CONTROLLED-RELEASE OF TGF-BETA(1) IMPEDES RAT COLON CARCINOGENESIS IN-VIVO

Transforming growth factor beta(1) (TGF-beta(1)) is a cytokine known t o play a key role in the control of cell growth. TGF-beta(1) potently inhibits the proliferation of human and rodent-derived epithelial cell s, Colonic precancerous and moderately differentiated cancer cells are responsive to TGF-beta(1) whereas malignant colon cancer cells are re sistant: to the inhibitory action of the cytokine, These observations have been derived exclusively from in vitro studies. Therefore, the ma in aim of our study was to determine whether TGF-beta(1) exerts a grow th-restraining action on colon carcinogenesis in vivo. TGF-beta(1) was sequestered into ethylene acetate copolymer matrices and ''loaded'' p reparations were implanted intraperitonearly (i.p.) in rats. One week later, the animals were treated with dimethylhydrazine (DMI-I), a colo n procarcinogen. Empty matrices devoid of TGF-beta(1) but containing b ovine serum albumin (BSA) carrier served as the appropriate control pr eparations. The number of aberrant crypt foci (ACF), considered to be preneoplastic lesions of the colon, was scored. Tumor formation and si ze were assessed at the appropriate times. TGF-beta(1) released in a s ustained manner from copolymer matrices: (i) markedly inhibited coloni c ACF formation and the number of aberrant crypts and (ii) significant ly reduced colonic tumor formation and size. (C) 1998 Wiley-Liss, Inc.