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The Antitumor Enediyne C-1027 Alters Cell Cycle Progression and Induces Chromosomal Aberrations and Telomere Dysfunction

Departments of ¹ Pharmacology and Therapeutics, and ² Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Terry A. Beerman, Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Grace Cancer Drug Center, Room 233, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-3443; Fax: 716-845-8857; E-mail: Terry.Beerman{at}roswellpark.edu.

This study examined the extent of chromosome instability induced in cultured human colon carcinoma HCT116 cells by the antitumor radiomimetic enediyne antibiotic C-1027. Spectral karyotype analysis showed frequent intrachromosomal fusions and fragmentations 26 hours after addition of as little as 0.035 nmol/L C-1027. When the concentration was increased to 0.14 nmol/L C-1027, 92% of cells showed chromosomal aberrations compared with only 2.9% after treatment with an equivalent growth inhibitory dose of ionizing radiation (20 Gy). Thus, chromosome misrejoining was associated to a much greater extent with C-1027–induced than with ionizing radiation–induced cell growth inhibition. Despite these aberrations, a large fraction of C-1027–treated cells progressed into G₁. Comet analysis showed that these extensive chromosomal anomalies were not due to increased induction or reduced repair of C-1027–induced compared with ionizing radiation–induced strand breaks. Fluorescence in situ hybridization analysis showed that misrejoining of telomere repeats (i.e., chromosomes joined end to end at their telomeres or fused together after complete loss of telomere sequences) was observed within 26 hours of C-1027 addition. The extreme cytotoxicity of C-1027 may reflect both induction and erroneous repair of DNA double-strand break in the whole genome and/or in subgenomic targets such as telomere sequences.

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