HEPATIC-ARTERY DEXAMETHASONE INFUSION INHIBITS COLORECTAL HEPATIC METASTASES - A REGIONAL ANTIANGIOGENIC THERAPY

Background: A randomized trial treating colorectal hepatic metastases demonstrated that hepatic arterial floxuridine (FUdR) with dexamethaso ne increased tumor response compared with hepatic arterial FUdR alone (Cancer 1992;69:327-34). The mechanism of this improvement is unclear. Methods: We investigated the effect of hepatic arterial dexamethasone with or without FUdR on the growth of colorectal hepatic metastases i n an animal model. BD-IX rats were inoculated intrasplenically with 10 (7) K12/TRb colon cancer cells on day 0. On day 14, the hepatic metast ases were counted and hepatic arterial catheters placed for chemothera py. Forty-eight animals were randomized to 4 groups for 14 days of inf usion with heparinized saline alone (group A), heparinized saline with dexamethasone 0.03 mg/kg/d (group B), heparinized saline with FUdR 2 mg/kg/d (group C), or heparanized saline with dexamethasone 0.03 mg/kg /d plus FUdR 2 mg/kg/d (group D). The hepatic metastases were recounte d by laparotomy on day 28. Response in each rat was expressed in terms of percentage change in number of hepatic nodules between the number of hepatic nodules seen on days 14 and 28. In vitro chemosensitivity o f K12/TRb to dexamethasone with or without FUdR was examined using an MTT (4,5-dimethylthiazole-2-yl-2,5-diphenyltetrazolium bromide; Sigma, St. Louis, MO, U.S.A.) assay. The effect of dexamethasone on tumor-in duced angiogenesis was tested using an in vivo assay. Results: The mea n percentage change in tumor nodules was + 129% in group A, + 17% in g roup B, -4% in group C, and -29% in group D (p = 0.002 A vs. B, p = 0. 04 C vs, D). The MTT assay showed that dexamethasone had no direct eff ect on K12/TRb growth or on tumor FUdR sensitivity. Dexamethasone inhi bited K12/TRb-induced angiogenesis in vivo. Conclusions: Hepatic arter ial dexamethasone is effective in treating colorectal hepatic metastas es and is more effective when combined with hepatic arterial FUdR, The antiangiogenic activity of dexamethasone may partially contribute to its efficacy.