A third‐generation matrix metalloproteinase (MMP) inhibitor (ONO‐4817) combined with docetaxel suppresses progression of lung micrometastasis of MMP‐expressing tumor cells in nude mice

Abstract

The lung is the common target organ of hematogenous metastasis that restricts the prognosis of cancer patients. MMPs play a pivotal role in metastasis by promoting tumor invasion and angiogenesis; therefore, a large number of MMPIs have been developed. Our purpose was to determine the therapeutic efficacy of a selective‐spectrum MMPI, ONO‐4817 (inhibits MMP‐2 and MMP‐9 but not MMP‐1), against established lung micrometastasis in combination with a cytotoxic anticancer drug, DOC, in a nude mouse model. Human non‐small cell lung cancer PC14PE6 (adenocarcinoma) or H226 (squamous cell carcinoma) cells, expressing MMP‐2, MMP‐9 and/or MMP‐1, were injected i.v. into nude mice on day 0. Mice received a single injection of DOC on day 7 (after establishment of micrometastasis) and/or ONO‐4817 mixed with food from day 7 to the end of experiments. Monotherapy with ONO‐4817 or DOC inhibited formation of lung metastasis by PC14PE6 and H226 cells. In addition, combined use of ONO‐4817 with DOC significantly suppressed the tumor burden of H226 and PC14PE6 cells in the lung and prolonged the survival of PC14PE6‐bearing mice compared to ONO‐4817 or DOC alone. These therapies did not affect the body weight or food intake of tumor‐bearing mice. FIZ revealed that lung lesions, but not nontumor parenchyma of the lung, expressed gelatinolytic activity and that treatment with ONO‐4817 abrogated the gelatinolytic activity in lung lesions. These results suggest that the combined use of MMPIs with cytotoxic anticancer drugs may be helpful in the control of established lung micrometastasis by tumor cells expressing MMPs.