Matrix metalloproteinase inhibitor, MMI270 (CGS27023A) inhibited hematogenic metastasis of B16 melanoma cells in both experimental and spontaneous metastasis models.
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.
Kasaoka
Tatsuhiko
T
Tsukuba Research Institute, Novartis Pharma K.K., Ohkubo 8, Tsukuba-shi, Ibaraki 300-2611, Japan. tatsuhiko.kasaoka@novartis.com
Nishiyama
Hiroko
H
Okada
Mikiko
M
Nakajima
Motowo
M
D000818:Animals; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000556:secondary*; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use
C097658:CGS 27023A; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011719:Pyrazines; D013449:Sulfonamides