Taxol, vincristine or nocodazole induces lethality in G(1)-checkpoint-defective human astrocytoma U373MG cells by triggering hyperploid progression

In this report, we describe a novel lytic mechanism exploited by antimicrot ubule drugs (AMDs) such as Taxol which are frequently used to treat multipl e human cancers including breast and ovarian cancers. In cells lacking the G(1)-arresting capacity due to the defect in retinoblastoma or p53 gene fun ction, AMDs trigger hyperploid progression and death. The hyperploid progre ssion occurs via continued cell-cycle progression without cell division, Bl ocking hyperploid progression through hydroxyurea or ectopically expressed p27(Kipl), GI-specific Cdk inhibitor, abrogates AMD cytotoxicity. Thus, AMD s induce lethality in G(1)-checkpointdefective cells by triggering hyperplo id progression. The phenomenon is reminiscent of that observed previously w ith bub-1 yeast mutant. The potential significance of this finding lies in that hyperploid progression-mediated death may be exploited to develop a th erapy with tumor-specificity at the genetic level. As a large fraction of h uman cancers are mutated in p53 gene, it may have a wide therapeutic applic ability.