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Paul J. Muller, Charles H. Tator and Martin Bloom

✓ The nitrosoureas are known to be substrates for hepatic microsomal enzymes. Since phenobarbital (PB) is a potent inducer of hepatic microsomal enzymes, and since PB and other enzyme-inducing drugs are commonly used in patients with brain tumors, the authors have assessed the effect of PB pretreatment on the toxic and tumoricidal activity of CCNU in a murine model.

In C57B1/6J mice, PB pretreatment markedly reduced the lethal toxicity of high doses of CCNU. The LD99 dose of CCNU was found to be 80 mg/kg given intraperitoneally. Pretreatment with PB reduced the toxic death rate of CCNU at 40, 60, 90, or 120 mg/kg to less than 10% (p < 0.01). Pretreatment with PB also reduced the tumoricidal activity of CCNU. In an intracerebral murine ependymoblastoma, intraperitoneal CCNU alone, at 30 mg/kg given on the 5th day after tumor transplantation, produced a percent increased life span (%ILS) of > 300, and 18 of 25 were long-term survivors (LTS). In contrast, after four daily doses of PB prior to the same dose of CCNU, the %ILS was reduced to 85 with no LTS among 25 mice (p < 0.01). When CCNU was given alone at 30 mg/kg intraperitoneally on Day 10, a %ILS of > 300 with 22 of 25 LTS resulted; whereas, PB pretreatment reduced the %ILS to 15, with two of 25 LTS (p < 0.01). When CCNU was administered directly into the tumors intracerebrally at 30 mg/kg on Day 10, the %ILS was > 300, with 16 of 20 LTS; whereas, PB pretreatment reduced the %ILS to 50 with five of 20 LTS (p < 0.01). Furthermore, PB pretreatment significantly reduced the ability of CCNU to retard tumor growth in a subcutaneous murine ependymoblastoma.

Thus, PB pretreatment significantly altered the activity of CCNU. Since enzyme-inducing drugs are so commonly used in patients with brain tumors, it is possible that the clinical failure of nitrosoureas in some cases may be due to an unsuspected drug antagonism.