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Single- and Double-Strand DNA Breakage and Repair in Human Lung Adenocarcinoma Cells Exposed to Etoposide and Teniposide

Bristol-Baylor Laboratory, Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030 [B. H. L., S. T. M., M. G. B.], and Pharmaceutical Research and Development Division, Bristol-Myers Co., Syracuse, New York 13201 [B. H. L., M. G. B.]

The anticancer agents 4'-demethylepipodophyllotoxin-4-(4,6-O-ethylidene-ß-D-glucopyranoside (etoposide) (VP16-213) and 4'-demethylepipodophyllotoxin-4-(4,6-O-thenylidene-ß-D-glucopyranoside (teniposide) (VM26) produce cytotoxicity by inhibiting type II topoisomerase, resulting in an accumulation of DNA breaks. By using alkaline elution techniques to assess in vivo DNA break frequencies, we have been able to follow formation and repair of both single- and double-strand DNA breaks induced by the exposure of A549 human lung adenocarcinoma cells to VP16-213 and VM26. Single-strand DNA breaks are detectable in cells within 2 min of drug exposure, increase in frequency to a maximum after as little as 15 min of exposure, and remain near maximum levels. Double-strand breaks accumulate more slowly, reaching a maximum after 1 to 2 h, and remaining constant thereafter upon continuous exposure to drug. Single-strand DNA breaks predominate at early incubation times and low drug concentrations, whereas the ratios between single- and double-strand DNA breaks decrease at higher drug concentrations. Changing to drug-free medium after 1-h drug exposure results in rapid exponential repair of both single- and double-strand DNA breaks with a time required for repair of one-half of the DNA breaks of 20 to 60 min. VM26 and VP16-213 have similar kinetics for DNA break formation and repair and similar relationships between DNA breakage and cytotoxicity, but VM26 is five to ten times more potent than VP16-213. Results indicate that DNA breakage plateaus may reflect a steady state equilibrium established between the drug and its nuclear target, possibly type II topoisomerase, and demonstrate unique properties of VP16-213- and VM26-induced DNA breakage.

¹ To whom requests for reprints should be addressed.

Received 4/17/84. Revised 9/21/84. Revised 2/25/85. Accepted 3/ 6/85.

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