The effects of testosterone on early atherogenesis and the role of aromatase, an enzyme that converts testosterone to estrogens, were assessed in low density lipoprotein receptor-deficient male mice fed a Western diet. Castration of male mice increased the extent of fatty streak lesion formation in the aortic origin compared with testes-intact animals. Administration of anastrazole, a selective aromatase inhibitor, to testes-intact males increased lesion formation to the same extent as that observed with orchidectomized animals. Testosterone supplementation of orchidectomized animals reduced lesion formation when compared with orchidectomized animals receiving the placebo. This attenuating effect of testosterone was not observed when the animals were treated simultaneously with the aromatase inhibitor. The beneficial effects of testosterone on early atherogenesis were not explained by changes in lipid levels. Estradiol administration to orchidectomized males attenuated lesion formation to the same extent as testosterone administration. Aromatase was expressed in the aorta of these animals as assessed by reverse transcription-PCR and immunohistochemistry. These results indicate that testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall.atherosclerosis ͉ androgens ͉ anastrazole ͉ mice ͉ estrogen

We previously reported that testosterone attenuated atherogenesis in LDLR ؊͞؊ male mice, and that this effect of testosterone was most likely caused by its conversion to estradiol. Estradiol inhibits vascular cell adhesion molecule-1 (VCAM-1) expression, and expression of VCAM-1 is one of the early events in atherogenesis. We assessed the cellular mechanism(s) involved by which testosterone attenuates atherogenesis. We evaluated whether testosterone inhibited TNF␣-induced VCAM-1 expression via its conversion to estradiol by the enzyme aromatase in human umbilical vein endothelial cells (HUVEC). Aromatase mRNA was dedected by reverse transcription-PCR in these cells. Testosterone (30 nM-1 M) attenuated VCAM-1 mRNA expression in a concentration-dependent manner. The non aromatizable androgen, dihydrotestosterone, had no effect on VCAM-1 mRNA expression. Testosterone was less effective in attenuating VCAM-1 expression in the presence of anastrozole, an inhibitor of aromatase, indicating that testosterone inhibited VCAM-1 via conversion to estradiol. Estradiol also attenuated VCAM-1 mRNA expression, but this action was not abolished in the presence of anastrozole, indicating that anastrozole itself did not modulate VCAM-1 mRNA expression. The effect of testosterone on VCAM-1 mRNA expression was inhibited in the presence of the estrogen receptor antagonist, ICI-182780. Testosterone also attenuated TNF␣-induced VCAM-1 protein expression, and this attenuation was abolished in the presence of anastrozole. In conclusion, testosterone inhibited VCAM-1 mRNA and protein expression in HUVEC by its conversion to estradiol via the enzyme aromatase present in the endothelial cells. Results from our study may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system. atherosclerosisat ͉ sex steroids ͉ androgens

SummaryIntroduction Aldoxorubicin, a prodrug of doxorubicin, binds covalently to serum albumin in the bloodstream and accumulates in tumors. Aldoxorubicin can be administered at doses several-fold higher than doxorubicin can, without associated acute cardiotoxicity. Purpose This study fully evaluated the pharmacokinetic profile of aldoxorubicin (serum and urine). Methods Eighteen patients with advanced solid tumors received aldoxorubicin 230 or 350 mg/m2 (equivalent in drug load to doxorubicin at doses of 170 or 260 mg/m2, respectively) once every 21 days. Blood samples were taken in cycle 1 before aldoxorubicin infusion, and at 5, 15, 30, and 60 min, and at 2, 4, 8, 12, 16, 24, 48, and 72 h after infusion. Urine samples were taken in cycle 1 at 24, 48, and 72 h after infusion. Limited blood sampling was done in cycle 3, before aldoxorubicin infusion, and at 60 min and at 2, 4, and 8 h after infusion. Results The long mean half-life (20.1–21.1 h), narrow mean volume of distribution (3.96–4.08 L/m2), and slow mean clearance rate (0.136–0.152 L/h/m2) suggest that aldoxorubicin is stable in circulation and does not accumulate readily in body compartments outside of the bloodstream. Very little doxorubicin and its major metabolite doxorubicinol, which has been implicated in doxorubicin-associated cardiotoxicity, are excreted in urine. This might explain the lack of cardiotoxicity observed thus far with aldoxorubicin. Conclusions Our findings support dosing and administration schemas used in an ongoing phase 3 clinical study of aldoxorubicin in soft tissue sarcoma, and phase 2 clinical studies in small cell lung cancer, glioblastoma, and Kaposi’s sarcoma.

17-␤ estradiol (17-␤ E 2 ) attenuates the expression of vascular cell adhesion molecule 1 (VCAM-1) in vivo at physiological levels (pg/ml), whereas supraphysiological concentrations of 17-␤ E 2 (ng/ml) are required in vitro. We assessed whether a metabolite of estrogen, which could only be generated in vivo, might be a more potent inhibitor of VCAM-1 expression and thereby explain this discrepancy. We report here that 17-epiestriol, an estrogen metabolite and a selective estrogen receptor (ER) ␤ agonist, is ϳ400؋ more potent than 17-␤ E 2 in suppressing tumor necrosis factor (TNF) ␣-induced VCAM-1 mRNA as well as protein expression in human umbilical vein endothelial cells. Genistein, an ER␤ agonist, at low concentrations (1 and 10 nM) also suppressed TNF␣-induced VCAM-1 mRNA expression. These actions of 17-epiestriol and genistein were significantly attenuated in the presence of the estrogen receptor antagonist ICI-182780. Other estrogenic compounds such as ethinyl estradiol and estrone did not have any effect on TNF␣-induced VCAM-1 expression at the concentrations tested. We further show that, 1) 17-epiestriol induces the expression of endothelial nitric-oxide synthase mRNA and protein, 2) 17-epiestriol prevents TNF␣-induced migration of NFB into the nucleus, 3) N G -nitro-L-arginine methyl ester, an inhibitor of NO synthesis, abolishes 17-epiestriol-mediated inhibition of TNF␣-induced VCAM-1 expression and migration of NFB from the cytoplasm to the nucleus. Our results indicate that 17-epiestriol is more potent than 17-␤ E 2 in suppressing TNF␣-induced VCAM-1 expression and that this action is modulated at least in part through NO.The mechanism by which estrogens attenuate the development of atherosclerosis is not known, although various actions of estrogens have been suggested to mediate this effect (1). We have previously demonstrated that 17-␤ estradiol (17-␤ E 2 ) in vivo inhibits the adhesion of monocytes to endothelial cells of the rabbit aorta (2). We also demonstrated that following a cholesterol-enriched diet to ovariectomized rabbits, expression of VCAM-1 1 protein was induced in the aorta, and this was attenuated by administration of 17-␤ E 2 (2). Treatment of cultured rabbit aortic endothelial cells with 17-␤ E 2 also attenuated the lysophosphatidylcholine-induced expression of VCAM-1 protein. However, the concentrations of 17-␤ E 2 required to suppress VCAM-1 expression in vitro were in the supraphysiological range when compared with the physiological levels required for in vivo studies. We therefore postulated that one mechanism by which only relatively low concentrations of 17-␤ E 2 were required for in vivo studies when compared with in vitro studies was that 17-␤ E 2 might be converted to a more potent metabolite in vivo (2).Some effects of estrogens are mediated through non-genomic mechanisms, whereas others require transcriptional activation of genes (3). These latter actions usually require that estrogens combine with specific receptors. Two types of estrogen receptors (ER) have been descr...

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