SELECTION OF A HIGHLY TUMORIGENIC BREAST-CANCER CELL-LINE SENSITIVE TO ESTRADIOL TO EVIDENCE IN-VIVO THE TUMOR-INHIBITORY EFFECT OF BUTYRATE DERIVATIVE MONOBUT-3

To increase butyric acid mean residence time in vivo, we have produced a stable butyric acid derivative, Monobut-3. Recently, we have described that Monobut-3 is able to induce phenotypic changes in human mammary tumor cells in vitro. In this study, we explore the in vivo effect of Monobut-3. Human breast tumor cell-lines did not easily produce in vivo xenografts, thus, MCF-7 cells required exogenous 17 beta-estradiol to grow and to form in vivo xenografts. To evaluate in vivo anti-tumor effects of monobut-3 without exogenous 17 beta-estradiol addition, we have established MCF-7 variant cells, highly tumorigenic MCF-7vht, in which transfection of ras oncogene induced a bypass of estrogen requirement but did nor delete the presence of functional estrogen receptor (ER). Monobut-3 inhibited growth of this variant by about 90% at 4 mM and reduced 17 beta-estradiol cell growth stimulation. In vivo, in absence of 17 beta-estradiol, 2 mg per mouse monobut-3 decreased tumor take by about 25% and tumor growth by about 50% in nude mice. This is the first experimental demonstration of an in vivo antitumoral effect of a butyric acid derivative alone on a solid human tumor. These data suggest that this compound does not only act by reducing of 17 beta-estradiol stimulation but it also has an 17 beta-estradiol-independent effect. Absence of toxicity and its antiproliferative effects could suggest its use in clinical treatment of well differentiated carcinoma.