Modulation of the anti-cancer efficacy of microtubule-targeting agents by cellular growth conditions

Mitotic spindle-disrupting agents target and alter microtubule dynamics. These agents include clinically important chemotherapies, such as taxanes (paclitaxel (Taxol), docetaxel (Taxotere)) and vinca alkaloids (vincristine (Oncovin), vinblastine). Taxanes are a standard component of treatment for many malignancies, often in conjunction with other cytotoxic agents. however, the optimal sequencing of these treatments and whether effi cacy may be influenced by in vitro cellular growth conditions remain incompletely investigated. Yet such preclinical investigations may guide clinical decision making. We therefore studied the effect of cell density on rapid killing by paclitaxel and vincristine. Breast, ovarian and prostate cancer cells were sensitive to rapid killing by either agent when grown at low density, but were markedly resistant when grown at high density, i.e., nearly confluent. The resistance of densely growing cells to rapid killing by these drugs translated to increased clonogenic survival. pretreatment of densely growing cancer cells with cisplatin followed by paclitaxel, partially reversed the treatment resistance. Gene ontology associations from microarray analyses of cells grown at low and high density, suggested roles for membrane signal transduction and adhesion, but potentially also DNa damage repair and metabolism. Taken together, the treatment resistance at higher cell density may be associated with a lower proportion of active cycling in cells growing at high density as well as transduction of survival signals induced by increased cell-cell adhesion. Collectively these findings suggest mechanisms by which growth conditions may contribute to resistance to rapid killing by microtubule-disrupting drugs.