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Schedule Dependence of Vincristine Lethality in Sarcoma 180 Cells following Partial Synchronization with Hydroxyurea

Section of Cell Kinetics, Clinical Pharmacology Branch, Division of Cancer Treatment, National Cancer Institute [H. M., B. M. C., C. A. S., S. J. O., S. E. S.], and Applied Clinical Engineering Section, Biomedical Engineering and Instrumentation Branch, Division of Research Services [W. H. S.], NIH, Bethesda, Maryland 20205

The effects of exposure to 0.1, 0.5, or 2 µM vincristine for 4 hr were studied in Sarcoma 180 cells at various times after synchronization with 5 mM hydroxyurea for 1 hr. Maximum sensitivity to the lethal effects of vincristine was observed at 10 to 14 hr after hydroxyurea exposure at the higher vincristine concentrations, compared to a period of a maximum sensitivity to a second dose of hydroxyurea at 8 to 12 hr. Serial flow cytometry studies indicated that the apparent decrease in sensitivity to vincristine at 14 to 18 hr was due to the division of cells in the leading segment of the synchronized wave and their entry into the relatively resistant G₁ phase prior to vincristine exposure. Synchronized cells that had not divided at the time of vincristine exposure were blocked transiently in G₂. Serial metaphase index studies suggested that the G₂ cells closest to the end of the cell cycle at the time of vincristine exposure were likely to exhibit the greatest degree of mitotic disorganization when they overcame the G₂ block and entered metaphase. The present studies suggest that sensitivity to vincristine increases progressively as cells approach mitosis. The molecular mechanisms underlying this phenomenon are considered in relation to the increase in cell tubulin content during the course of cell cycle progression.

¹ To whom requests for reprints should be addressed, at Building 10, Room 12C216, National Cancer Institute, Bethesda, Md. 20205.

Received 10/22/82. Accepted 5/ 5/83.