Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer

Abstract

Matrix metalloproteinases (MMP) are considered to be critically involved in tumor invasion and the metastasis of various cancers. MMI-166 is a selective inhibitor of matrix metalloproteinase (MMP-2, MMP-9, and MMP-14). The purpose of this study was to evaluate the effects of MMI-166 on both the growth of the implanted tumor and the lymph node metastasis of the mediastinum and prolonging the life span, using an orthotopic implantation model of the Ma44-3 cancer cell line. We examined the anti-invasive effect of MMI-166 in lung cancer cell lines using an in vitro invasion assay. Next, we examined the anticancer effect of MMI-166 in vivo. MMI-166 (200 mg/kg body weight) or a vehicle was administered orally to the orthotopically implanted lung cancer model. MMI-166 dose-dependently inhibited the invasion of cancer cell lines with expressions of MMP-2 and/or MMP-9 in vitro. In vivo, MMI-166 significantly inhibited mediastinal lymph node metastasis in this orthotopic model (weight of the mediastinum: control, 0.089 F 0.009 versus MMI-166, 0.069 F 0.008 mg; P = 0.005; metastatic area: control, 93,495 F 55,747 versus MMI-166, 22,747 F 17,478 pixels; P = 0.045). MMI-166 prolonged the life span by 6 days in median survival time in the orthotopically implanted model (P = 0.039). These results showed that MMI-166 could possibly inhibit lymph node metastasis and prolong the life span in lung cancer patients. [Mol Cancer Ther 2005; 4(9):1409 -16]

Safe lipid nanocapsule-based gel technology to target lymph nodes and combat mediastinal metastases from an orthotopic non-small-cell lung cancer model in SCID-CB17 mice

“…Arrows and circles in the picture indicate the localization of detectable, mediastinal lymph nodes and tumor mass, respectively. 36 Despite the presence of the primary lung tumor responsible for cancer cells spreading to the mediastinum, Gem-C12 LNCs only localized in mediastinum lymph nodes were able to exert the same antitumor efficacy as the systemic administration of Gem-C12 (loaded in LNCs or micelles) (Figure 2, A), which exerted a systemic anticancer activity (i.e., on primary lung tumor and therefore on the spreading of mediastinal metastases) and resulting in the increase of the survival lifespan to the same extent (Figure 2, A). Moreover, this similar survival improvement by targeting only lymph nodes was also accompanied by lower systemic side effects.…”

Matrix metalloproteinases and tumor metastasis

“…Significant inhibition of breast cancer metastases in brain was achieved in a rat model when animals were treated with a synthetic inhibitor (PD 166793) [107]. In animals that received a selective MMP inhibitor against MMP-2, MMP-9 and MMP-14 (MMI-166), a significant decrease was shown for lymph node metastasis from lung carcinoma [108]. Overall, the results of these MMP inhibition studies indicated a beneficial effect of early administration of MMP inhibitors, a notion which became apparent after evaluation of clinical trials in cancer patients.…”

Recent advances in MMP inhibitor design

“…It is an MMP-2, -9 and -14 selective inhibitor that spares MMP-1, -3 and -7. While it has shown anticancer activity in numerous animal models of human cancer (including implanted lung cancer, melanoma, squamous carcinoma, colon and cervical) [64,65], there are no data as to its clinical performance. The key structural feature exemplified by MMI-166 is the "deep" aryl (here, a triaryl) substitution.…”