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Effects of the Epipodophyllotoxin VP-16-213 on Cell Cycle Traverse, DNA Synthesis, and DNA Strand Size in Cultures of Human Leukemic Lymphoblasts¹

Divisions of Hematology-Oncology [D. K. K., A. T. L.] and Biochemical Pharmacology [A. F.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101, and Department of Pediatrics, University of Texas Health Sciences Center at Dallas, Dallas, Texas 75230 [J. D.]

Serial studies of human leukemic lymphoblasts (CCRF-CEM line) cultured with 0.25 to 2.5 µM VP-16-213 for 0 to 6 hr indicated that the mechanism of cytotoxicity of this compound involves a primary effect on DNA. The most striking early change shown by flow cytometry in VP-16-213-treated cells was a delay in Sphase transit before arrest of cells in G₂. Coinciding with this Sphase delay was a selective inhibition of thymidine incorporation into DNA as well as concentration-dependent scission of DNA strands. Using alkaline elution methods, we were able to detect DNA breakage at concentrations of VP-16-213 well below the level required to demonstrate kinetic effects or inhibition of DNA synthesis. These data suggest that DNA strand scission is the initial event in the sequence of kinetic and biosynthetic changes leading to growth inhibition and death of VP-16-213-treated cells. Inhibition of replicon initiation due to strand scission is a plausible explanation for the cytotoxic action of this podophyllotoxin derivative.

¹ Supported by American Cancer Society Research Project Grant IN-99G, a National Cancer Institute Leukemia Program Project Grant CA-20180, a National Cancer Institute Cancer Center Core Grant CA-21765, and ALSAC.

² To whom requests for reprints should be addressed.

Received 9/ 8/82. Accepted 1/ 5/83.

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