Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Antimetastatic and Antitumor Effect of a Recombinant Human Tissue Inhibitor of Metalloproteinases-2 in Murine Melanoma Models
Tohru OKUNaomi ATAKayoko YONEZAWAHideaki TOKAIHideki FUJIIAkira SHINAGAWAEiko OHUCHIIkuo SAIKI
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1997 Volume 20 Issue 8 Pages 843-849

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Abstract

Tumor metastasis into distinct organs and tissues, of which many patients with malignancies die, is regulated in multiple steps. Using a murine metastasis model, in which highly metastatic B16-BL6 melanoma cells were inoculated i.v. into syngeneic C57BL/6 mice, the administration of a recombinant human tissue inhibitor of metalloproteinases-2 (r-hTIMP-2) once a day on days -1 to 3 after the implantation significantly inhibited the formation of metastatic foci in the lungs. The antimetastatic 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 manner. The i.m.-injection of r-hTIMP-2 during the early phase after tumor inoculation is suggested to be essential for antimetastasis. In another model using spontaneously metastasing B16-BL6 cells, multiple i.m.-injections of r-hTIMP-2 also resulted in a reduced but not statistically significant number of pulmonary metastases. In addition to these antimetastatic effects, a slight inhibitory effect on tumor cell growth was observed in vitro and in vivo. In conclusion, the antimetastasis by r-hTIMP-2 may be due to inhibition of the degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and, in part, to the suppression of the tumor cell growth.

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