The new
anticancer agent poly(L-glutamic acid)-paclitaxel (
PG-TXL) is a conjugate of
paclitaxel and the water-soluble
polyglutamate carrier. The observation that
PG-TXL appears to possess antitumor activity superior to free
paclitaxel in preclinical studies suggests that
PG-TXL might possess favorable pharmacokinetic properties and/or have a mechanism of action different from that of
paclitaxel. The purpose of this study was to compare the pharmacological action of
PG-TXL and free
paclitaxel in a panel of
breast cancer cell lines with emphasis on their ability to induce apoptosis, their effects on cell cycle progression, and their cellular uptake. Morphological analysis and biochemical characterizations demonstrated that both compounds have similar abilities to induce apoptosis in cells expressing wild-type p53 (MCF-7) or mutant p53 (MDA-MB435 and MDA-MB453). Although MCF-7 cells were less sensitive to each compound than MDA-MB435 and MDA-MB453 cells, transfection experiments demonstrated that p53 did not appear to play a significant role in
drug-induced cell death with either agent. Flow cytometry analysis further revealed that both free
paclitaxel and
PG-TXL induced a characteristic G2/M arrest in the cell cycle, consistent with the disturbance of microtubule polymerization as their mechanism of action. Western blot analysis showed that
paclitaxel and
PG-TXL downregulated HER2/neu expression in a similar fashion. HPLC analysis revealed that
paclitaxel was released from the
PG-TXL conjugate in vitro. The released
paclitaxel, not the
glutamic acid polymer, was subsequently transported into the cells. These results suggest that
PG-TXL exerts its anticancer activity by continuous release of free
paclitaxel, and that the favorable pharmacokinetics and
drug distribution of the
PG-TXL conjugate in vivo are likely the main factors contributing to its superior anticancer activity.