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Dissociation between Bulk Damage to DNA and the Antiproliferative Activity of Teniposide (VM-26) in the MCF-7 Breast Tumor Cell Line: Evidence for Induction of Gene-specific Damage and Alterations in Gene Expression¹

Departments of Pharmacology/Toxicology and Medicine, Medical College of Virginia, Richmond, Virginia 23298 [D. A. G., M. S. O., F. A. F., J. K. R., L. F. P., R. T. B.]; and Department of Pharmacology and The Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 [J. C. Y., M. K. R.]

In the MCF-7 breast tumor cell line, induction of bulk damage to DNA (measured either as total strand breaks or as double-strand breaks) fails to correspond with the antiproliferative activity of the demethylepipodophyllotoxin derivative, VM-26. In contrast, VM-26 produces an early (within 2–3 h) concentration-dependent reduction in c-myc expression (and of DNA synthesis) which parallels inhibition of cell growth, suggesting the possibility of effects of VM-26 at the level of genomic regions which regulate DNA replicative function. Although VM-26 also produces a reduction in c-myc expression in K562 human leukemic cells, these alterations fall to correspond with the concentration-dependent effects on cell growth in this cell line. Utilizing the newly developed alkaline unwinding/Southern blotting assay in the MCF-7 breast tumor cell line, it was determined that VM-26 induces damage within regions surrounding the c-myc gene and the ß-globin gene which exceeds that induced in both -satellite DNA and in L1 repeat sequences; damage within c-myc and ß-globin also exceeds that observed throughout the genome as a whole. These findings indicate that certain genomic regions incur preferential damage in MCF-7 cells exposed to VM-26. It appears possible that damage within such genomic regions could lead to alterations in expression of select genes associated with regulation of cellular proliferation, resulting in reduced DNA synthesis, compromised cell growth, and, ultimately, cell death.

¹ Supported by a grant from the Thomas F. and Kate M. Jeffress Trust, a Grant-In-Aid to faculty at the Medical College of Virginia, a grant from the AD Williams Foundation, NIH Grants CA-40615 and CA-51657, ACS Grant DHP-49, and a Pittsburgh Cancer Institute Postdoctoral Fellowship (M. K. R.).

² To whom requests for reprints should be addressed.

Received 2/16/93. Accepted 5/21/93.