The effect of phenobarbital on the toxicity and tumoricidal activity of CCNU in a murine brain tumor model

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Abstract
The nitrosoureas are 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 effect of PB pretreatment on the toxic and tumoricidal activity of CCNU in a murine model was assessed. In C57B1/6J mice, PB pretreatment markedly reduced the lethal toxicity of high doses of CCNU. The LD99 [99% effective lethal dose] of CCNU was 80 mg/kg given i.p. Pretreatment with PB reduced the toxic death rate of CCNU at 40, 60, 90 or 120 mg/kg to less than 10%. Pretreatment with PB also reduced the tumoricidal activity of CCNU. In an intracerebral murine ependymoblastoma, i.p. 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). After 4 daily doses of PB prior to the same dose of CCNU, the %ILS was reduced to 85 with no LTS among 25 mice. When CCNU was given alone at 30 mg/kg i.p. on Day 10, a %ILS of > 300 with 22 of 25 LTS resulted; PB pretreatment reduced the %I5S to 15, with 2 of 25 LTS. 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; PB pretreatment reduced the %ILS to 50 with 5 of 20 LTS. PB pretreatment significantly reduced the ability of CCNU to retard tumor growth in a subcutaneous murine ependymoblastoma. 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.