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-EXPRESSION

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) fai ls to correspond with the antiproliferative activity of the demethylep ipodophyllotoxin derivative, VM-26. In contrast, VM-26 produces an ear ly (within 2-3 h) concentration-dependent reduction in c-myc expressio n (and of DNA synthesis) which parallels inhibition of cell growth, su ggesting the possibility of effects of VM-26 at the level of genomic r egions which regulate DNA replicative function. Although VM-26 also pr oduces a reduction in c-myc expression in K562 human leukemic cells, t hese alterations fail to correspond with the concentration-dependent e ffects 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 beta-globin gene which exceeds that induced in both alpha-satellite DNA and in L1 repeat sequences; damag e within c-myc and beta-globin also exceeds that observed throughout t he genome as a whole. These findings indicate that certain genomic reg ions incur preferential damage in MCF-7 cells exposed to VM-26. It app ears possible that damage within such genomic regions could lead to al terations in expression of select genes associated with regulation of cellular proliferation, resulting in reduced DNA synthesis, compromise d cell growth. and, ultimately, cell death.