Antiangiogenic effect of inhibitors of cytochrome P450 on rats with glioblastoma multiforme.
Cytochrome P450 epoxygenase catalyzes 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) from arachidonic acid (AA). In 1996, our group identified the expression of the cytochrome P450 2C11 epoxygenase (CYP epoxygenase) gene in astrocytes. Because of our finding an array of physiological functions have been attributed to EETs in the brain, one of the actions of EETs involves a predominant role in brain angiogenesis. Blockade of EETs formation with different epoxygenase inhibitors decreases endothelial tube formation in cocultures of astrocytes and capillary endothelial cells. The intent of this investigation was to determine if pharmacologic inhibition of formation of EETs is effective in reducing capillary formation in glioblastoma multiforme with a concomitant reduction in tumor volume and increase in animal survival time. Two mechanistically different inhibitors of CYP epoxygenase, 17-octadecynoic acid (17-ODYA) and miconazole, significantly reduced capillary formation and tumor size in glial tumors formed by injection of rat glioma 2 (RG2) cells, also resulting in an increased animal survival time. However, we observed that 17-ODYA and miconazole did not inhibit the formation of EETs in tumor tissue. This implies that 17-ODYA and miconazole appear to exert their antitumorogenic function by a different mechanism that needs to be explored.
Zagorac
Drazen
D
Department of Physiology, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Jakovcevic
Danica
D
Gebremedhin
Debebe
D
Harder
David R
DR
D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D001253:Astrocytes / Q000201:enzymology* / Q000473:pathology; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008825:Miconazole / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D039181:Steroid 16-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D009363:Neoplasm Proteins; D016718:Arachidonic Acid; C047008:17-octadecynoic acid; D008825:Miconazole; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D015126:8,11,14-Eicosatrienoic Acid