The preventive effect of ketoconazole on experimental metastasis from a human pancreatic carcinoma may be related to its effect on prostaglandin synthesis.
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.
Tzanakakis
George N
GN
Department of Histology, School of Medicine, University of Crete, Heraklion, Greece. tzanakak@med.uoc.gr
Krambovitis
Elias
E
Tsatsakis
Aristidis M
AM
Vezeridis
Michael P
MP
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000230:Adenocarcinoma / Q000188:drug therapy / Q000517:prevention & control / Q000556:secondary*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D007274:Injections, Intraperitoneal; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011448:Prostaglandin Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011453:Prostaglandins / Q000096:biosynthesis*; D013929:Thromboxane B2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D015232:Dinoprostone; D007654:Ketoconazole; D015230:Prostaglandin D2