Hepatic artery dexamethasone infusion inhibits colorectal hepatic metastases: A regional antiangiogenic therapy |
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Authors: | Yoshito Arisawa MD PhD Erika Sutanto-Ward BS Lucio Fortunato MD Dr Elin R Sigurdson MD PhD |
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Institution: | (1) From the Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA;(2) Surgical Oncology Laboratory, Fox Chase Cancer Center, 7701 Burholme Avenue, 19111 Philadelphia, PA, USA |
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Abstract: | Background: A randomized 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 107 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 heparanized
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. |
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Keywords: | Hepatic metastasis Colorectal cancer Intraarterial chemotherapy Dexamethasone Angiogenesis |
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