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Schedule Optimization of Hydroxyurea and 1-ß-D-Arabinofuranosylcytosine in Sarcoma 180 in Vitro¹

Clinical Pharmacology [S. E. S., S. S. F., S. J. O., P. S. R., B. W. E.] and Pediatric Oncology [R. R.] Branches, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205

The lethal and sublethal effects of 1-ß-D-arabinofuranosylcytosine (ara-C) were studied in Sarcoma 180 in vitro in relation to drug concentration and drug exposure duration. Drug lethality was found to be dependent on both drug concentration and drug exposure duration. These studies confirmed that radioautographic grain counts reflect relative rates of DNA synthesis in individual cells. When the radioautographic data and flow cytometry data are considered together, it is apparent that ara-C blocked cells at multiple points in the cell cycle. However, blockade was not complete; low levels of DNA synthesis persisted, even during prolonged drug exposure. The time course of recovery of rapid DNA synthesis following exposure to ara-C was delayed in comparison with that observed following exposure to hydroxyurea. The optimal time interval between two split 1-hr exposures to ara-C or two split 1-hr exposures to hydroxyurea coincided with the time that cells recruited into rapid cycle by the first dose were passing through mid-S and synthesizing DNA at high rates. These findings suggest that the concept of graded DNA synthesis rate-dependent drug lethality may be preferable to the all-or-none concept of S-phase specificity. The optimum interval between split doses of ara-C was not related to intracellular levels of 1-ß-D-arabinofuranosylcytosine 5'-triphosphate as a function of time after exposure to the first dose. Overall, the dependence of ara-C lethality on drug concentration, drug exposure duration, and the rate of cellular DNA synthesis are most consistent with the premise that the amount of ara-CTP incorporated into DNA is a major determinant of drug lethality.

¹ Excerpted in Cell Kinetics (20).

² To whom requests for reprints should be addressed, at Building 10, Room 12C101, National Cancer Institute, Bethesda, Md. 20205.

Received 9/12/79. Accepted 8/ 2/82.