BACKGROUND Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. METHODS We tested the anti–basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. RESULTS In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (−65% vs. −11%, P = 0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas. CONCLUSIONS Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.)
The cytochrome P-450 4A (CYP4A)-derived arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) affects renal tubular and vascular functions and has been implicated in the control of arterial pressure. We examined the effect of antisense oligonucleotide (ODN) to CYP4A1, the low K(m) arachidonic acid omega-hydroxylating isoform, on vascular 20-HETE synthesis, vascular reactivity, and blood pressure in the spontaneously hypertensive rat (SHR). Administration of CYP4A1 antisense ODN decreased mean arterial blood pressure from 137 +/- 3 to 121 +/- 4 mmHg (P < 0.05) after 5 days of treatment, whereas treatment with scrambled antisense ODN had no effect. Treatment with CYP4A1 antisense ODN reduced the level of CYP4A-immunoreactive proteins along with 20-HETE synthesis in mesenteric arterial vessels. Mesenteric arteries from rats treated with antisense ODN exhibited decreased sensitivity to the constrictor action of phenylephrine (EC(50) 0.69 +/- 0.17 vs. 1.77 +/- 0.40 microM). Likewise, mesenteric arterioles from antisense ODN-treated rats revealed attenuation of myogenic constrictor responses to increases of transmural pressure. The decreased vascular reactivity and myogenic responses were reversible with the addition of 20-HETE. These data suggest that CYP4A1-derived 20-HETE facilitates myogenic constrictor responses in the mesenteric microcirculation and contributes to pressor mechanisms in SHR.
20-Hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictor and mediator of the myogenic response, is a major arachidonic acid metabolite in the microvasculature of the rat kidney formed primarily by the cytochrome P-450 (CYP) 4A isoforms, CYP4A1, CYP4A2, and CYP4A3. We examined CYP4A isoform expression and 20-HETE synthesis in microdissected interlobar, arcuate, and interlobular arteries; mRNA for all CYP4A isoforms was identified by RT-PCR. Western blot analysis indicated that the levels of CYP4A2/4A3-immunoreactive protein increased with decreased arterial diameter, whereas those of CYP4A1-immunoreactive protein remained unchanged. 20-HETE synthesis was the highest in the interlobular arteries (17 +/- 1.62 nmol. mg(-1). h(-1)) and, like CYP4A2/4A3-immunoreactive protein, decreased with increasing vessel diameter (4.5 +/- 1.21, 2.65 +/- 0.58, and 0.81 +/- 0.14 nmol. mg(-1). h(-1) in the arcuate, interlobar, and segmental arteries, respectively). 20-HETE synthesis in the renal artery and the abdominal aorta was undetectable. The observed decreased immunoreactivity of NADPH-cytochrome P-450 (c) oxidoreductase with increased arterial diameter provided a possible explanation for the decreased capacity to generate 20-HETE in the large arteries. The increase in CYP4A isoform expression and 20-HETE synthesis with decreasing diameter along the preglomerular arteries and the potent biological activity of 20-HETE underscore the significance of 20-HETE as a modulator of renal hemodynamics.
Hypertension is a leading cause of cardiovascular, cerebral, and renal disease morbidity and mortality, and epidemiological evidence suggests a role for sex-dependent mechanisms in the pathophysiology of hypertension. We show here that treatment of rats with 5␣-dihydrotestosterone increases the activity of the kidney arachidonate /-1 hydroxylase and the biosynthesis of 20-HETE (165 and 177% of control untreated male and female rats, respectively) and raises the systolic blood pressures of male and females rats by 46 and 57 mmHg, respectively. These androgen effects are associated with an upregulation in the kidney levels of CYP 4A8 mRNA and a decrease in CYP 4A1 transcripts. Dissected renal microvessels, the target tissue for most of the prohypertensive actions of 20-HETE, show an androgen-dependent upregulation of vascular CYP 4A8 mRNA and a fourfold increase in 20-HETE synthase activity. We propose that androgens regulate renal function and systemic blood pressure through a combination of transcriptional and hemodynamic mechanisms that are ultimately responsible for the regulation of renovascular tone and function. P-450 eicosanoids; androgens; CYP 4A8A NOW CONSIDERABLE BODY of evidence shows that microsomal P-450s (CYPs) participate in the in vivo metabolism of arachidonic acid (AA) and that products of this P-450-catalyzed pathway are in vitro modulators of renal ion transport and vascular reactivity and may be involved in the regulation of systemic blood pressure (3, 4,22,29). During catalytic turnover, the P-450 monooxygenase(s) metabolize AA via /-1 hydroxylation (AA /-1 hydroxylase) to 19-and 20-HETE and/or epoxidation (AA epoxygenase) to 5,8,11,or 14,5). Recombinant CYPs 4A1, 4A2, 4A8, and to a lesser extent 4A3, support the hydroxylation of AA to either 20-HETE or to mixtures of 16,19,31). All four CYP 4A isoforms are expressed in the male rat kidney (4,16,19,31), with CYPs 4A1 and 4A2/4A3 characterized as the predominant microsomal AA /-1 hydroxylases (16). The transcriptional regulation of rat CYPs P-450 4A1 and 4A2/4A3 by the peroxisomal proliferator activated receptor-␣ (45), as well as the sexually dimorphic, testosterone-sensitive expression of rat CYPs 4A2 and 4A8 and of murine Cyp 4a12, has been reported (18,20,40,42).Studies with the spontaneously hypertensive-Wistar Kyoto (SHR/WKY) rat model of spontaneous hypertension, an extensively characterized model of genetic hypertension (29), suggest a role for renal CYP 4As in the pathophysiology of the disease (3, 29). Thus based on 1) temporal associations between the increases in blood pressure, renal CYP 4A expression and 20-HETE formation (3, 29), 2) experimental manipulations of CYP 4A activity and/or expression (29,32,43), and 3)
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