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 dexamethasone 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 in 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 metastases were counted and hepatic arterial catheters placed for chemotherapy. Forty-eight animals were randomized to 4 groups for 14 days of infusion 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 heparinized saline with dexamethasone 0.03 mg/kg/d plus FUdR 2 mg/kg/d (group D). The hepatic metastases were recounted 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 of K12/TRb to dexamethasone with or without FUdR was examined using an MTT (3-(4,5-dimethylthiazole-2-yl-2,5-diphenyltetrazolium bromide; Sigma, St. Louis, MO, U.S.A.) assay. The effect of dexamethasone on tumor-induced angiogenesis was tested using an in vivo assay.


RESULTS
The mean percentage change in tumor nodules was +129% in group A, +17% in group 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 effect on K12/TRb growth or on tumor FUdR sensitivity. Dexamethasone inhibited K12/TRb-induced angiogenesis in vivo.


CONCLUSIONS
Hepatic arterial dexamethasone is effective in treating colorectal hepatic metastases and is more effective when combined with hepatic arterial FUdR. The antiangiogenic activity of dexamethasone may partially contribute to its efficacy.
Arisawa
Y
Y
Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Sutanto-Ward
E
E
Fortunato
L
L
Sigurdson
E R
ER
D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002460:Cell Line; D010478:Chemotherapy, Cancer, Regional Perfusion; D003110:Colonic Neoplasms / Q000473:pathology*; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005467:Floxuridine / Q000008:administration & dosage; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D011919:Rats, Inbred Strains; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D005467:Floxuridine; D003907:Dexamethasone