Premium
Studies on the chemistry, antitumor activity, and pharmacology of ethyl Di‐(2,2 ‐dimethyl)ethylenamido phosphate (AB‐163)
Author(s) -
Munson A. E.,
Babbitt H.,
Chmielewicz Z. F.,
Bardos T. J.,
Ambrus J. L.
Publication year - 1969
Publication title -
journal of surgical oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.201
H-Index - 111
eISSN - 1096-9098
pISSN - 0022-4790
DOI - 10.1002/jso.2930010209
Subject(s) - pharmacology , toxicity , medicine , vomiting , ehrlich ascites carcinoma , chemistry , biochemistry , in vitro
AB‐163, a new alkylating agent containing the 2,2‐dimethylaziridine moiety, was found to be active against a number of transplanted and virus‐induced tumor systems in mice. This compound hydrolyzes in water at 37 C. The hydrolysis product was isolated and identified as ethanol and amino‐tert‐butyl phosphate. The compound was shown to react with the model nucleophile 4‐( p ‐nitrobenzyl) pyridine (NBP) comparably to previously studied alkylating agents. The intravenous LD 50 was 198 mg/kg and the intraperitoneal LD 50 was 159 mg/kg in ICR/Ha male mice. In mice carrying Ehrlich ascites tumor (E‐2), 30 mg/kg of AB‐163 resulted in 95% tumor inhibition. In Sarcoma‐180 inoculated mice, 15 mg/kg caused a 20–30% apparent cure rate and a 62% tumor inhibition of the animals having tumors. Against Adenocarcinoma 755, 40 mg/kg exhibited a 60% cure rate and 50% tumor inhibition of the animals with tumors. Leukemia L1210 treated on days 1–11 was cured in 20–30% of the animals receiving 30 mg/kg of AB‐163 and there was a 76–170% increase in survival time in the remaining animals. In animals infected with Friend virus, a 40 mg/kg dose resulted in 65% reduction of splenic weight as compared to controls. Studies in dogs indicated that the main toxicity is hematopoietic depression. Terminally, depression of liver functions was observed. High doses produced central nervous system effects which manifested themselves in loss of appetite, vomiting, increased salivation, lethargy, and convulsions.