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Cell Cycle Phase Specificity of Antitumor Agents¹

Research Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001

The sensitivity to drugs of synchronous and asynchronous populations of DON cells was studied. Agents that were cytotoxic at a specific phase of the cell cycle gave dose-survival curves that decreased to a constant saturation value. DNA synthesis inhibitors such as 1-ß-D-arabinofuranosylcytosine, 5-azacytidine, 5-hydroxy-2-formylpyridinethiosemicarbazone (NSC 107392), sodium camptothecin (NSC 100880), 5-fluorodeoxyuridine, and pseudourea (NSC 56054) were most cytotoxic to cells in the S phase. However, the DNA synthesis inhibitor, neocarzinostatin, was most cytotoxic to cells in the G₁ phase. The protein synthesis inhibitors, pactamycin and sparsomycin, were also most cytotoxic to cells in the S phase. Cells in the G₁-S border region were most sensitive to the RNA synthesis inhibitors, actinomycin D and nogalamycin, and to the alkylating agents, 1,3-bis(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. Streptozotocin and tubercidin, which markedly inhibit the synthesis of DNA, RNA, and protein, were cytotoxic to cells in all phase of the cell cycle. 5-Fluorouracil was also not phase specific. Cells in mitosis and in the G₁ phase were most sensitive to chlorambucil, L-phenylalanine mustard, and ellipticine.

¹ This study was supported in part by Contract PH43-68-1023 with Chemotherapy, National Cancer Institute, NIH, Bethesda, Md. 20014.

Received 12/21/70. Accepted 11/ 3/71.

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