Our previous studies of intraperitoneal ovarian
carcinoma in a mouse model demonstrated that bikunin gene transfection could prevent
ascites formation and intraperitoneal disseminated
metastasis. Although
ascites was almost completely inhibited,
tumor burden was variably reduced. Several reports have indicated that bikunin may be involved in
tumor survival. In the present study, the effectiveness of exogenous bikunin and the biodistribution characteristics of (125)I-bikunin were initially examined in a mouse model of human
ovarian cancer HRA cells. The once-daily i.p. administration of bikunin significantly decreased progressive growth of HRA
tumors and
ascites formation in a dose-dependent manner. Maximal
radioisotope tumor uptake peaked at 7.4% injected dose/g at 3 hr. Bikunin binding specificity was demonstrated by reduced
tumor uptake after coinjection of excess nonradioactive bikunin. Bikunin was rapidly excreted renally. The bikunin
therapy produced the significant inhibition in expression of the proteolysis (uPA and uPAR) and angiogenesis-related molecules (
VEGF and bFGF). The second purpose of our study was to optimize the antimetastatic activity of bikunin in combination with
paclitaxel against HRA cells growing orthotopically in mice. The once-daily i.p. administration of bikunin (25 microg/g
body weight/day) in combination with
paclitaxel (i.p., 100 microg/20 g at days 2 and 5) significantly decreased progressive growth of HRA cells in a synergistic fashion. In conclusion, combination
therapy with bikunin plus
paclitaxel may be an effective way to markedly reduce i.p.
tumor growth and
ascites in ovarian
carcinoma possibly through suppression of uPA, uPAR,
VEGF and bFGF expression.