ANTIMETASTATIC AND ANTITUMOR EFFECT OF A RECOMBINANT HUMAN TISSUE INHIBITOR OF METALLOPROTEINASES-2 IN MURINE MELANOMA MODELS

Tumor metastasis into distinct organs and tissues, of which many patie nts with malignancies die, is regulated in multiple steps. Using a mur ine metastasis model, in which highly metastatic B16-BL6 melanoma cell s were inoculated i.v. into syngeneic C57BL/6 mice, the administration of a recombinant human tissue inhibitor of metalloproteinases-2 (r-hT IMP-2) once a day on days -1 to 3 after the implantation significantly inhibited the formation of metastatic foci in the lungs. The antimeta static effect of r-hTIMP-2 was detected irrespective of administration route [i.v., i.p., s.c., and i.m. routes] and in a dose-dependent man ner. The i.m.-injection of r-hTIMP-2 during the early phase after tumo r inoculation is suggested to be essential for antimetastasis. In anot her model using spontaneously metastasing B16-BL6 cells, multiple i.m. -injections of r-hTIMP-2 also resulted in a reduced but not statistica lly significant number of pulmonary metastases. In addition to these a ntimetastatic effects, a slight inhibitory effect on tumor cell growth was observed in vitro and in vivo. In conclusion, the antimetastasis by r-hTIMIP-2 may. be due to inhibition of the degradation of the extr acellular matrix by matrix metalloproteinases (MMPs) and, in part, to the suppression of the tumor cell growth.