Journal Article

Taxol, vincristine or nocodazole induces lethality in G<sub>1</sub>-checkpoint-defective human astrocytoma U373MG cells by triggering hyperploid progression

Frank D. Hong, Jun Chen, Scott Donovan, Nancy Schneider and Perry D. Nisen

in Carcinogenesis

Volume 20, issue 7, pages 1161-1168
Published in print July 1999 | ISSN: 0143-3334
Published online July 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.7.1161
Taxol, vincristine or nocodazole induces lethality in G1-checkpoint-defective human astrocytoma U373MG cells by triggering hyperploid progression

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In this report, we describe a novel lytic mechanism exploited by antimicrotubule drugs (AMDs) such as Taxol which are frequently used to treat multiple human cancers including breast and ovarian cancers. In cells lacking the G1-arresting capacity due to the defect in retinoblastoma or p53 gene function, AMDs trigger hyperploid progression and death. The hyperploid progression occurs via continued cell-cycle progression without cell division. Blocking hyperploid progression through hydroxyurea or ectopically expressed p27Kip1, a G1-specific Cdk inhibitor, abrogates AMD cytotoxicity. Thus, AMDs induce lethality in G1-checkpoint-defective cells by triggering hyperploid progression. The phenomenon is reminiscent of that observed previously with bub-1 yeast mutant. The potential significance of this finding lies in that hyperploid progression-mediated death may be exploited to develop a therapy with tumor-specificity at the genetic level. As a large fraction of human cancers are mutated in p53 gene, it may have a wide therapeutic applicability.

Keywords: AMD, antimicrotubule drug; MEF, mouse embryo fibroblast; MT, microtubule; RB, retinoblastoma.

Journal Article.  5658 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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