Derivatives of butyric acid as potential anti-neoplastic agents

Abstract

A novel derivative of butyric acid, pivalyloxymethyl butyrate (AN-9) has been shown, in vitro, to: (a) induce cytodifferentiation and inhibit the proliferation of leukemic cells; (b) inhibit the growth and formation of Lewis lung carcinoma colonies in semi-solid agar. AN-9 affect cells at about 10-fold lower concentration and at a faster rate than does butyric acid. The pivalyloxymethyl esters of propionic, isobutyric and valeric acids do not elicit effects similar to those of AN-9, while the isobutyryloxymethyl butyrate does, which strongly suggests that the activity of AN-9 stems from intracellular metabolic degradation of the pro-drug to butyric acid. In vivo, AN-9, increased the survival of mice in Lewis lung carcinoma primary cancer model and significantly decreased the number of lung lesions of the animals inoculated with highly metastatic cells, but did not affect their life span. Acute LD50 studies have shown that AN-9 possesses low toxicity. These results suggest that AN-9 is a potential anti-neoplastic agent as well as a tool for investigation of the differentiation induction mechanism.