Cell-kill kinetics of several S-phase-specific drugs.

Abstract

Summary The drugs [1-β-d-arabinofuranosylcytosine (ara-C), hydroxyurea (HU), 5-hydroxy-2-formylpyridine thiosemicarbazone (5-HP), and camptothecin sodium salt (camptothecin)] considered in this paper markedly inhibit DNA synthesis and are maximally cytotoxic to cells in S phase. In these studies, high-specific-activity thymidine- 3 H (HSA-TdR- 3 H) was used as a control compound which killed cells in S but which did not affect the progression of cells into S. The cell-kill kinetics indicated that ara-C, HU, and 5-HP, unlike camptothecin, blocked the L1210 cells from progressing into S in the presence of the drug. We found that L1210 cells that were blocked in G 1 by HU started moving into S immediately after the drug was removed. Therefore, the time interval between two doses of HU that gave maximal cell kill was the same as that for HSA-TdR- 3 H. However, L1210 cells exposed to ara-C and 5-HP took about 2 hr to recover from the effect of the drug and then progress into S. Therefore, the time interval (between two doses of either ara-C or 5-HP) that gave maximal cell kill was longer than that needed for HSA-TdR- 3 H. Camptothecin did not block L1210 cells from moving into S and, therefore, the cell-kill kinetics with camptothecin were the same as those with HSA-TdR- 3 H. The time for maximal recovery of DNA synthesis by L1210 cells after a single exposure to the drugs was determined. The time for maximal recovery of DNA synthesis correlated well with the interval required for maximal cell kill.