Clinically relevant doses of paclitaxel induce chromosome missegregation, not mitotic arrest.
Major finding: Clinically relevant doses of paclitaxel induce chromosome missegregation, not mitotic arrest.
Clinical relevance: Mitotic arrest was not necessary for paclitaxel response in patients with breast cancer.
Impact: Antimitotic agents that cause abnormal mitoses may be more effective than agents that induce mitotic arrest.
Paclitaxel, a chemotherapy drug frequently used to treat a range of cancers, is considered a microtubule inhibitor that arrests tumor cells in mitosis, but concentrations that have been used in cell culture to characterize the mechanism of action may be much higher than intratumoral concentrations. To determine clinically relevant paclitaxel concentrations in breast cancer, Zasadil and colleagues enrolled 6 patients in a clinical trial in which intratumoral paclitaxel levels and mitotic status were evaluated before and 20 hours after infusion with neoadjuvant paclitaxel, and tumor response was evaluated after 3 additional standard cycles of paclitaxel therapy. Interestingly, in 5 evaluable patients, mitotic arrest did not correlate with tumor regression. Concentrations of paclitaxel deemed clinically relevant based on levels in patient plasma and tumor samples 20 hours after initial infusion remained sufficient in inducing cell death in breast cancer cell lines but did so by increasing the frequency of multipolar spindles and promoting chromosome missegregation, not by causing substantial mitotic arrest. The additional spindles formed before anaphase and led to a significant increase in abnormal mitoses and aneuploidy. Consistent with these findings, the frequency of multipolar spindles increased in all patient tumors following paclitaxel treatment. Moreover, the tumors with the highest level of multipolar spindles were the most responsive to paclitaxel treatment, pointing to abnormal spindle formation as a potential biomarker for predicting paclitaxel response. Although confirmatory studies are needed in a larger number of patients and after additional time points after paclitaxel treatment, these findings strongly suggest that paclitaxel induces tumor cell death by a mechanism other than mitotic arrest and raise the possibility that antimitotic agents that only induce mitotic arrest may not be as effective as those that induce lethal mitotic divisions.