Antitumor action of several new piperazine derivatives compared to certain standard anticancer agents

Abstract

The single intraperitoneal acute LD50 doses of the following piperazine derivatives for Sprague-Dawley rats were as follows: bulk lot crystals A 8103, 200 to 225 mg./kg., and A 20065, 375 mg./kg.; for powdered processed vial packaged A 8103, 75 mg./kg., and A 20968 150 mg./kg. The single intraperitoneal acute LD50 of the latter two drugs in Swiss mice was as follows: A 8103, 225 mg./kg., and A 20968, 400 mg./kg. A 8103 and A 20065 were more effective at comparable doses in preventing Walker 256 tumor takes in rats and in depressing established tumor growth than were nitrogen mustard or 5-FU. These two piperazine agents were equally effective in preventing tumor takes when administered orally or by the intraperitoneal routes. The time of first appearance of Walker 256 tumor in rats was delayed more than twice as long in animals treated with A 8103, compared with groups treated with the selected standard antineoplastic agents. A 8103 was effective in reducing subcutaneous tumor takes in rats in doses as low as 0.1 LD50, in contrast to HN2 and 5-FU, both inactive in 0.4 LD50. A 8103 prepared in vials (LD50 75 mg./kg.) had greater antineoplastic activity against Walker 256 tumor in the rat than did A 20968, but the latter was more effective against sarcoma 180 in the mouse than A 8103 in comparable doses. Intraperitoneal LD50 value for A 8103 was 35 mg./kg. in dogs. Leukopenia and agranulocytosis were the chief signs of laboratory toxicity due to A 8103. Autopsy revealed pulmonary consolidation and hemorrhage, aplasia of myelocytic elements of the bone marrow, renal tubular necrosis and hepatic lobular necrosis. Of the three piperazine derivatives studied, bromopropionyl piperazine (A 8103) appeared to be most effective and superior to HN2 or 5-FU against Walker 256 tumor in the rat. The single intraperitoneal acute LD50 doses of the following piperazine derivatives for Sprague-Dawley rats were as follows: bulk lot crystals A 8103, 200 to 225 mg./kg., and A 20065, 375 mg./kg.; for powdered processed vial packaged A 8103, 75 mg./kg., and A 20968 150 mg./kg. The single intraperitoneal acute LD50 of the latter two drugs in Swiss mice was as follows: A 8103, 225 mg./kg., and A 20968, 400 mg./kg. A 8103 and A 20065 were more effective at comparable doses in preventing Walker 256 tumor takes in rats and in depressing established tumor growth than were nitrogen mustard or 5-FU. These two piperazine agents were equally effective in preventing tumor takes when administered orally or by the intraperitoneal routes. The time of first appearance of Walker 256 tumor in rats was delayed more than twice as long in animals treated with A 8103, compared with groups treated with the selected standard antineoplastic agents. A 8103 was effective in reducing subcutaneous tumor takes in rats in doses as low as 0.1 LD50, in contrast to HN2 and 5-FU, both inactive in 0.4 LD50. A 8103 prepared in vials (LD50 75 mg./kg.) had greater antineoplastic activity against Walker 256 tumor in the rat than did A 20968, but the latter was more effective against sarcoma 180 in the mouse than A 8103 in comparable doses. Intraperitoneal LD50 value for A 8103 was 35 mg./kg. in dogs. Leukopenia and agranulocytosis were the chief signs of laboratory toxicity due to A 8103. Autopsy revealed pulmonary consolidation and hemorrhage, aplasia of myelocytic elements of the bone marrow, renal tubular necrosis and hepatic lobular necrosis. Of the three piperazine derivatives studied, bromopropionyl piperazine (A 8103) appeared to be most effective and superior to HN2 or 5-FU against Walker 256 tumor in the rat.