The preventive effect of ketoconazole on experimental metastasis from a human pancreatic carcinoma may be related to its effect on prostaglandin synthesis

George N Tzanakakis, Elias Krambovitis, Aristidis M Tsatsakis, Michael P Vezeridis
International Journal of Gastrointestinal Cancer 2002, 32 (1): 23-30

BACKGROUND: Arachidonic acid metabolites known to affect platelet function also interfere with tumor growth and metastases. The purpose of this study was to evaluate the anti-metastatic potential of ketoconazole, a thromboxane synthetase and 5-lipoxygenase inhibitor, on hepatic metastasis from a human pancreatic adenocarcinoma in nude mice and its effect on serum prostaglandin levels.

METHODS: The human pancreatic tumor cells (RWP-2) were injected intrasplenically in nude mice grouped into control, ketoconazole (270 microg), ketoconazole (360 microg), and ketoconazole (540 microg). The agent was administered intraperitoneally 30 min before and every 24 h after the tumor cell inoculation for 8 days. In a separate experiment thromboxane B2 (TxB2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2) and 6-Keto-F1a (stable prostacyclin derivative) were measured on blood from controls, tumor bearing animals and animals bearing tumors treated with 270 microg of ketoconazole.

RESULTS: Statistically significant differences were observed between the control and three-treatment groups on the reduction of liver tumor nodules (p < 0.001), and in the liver surface areas occupied by tumor (p < 0.001). The TxB2 levels decreased from 150.6 ng/mL in the tumor bearing to 104.8 ng/mL in the ketoconazole treated animals (p < 0.05). PGD2, PGE2 and 6-keto-F1a levels increased to 7.1 ng/mL, 8.3 ng/mL, and 13.6 ng/mL from 3 ng/mL, 5.8 ng/mL, and 0.02 ng/mL respectively (p < 0.001).

CONCLUSIONS: These results indicate that ketoconazole significantly reduced hepatic metastases from the human pancreatic carcinoma RWP-2 in the nude mouse model, and inhibited thromboxane B2 formation, potentiating a concomitant redirection of platelet endoperoxide metabolism into PGD2, PGE2, and 6-keto-F1a. It is hypothesized that the changes in the arachidonic acid metabolism mediate the ameliorating effect of ketoconazole on experimental hepatic metastasis.

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