cgs-27023a and Lung-Neoplasms

Matrix metalloproteinases (MMP) have been implicated in several steps of tumor metastasis, such as invasion in the extracellular matrix, intravasation, extravasation, and growth in a distant organ site. Various synthetic MMP inhibitors have been reported to suppress tumor metastasis in animal models. However, there are few reports describing which steps in the metastasis process are most critical for inhibition by MMP inhibitors. In the experimental lung colonization model by i.v. injection of mouse B16-F10 melanoma cells, we found that the daily administration of MMI270 for 2 weeks significantly decreased the number of colonies in the lung compared with the control without affecting the size of colony. Micrometastasis was monitored day 7 post-inoculation by measuring the melanin content in the lung as well as by microscopic examination of the lung tissue sections. Even only twice administrations of MMI270 on the first day after tumor injection significantly inhibited micrometastasis in the lung. In the spontaneous metastasis model using B16-BL6 melanoma cells, lung metastasis was not affected by a continuous administration of MMI270 using a mini osmotic-pump. On the contrary, when mice were subjected to popliteal lymphadenectomy on day 7 after the cell inoculation in the footpad subdermis, the continuous administration of MMI270 significantly suppressed the lung metastasis. These results suggest that the tumor cell extravasation in the target organ is the most critical step where MMPs can play their significant role in the experimental metastasis, and that the lymphatic metastasis process is less susceptible to MMI270 than the hematogenic metastasis process in the spontaneous metastasis model.

Topics: Animals; Hydroxamic Acids; Lung Neoplasms; Male; Matrix Metalloproteinase Inhibitors; Melanoma, Experimental; Mice; Neoplasm Metastasis; Protease Inhibitors; Pyrazines; Sulfonamides

We have investigated the antitumor effects of synthetic MMP inhibitor MMI270 against postoperative lung metastasis from colon cancer in nude rat. The KM12SM human colon cancer cells were injected into the cecal wall, and at 5 weeks after the injection, the cecum was removed including the tumor. Then, 30 mg/kg of MMI270 was administered perorally twice per day for 2 or 4 weeks, either immediately after removal or after week 2 after the removal. At week 7 after the removal, lung metastasis was significantly inhibited by the early administration of MMI270 immediately after the tumor removal but not by the late administration. The survival rates were significantly higher in the rats treated by early administration of MMI270 compared to the survival rate in untreated rats. Moreover, no lung metastasis was detected in some rats with 24-weeks' survival treated by early administration. Lower microvessel density, lower PCNA Index and higher Apoptotic Index in the lung metastases of the rats treated with MMI270 were found compared to those in untreated rats. A beneficial effect of by early administration of MMI270 against postoperative lung metastases may be expected through inhibiting neovascularization of metastases in nude rat.

Topics: Administration, Oral; Animals; Apoptosis; Chemoprevention; Colonic Neoplasms; Humans; Hydroxamic Acids; Lung Neoplasms; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Pyrazines; Rats; Rats, Nude; Sulfonamides; Survival Analysis; Transplantation, Heterologous