Influence of drug exposure parameters on the activity of paclitaxel in multicellular spheroids

Paclitaxel is a chemotherapeutic drug which has clinical activity against several solid tumours including ovarian and metastatic breast cancers. Despite extensive preclinical evaluation in several experimental models, no studies have determined the effect of taxol on multicellular spheroids, a model which closely mimics the microregions of solid tumours. MCF-7 human breast carcinoma spheroids were significantly less sensitive than monolayers with IC50 values of 14.33 +/- 4.51 microM and 0.15 +/- 0.09 microM, respectively, following a 1 h drug exposure. Similarly, DLD-1 human colon carcinoma spheroids were also more resistant (IC50 = 33.0 +/- 8.89 microM) than monolayers (IC50 = 0.36 +/- 0.14 microM) following a 1 h drug exposure. Paclitaxel was unable to penetrate DLD-1 multicell layers (22 microns in thickness), suggesting that suboptimal drug exposures to paclitaxel occur in cells which reside some distance away from the surface of the spheroid. In the case of DLD-1 spheroids, extending the exposure time to 24 h whilst maintaining the same overall concentration x time (C x T) drug exposure parameters, resulted in greater cell kill (C x T required to kill 50% of cells = 13.67 +/- 3.21 microM/h) compared with 1 h drug exposures (C x T required to kill 50% of cells = 33.00 +/- 8.89 microM/h). Similar results were obtained with MCF-7 spheroids. In monolayers cultures, dose-response curves contained a marked plateau phase (a characteristic feature of cell cycle phase specific drug) and in the case of MCF-7 cells, cell kill was proportional to T as opposed to C x T. These results support the use of prolonged infusions of paclitaxel in the clinic, as extending the duration of drug exposure not only allows more cells to enter sensitive phases of the cell cycle, but would also allow paclitaxel more time to penetrate into avascular regions of solid tumours. It is likely that paclitaxel will only be effective against cells which reside close to tumour blood vessels and combination therapy with bioreductive drugs (such as tirapazamine) may produce synergistic effects in vivo.