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Carcinogenesis, Vol. 20, No. 7, 1161-1168, July 1999
© 1999 Oxford University Press

Accelerated Paper

Taxol, vincristine or nocodazole induces lethality in G1-checkpoint-defective human astrocytoma U373MG cells by triggering hyperploid progression

Frank D. Hong3, Jun Chen1, Scott Donovan2, Nancy Schneider2 and Perry D. Nisen1

Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Box 69, 1515 Holcombe Boulevard, Houston, TX 77030,
1 Abbott Laboratories, PPD, D-460, AP10-1, 100 Abbott Park Road, Abbott Park, IL 60064 and
2 University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA

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.

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

3 To whom correspondence should be addressed Email: fhong{at}notes.mdacc.tmc.edu


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