ABROGATION OF TAXOL-INDUCED G(2)-M ARREST AND APOPTOSIS IN HUMAN OVARIAN-CANCER CELLS GROWN AS MULTICELLULAR TUMOR SPHEROIDS

Tumor cells grown as multicellular spheroids are known to be intrinsic ally more resistant to a large and diverse array of anticancer chemoth erapeutic drugs compared to the same cells grown as dispersed monolaye r cell cultures. Some drugs, however, seem relatively insensitive to t his multicellular drug resistance, e.g., cisplatinum. Whether the cyto toxic effects of Taxol, an anticancer drug of growing importance in th e treatment of breast and ovarian carcinomas, are diminished by multic ellular growth conditions is unknown. To study this question, we exami ned the relative sensitivity of a panel of four different human ovaria n carcinoma cell lines to either Taxol or cisplatinum. Upon exposure t o Taxol, all the cell lines manifested a relative drug-resistant pheno type when grown as multicellular tumor spheroids, compared to the same cells grown as sparse monolayer cultures. This multicellular-dependen t drug-resistant phenotype was not observed when the same cells were e xposed to cisplatinum for an equivalent length of time. Monolayer but not spheroid cultures exposed to Taxol demonstrated an accumulation of cells at G(2)-M and a sub-G(1) apoptotic region. In addition, Taxol-i nduced apoptosis was detected in monolayer conditions but not in the s pheroid cultures. The relative sensitivity of the monolayer cell cultu res was associated with a decrease in bcl-X-L protein levels after Tax ol exposure, an effect not observed in drug-exposed spheroids. Taken t ogether, these results suggest that some aspects of intrinsic Taxol re sistance in ovarian carcinoma may be due to multicellular-dependent or -associated mechanisms. This raises the possibility of using antiadhe sive agents to reverse multicellular-dependent Taxol resistance in cer tain circumstances as a potential means of increasing the initial effi ciency of Taxol therapy against ovarian carcinoma.