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

Abstract

v' 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 routine model.In C57B1/6J mice, PB pretreatment markedly reduced the lethal toxicity of high doses of CCNU. The LD,~ 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.

Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors [RETIRED]

“…In addition, the ability of these anticonvulsants to stimulate the cytochrome P450 enzyme system results in markedly accelerated metabolism of a wide spectrum of chemotherapeutic agents including nitrosoureas, paclitaxel, cyclophosphamide, topotecan, irinotecan, thiotepa, 9-aminocampo-thecin, adriamycin, and methotrexate. [22][23][24][25][26][27][28][29][30][31][32][33][34] As a result, inadequate chemotherapeutic dosing of brain tumor patients has been identified recently as a widespread and critically important problem. 35 Conversely, corticosteroids and many chemotherapeutic agents alter the metabolism of anticonvulsants, making anticonvulsant under-and overdosing more common.…”

Does giving patients, who have never had a seizure, an anti-epileptic drug before surgery help prevent them from developing seizures?

“…Lastly, there is some evidence that levetiracetam may inhibit malignant glioma cell proliferation and increase glioma cell sensitivity to the alkylating agent temozolomide [ 28 ]. [ 32 ]. Direct injury to the patient, as well as secondary injuries to others, can occur with seizure activity [ 33 ].…”

The Murine Ependymoblastoma: Growth Pattern and Survival in C57B1/6J Mice

“…The murine ependymoblastoma was induced and serially transplanted intracerebrally byZimmerman and Arnold (1941). This experimental tumor has been used extensively to test the tumoricidal activity of chemotherapeutic agents which might have application in the treatment of human malignant brain tumors (Ausman et al, 1970;Geran et al, 1974;Muller and Tator, 1978;Muller et al, 1980;Shapiro, 1971;Shapiro et al, 1970). The model has also been used in the assessment of radiotherapeutic fractionation (Muller and Shin, 1982), and drug distribution studies Schwartz et al, 1972;Tator, 1972;Wassenaar and Tator, 1976).…”