Rephaeli A, Rabizadeh E, Aviram A, Shaklai M, Ruse M, Nudelman A
Hematology Division, Beilinson Hospital, Petach Tikva, Israel.
Int J Cancer. 1991 Aug 19;49(1):66-72. doi: 10.1002/ijc.2910490113.
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.
一种新型丁酸衍生物，特戊酰氧基甲基丁酸酯（AN - 9），在体外已显示出：（a）诱导细胞分化并抑制白血病细胞的增殖；（b）抑制Lewis肺癌细胞在半固体琼脂中的生长和集落形成。与丁酸相比，AN - 9影响细胞的浓度约低10倍，且速度更快。丙酸、异丁酸和戊酸的特戊酰氧基甲酯不会引发与AN - 9类似的效应，而异丁酰氧基甲基丁酸酯则会，这强烈表明AN - 9的活性源于前药在细胞内代谢降解为丁酸。在体内，AN - 9提高了Lewis肺癌原发癌模型中小鼠的存活率，并显著减少了接种高转移性细胞的动物肺部病变的数量，但不影响它们的寿命。急性半数致死量研究表明AN - 9毒性较低。这些结果表明AN - 9是一种潜在的抗肿瘤药物以及研究分化诱导机制的工具。
