

Division of Cancer Biology Research, Sunnybrook Health Science Centre, Toronto, Ontario, M4N 3M5 Canada [A. F., R. B., R. S. K.], and Toronto Sunnybrook Regional Cancer Centre [R. B., R. S. K.], and Departments of Clinical Biochemistry [A. F.] and Medical Biophysics [R. S. K.], University of Toronto, Toronto, Canada

Tumor cells grown as multicellular spheroids are known to be intrinsically more resistant to a large and diverse array of anticancer chemotherapeutic drugs compared to the same cells grown as dispersed monolayer cell cultures. Some drugs, however, seem relatively insensitive to this multicellualr drug resistance, e.g., cisplatinum. Whether the cytotoxic effects of Taxol, an anticancer drug of growing importance in the treatment of breast and ovarian carcinomas, are diminished by multicellular growth conditions is unknown. To study this question, we examined the relative sensitivity of a panel of four different human ovarian carcinoma cell lines to either Taxol or cisplatinum. Upon exposure to Taxol, all the cell lines manifested a relative drug-resistant phenotype when grown as multicellular tumor spheroids, compared to the same cells grown as sparse monolayer cultures. This multicellular-dependent drug-resistant phenotype was not observed when the same cells were exposed to cisplatinum for an equivalent length of time. Monolayer but not spheroid cultures exposed to Taxol demonstrated an accumulation of cells at G₂-M and a sub-G₁ apoptotic region. In addition, Taxol-induced apoptosis was detected in monolayer conditions but not in the spheroid cultures. The relative sensitivity of the monolayer cell cultures was associated with a decrease in bcl-X_L protein levels after Taxol exposure, an effect not observed in drug-exposed spheroids. Taken together, these results suggest that some aspects of intrinsic Taxol resistance in ovarian carcinoma may be due to multicellular-dependent or -associated mechanisms. This raises the possibility of using antiadhesive agents to reverse multicellular-dependent Taxol resistance in certain circumstances as a potential means of increasing the initial efficiency of Taxol therapy against ovarian carcinoma.

¹ Supported by a grant to R. S. K. from the National Cancer Institute of Canada. R. S. K. is a Terry Fox Scientist of the National Cancer Institute of Canada supported by funds from the Terry Fox Run. A. F. is a recipient of a studentship from the Medical Research Council of Canada.

² To whom requests for reprints should be addressed, at Division of Cancer Biology Research, Research Building, S-218, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. Phone: (416) 480-5711; Fax: (416) 480-5703.

Received 4/14/97. Accepted 4/30/97.

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