Inhibition of spontaneous rat osteosarcoma lung metastasis by 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril, a novel matrix metalloproteinase inhibitor
A. Kido et al., Inhibition of spontaneous rat osteosarcoma lung metastasis by 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril, a novel matrix metalloproteinase inhibitor, JPN J CANC, 90(3), 1999, pp. 333-341
In the present experiment, we examined the effects of OPB-3206, 3S-[4-(N-hy
droxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril a no
vel metalloproteinase inhibitor, on the growth and metastasis of transplant
able osteosarcomas (spontaneous osteosarcoma, selected lung metastatic lesi
ons; S-SLM), which were previously established in rats. OPE-3206 inhibited
the activities of interstitial collagenase, gelatinases A and B, and strome
lysin ill vitro. After oral administration to rats, its serum concentration
peaked at 40 min and the drug was no longer detectable at 8 h, When OPE-32
06 was orally administered at 0%, 0.1% and 0.4% in the diet for 4 weeks, st
arting 7 days after subcutaneous transplantation of osteosarcomas to male F
ischer 344 rats, numbers of lung metastatic nodules were significantly redu
ced by the highest dose, while the growth of subcutaneous tumors was not af
fected. Zymographic analysis showed the presence of pro matrix metalloprote
inase (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 OPE-3206 selectively in
hibits lung metastasis of rat transplantable osteosarcomas by inhibiting MM
P-9 activation.