Abstract
The anti-tumor effect of ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride], a new nitrosourea derivative, was studied in Rous sarcoma virus-induced transplanted mouse malignant gliomas.
1) The survival time of mice with intracerebrally transplanted tumors was markedly prolonged by a single intraperitoneal dose of ACNU : the mean survival times were 26.2 in control mice, and 36.8 days in mice given doses of 10 mg/kg. Larger doses of 20 or 40 mg/kg produced large numbers of long-term survivors (more than 100 days). Similar effects of ACNU were noted in mice with subcutaneously transplanted tumors: the mean survival times were 27.8 in control mice, 30.2 in mice given doses of 10 mg/kg, 34.4 in mice given doses of 20 mg/kg, and 43.0 days in mice given doses of 40 mg/kg. The results showed a dose dependent anti-tumor effect on this experimental brain tumor within a dose range from 10 to 40 mg/kg.
2) When the total dose was kept at 40 mg/kg, a single administration of ACNU was found to be more effective than fractionated administration for the inhibition of subcutaneous tumors. The loss of body weight was more evident in mice given a single dose than in mice with fractionated administration.
3) The intraneoplastic injections were more effective in the median survival time than the intraperitoneal injections (p<0.05) when the animals were given the drug at 2 mg/kg/day for 7 days.
4) Combined therapy with ACNU and irradiation caused a greater anti-tumor effect than the additional effect on the subcutaneous tumors. Simultaneous combined therapy using both was much more effective than combined therapy in which irradiation was performed 2 or 3 days after ACNU administration.
5) Combined therapy with ACNU (10 mg/kg × 1) and PSK (300 mg/kg×10), a non-specific immunopotentiator, showed prolongation of the survival time of mice with subcutaneous tumors.
6) Uptake and distribution of 14C-ACNU in intracerebral and subcutaneous tumors were investigated by radioactive assay. The radioactivity in the intracerebral tumors was approximately two times higher than that in the normal brain tissues and was similar to that in subcutaneous tumors.
