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Use of Phenobarbital and High Doses of 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea in the Treatment of Brain Tumor-bearing Mice¹

Division of Neurosurgery, University of Toronto [P. J. M., M. L. B.], and Sunnybrook Medical Centre [C. H. T.], Toronto, Ontario, M4N 3M5, Canada

It has been shown that the nitrosoureas are substrates for hepatic microsomal enzymes in vitro and that phenobarbital (PB) administered in multiple doses prior to nitrosourea administration significantly reduces the activity of the nitrosoureas in murine brain tumor models.

In the present study, the effect of PB on 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was assessed by determining the CCNU dose which would result in the long-term survival of 50% of the treated mice, and the CCNU dose which would result in the toxic death of 50% of the treated mice, with or without PB pretreatment in C56BL/6J mice. The therapeutic index, the CCNU dose which would result in the long-term survival of 50% of the treated mice, per the CCNU dose which would result in the toxic death of 50% of the treated mice, without PB pretreatment was 2.1; the therapeutic index of CCNU after PB pretreatment was 1.7. There is no significant difference between the therapeutic indices. Thus, the reduction in the tumoricidal activity of CCNU after PB pretreatment was restored by increasing the dose of CCNU without a significant change in its lethal toxicity.

¹ Supported by the Ontario Cancer Treatment and Research Foundation Grant 247.

² Fellow, Medical Research Council of Canada. Presently, Associate Professor, Division of Neurosurgery, St. Michael's Hospital, University of Toronto, Ontario, Canada.

³ Professor of Surgery, University of Toronto; Head, Division of Neurosurgery, Sunnybrook Medical Centre, Toronto, Ontario, Canada. To whom requests for reprints should be addressed, at Neurosurgical Laboratory, R Wing, Sunnybrook Medical Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5 Canada.

⁴ Medical Student, University of Toronto, Ontario, Canada.

Received 3/ 1/82. Accepted 1/ 7/83.

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