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

Citation
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
Citations number
29
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
JAPANESE JOURNAL OF CANCER RESEARCH
ISSN journal
09105050 → ACNP
Volume
90
Issue
3
Year of publication
1999
Pages
333 - 341
Database
ISI
SICI code
0910-5050(199903)90:3<333:IOSROL>2.0.ZU;2-A
Abstract
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.