Ketoconazole: a thromboxane synthetase and 5-lipoxygenase inhibitor with antimetastatic activity in B16-F10 melanoma.
Arachidonic acid metabolites have been implicated in the development of hematogenous tumor metastases. The purpose of this study was to determine the antimetastatic potential of ketoconazole, a thromboxane synthetase and 5-lipoxygenase inhibitor. One hundred seventy-four C57 black male mice were randomized to receive either placebo or 0.0057 mg/g of ketoconazole. Drug and placebo were delivered once daily by intraperitoneal injection beginning 24 hr prior to tumor injection and continuing until sacrifice. All animals were injected subcutaneously in the flank with 5 x 10(6) B16-F10 melanoma cells. Animals were sacrificed at 3 weeks (n = 60), 4 weeks (n = 84), and 5 weeks (n = 30). Metastases were assessed by circumferential inspection of the lungs of all animals at autopsy. Differences in survival and primary tumor mass between study groups were not statistically significant. Pulmonary metastases were present in 37/174 animals. Twenty-nine of the mice with metastases were in the placebo groups, and 8 were in the ketoconazole groups. The incidence of metastases was significantly reduced in the ketoconazole-treated mice compared to placebo both within each group and overall, P was less than 0.05 and 0.001, respectively. This effect was not mediated through changes in local tumor growth.
Nardone
P A
PA
Department of Internal Medicine, University of Massachusetts Medical School, Worcester.
Slotman
G J
GJ
Vezeridis
M P
MP
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D007654:Ketoconazole / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D008545:Melanoma / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D016859:Lipoxygenase Inhibitors; D001091:Arachidonate Lipoxygenases; D013930:Thromboxane-A Synthase; D007654:Ketoconazole