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Effects of Hypoxia, pH, and Growth Stage on Cell Killing in Chinese Hamster V79 Cells in Vitro by Activated Cyclophosphamide¹

Gray Laboratory, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, England

Several factors which influence the sensitivity of Chinese hamster V79 cells to cyclophosphamide (CY) have been studied in vitro in both suspension and monolayer cultures. Activated CY was obtained from the blood of mice 15 to 30 min after i.p. injection of CY (400 mg/kg).

At pH 7.4, hypoxia rendered the cells more sensitive to activated CY. At lower values of pH (6.6 and 7.0), there was no difference between the sensitivities of oxic and hypoxic cells, although cells in both conditions were more sensitive to CY than at pH 7.4.

Drug sensitivity was markedly affected by the stage of cell growth. Monolayer cultures were most sensitive to CY within a few hours of plating. Cultures then rapidly became less sensitive, with maximum resistance occurring between 24 and 48 h after plating, while the cells were still exhibiting rapid exponential growth. This development of resistance parallelled the formation of small colonies (2 to 4 cells), implying that intercellular contact may confer resistance to killing by activated CY.

¹ Funded by the Cancer Research Compaign.

² Present address and address for reprints: Dept. of Experimental Radiotherapy, The Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

³ Present address: Radiation Oncology Research Laboratory, University of California CED-200, San Francisco CA 94143.

Received 9/28/84. Revised 2/28/85. Accepted 4/ 2/85.