Inhibition of spontaneous rat osteosarcoma lung metastasis by 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydroc arbostyril, a novel matrix metalloproteinase inhibitor.
In the present experiment, we examined the effects of OPB-3206, 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4- dihydrocarbostyril, a novel metalloproteinase inhibitor, on the growth and metastasis of transplantable osteosarcomas (spontaneous osteosarcoma, selected lung metastatic lesions; S-SLM), which were previously established in rats. OPB-3206 inhibited the activities of interstitial collagenase, gelatinases A and B, and stromelysin in vitro. After oral administration to rats, its serum concentration peaked at 40 min and the drug was no longer detectable at 8 h. When OPB-3206 was orally administered at 0%, 0.1% and 0.4% in the diet for 4 weeks, starting 7 days after subcutaneous transplantation of osteosarcomas to male Fischer 344 rats, numbers of lung metastatic nodules were significantly reduced by the highest dose, while the growth of subcutaneous tumors was not affected. Zymographic analysis showed the presence of pro matrix metalloproteinase (proMMP)-2, proMMP-9 and MMP-9 activities in S-SLM. In animals fed 0.4% OPB-3206, the activity of proMMP-9 was increased, but that for MMP-9 had become undetectable. The results thus suggest that OPB-3206 selectively inhibits lung metastasis of rat transplantable osteosarcomas by inhibiting MMP-9 activation.
Kido
A
A
Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara.
Tsutsumi
M
M
Iki
K
K
Motoyama
M
M
Takahama
M
M
Tsujiuchi
T
T
Morishita
T
T
Tatsumi
K
K
Tamai
S
S
Konishi
Y
Y
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D017364:Collagenases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000556:secondary*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D009929:Organ Size; D012516:Osteosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000556:secondary; D015363:Quinolones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D015363:Quinolones; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; C119316:OPB 3206; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3