Combination chemotherapy with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride and bleomycin in meningeal carcinomatosis in rats.

Combination chemotherapy with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and bleomycin (BLM) was evaluated using an experimental model of meningeal carcinomatosis induced in Sprague-Dawley rats by intracisternal inoculation of 1 X 10(4) Walker 256 tumor cells. Tumor-bearing animals were treated by i.v. administration of cyclophosphamide, BLM, ACNU, or a combination thereof, starting on Day 5 after tumor inoculation. BLM, 5 mg/kg on Day 5 as well as 5 mg/kg/day on Days 5, 7, 9, 11, and 13, was ineffective. Cyclophosphamide, 30 mg/kg, or ACNU, 15 or 30 mg/kg, on Day 5 increased the median survival time by 52, 70, and 82%, respectively. The combination of ACNU, 15 mg/kg, and cyclophosphamide, 15 mg/kg, increased median survival time by 73%, while the combination of ACNU, 15 mg/kg, and BLM, 5 mg/kg, resulted in a maximal increase of median survival time of 200% when the agents were given on Day 5. The combination of ACNU, 15 mg/kg on Day 5, and BLM, 5 mg/kg/day on Days 5, 7, 9, 11, and 13, increased median survival time by over 360% and cured 60% of the animals. These results point to the therapeutic advantage inherent in ACNU and BLM combination therapy.