Originally published as JCO Early Release 10.1200/JCO.2005.02.0503 on January 30 2006

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Mechanisms of Hypertension Associated With BAY 43-9006

Maria Luisa Veronese, Ari Mosenkis, Keith T. Flaherty, Maryann Gallagher, James P. Stevenson, Raymond R. Townsend, Peter J. O'Dwyer

From the Abramson Cancer Center at the University of Pennsylvania; and Department of Medicine, University of Pennsylvania, Philadelphia, PA

Address reprint requests to Peter J. O'Dwyer, MD, Abramson Cancer Center, University of Pennsylvania, 51 N 39th St, MAB-103, Philadelphia, PA 19104; e-mail: peter.odwyer{at}uphs.upenn.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: BAY 43-9006 (sorafenib) is an inhibitor of Raf kinase, the vascular endothelial growth factor (VEGF) receptor-2, and angiogenesis in tumor xenografts. The current study investigated the incidence, severity, and mechanism of blood pressure (BP) elevation in patients treated with BAY 43-9006.

PATIENTS AND METHODS: Twenty patients received BAY 43-9006 400 mg orally twice daily. BP and heart rate were measured at baseline and then every 3 weeks for 18 weeks. VEGF, catecholamines, endothelin I, urotensin II, renin, and aldosterone were measured at baseline and after 3 weeks of therapy. We assessed vascular stiffness at baseline, after 3 to 6 weeks of therapy, and again after 9 to 10 months of therapy.

RESULTS: Fifteen (75%) of 20 patients experienced an increase of 10 mmHg in systolic BP (SBP), and 12 (60%) of 20 patients experienced an increase of 20 mmHg in SBP compared with their baseline value, with a mean change of 20.6 mmHg (P < .0001) after 3 weeks of therapy. There were no statistically significant changes in humoral factors, although there was a statistically significant inverse relationship between decreases in catecholamines and increases in SBP, suggesting a secondary response to BP elevation. Measures of vascular stiffness increased significantly during the period of observation.

CONCLUSION: Treatment with BAY 43-9006 is associated with a significant and sustained increase in BP. The lack of significant change in circulating factors suggests that these humoral factors had little role in the increase in BP.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Hypertension is emerging as one of the most common adverse effects of therapy with angiogenesis inhibitors. In a phase III trial of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), irinotecan, fluorouracil, and leucovorin in patients with colorectal cancer, hypertension was observed in 22.4% of patients (11% of patients had grade 3 hypertension).¹ Yang et al² reported hypertension in 36% of patients with renal cell carcinoma treated with high-dose bevacizumab. The median time of onset of hypertension was 131 days (range, 7 to 316 days) from the first dose of bevacizumab, and there were no hypertensive crises or deaths attributed to bevacizumab. The hypertension was manageable with standard oral antihypertensive agents. Small-molecule inhibitors of VEGF signaling (PTK787 and SU11248) are associated with similar proportions of patients with hypertension.^3,4

The mechanisms underlying the development of essential hypertension are not well known, but there seem to be several mechanisms. Recent work implicates abnormalities in endothelial function and angiogenesis. Several features of hypertensive patients, including reduced number of arterioles and capillaries, alterations of the microvascular network, decrease in vascular wall compliance and distensibility, reduced nitric oxide bioactivity, and increases in plasma VEGF, are associated with angiogenesis and its control.^5-7 Therefore, it is plausible that disruption of angiogenesis may be reflected in altered blood pressure (BP) control.

BAY 43-9006 (sorafenib) is an orally available inhibitor of c-RAF and b-RAF kinases. A key role for RAF in the control of endothelial cell proliferation and survival has been suggested.⁸ BAY 43-9006 is also a potent inhibitor of the VEGF receptor (VEGFR) -2, VEGFR-3, FLT-3, c-kit, and the platelet-derived growth factor receptor in vitro.⁹ Preclinical studies have demonstrated inhibition of the mitogen-activated protein/extracellular signal-regulated kinase signaling pathway in numerous human cancer cell lines and inhibition of angiogenesis in human tumor xenograft models.⁹ Preliminary results of a large, phase II, multicenter, randomized discontinuation trial revealed significant clinical antitumor activity of BAY 43-9006 in patients with renal cell carcinoma who had failed multiple prior therapies including interferon or interleukin-2.¹⁰ The toxicity profile was favorable, with the most notable adverse events being fatigue, hypertension, diarrhea, and hand-foot syndrome. In the context of this clinical trial at our institution, we had observed the onset and progression of systemic hypertension in seven of the first 24 patients treated with BAY 43-9006 at 400 mg twice daily. These patients experienced an increase of 20 mmHg or more in systolic BP (SBP) compared with their baseline value over the course of the first 6 weeks of therapy. The frequency of significant BP elevations in this and other studies involving inhibitors of angiogenesis suggests that this adverse effect warrants more thorough evaluation. In the current study, we performed serologic and noninvasive vascular compliance evaluations to pursue the mechanisms of hypertension in patients treated with BAY 43-9006. In particular, we analyzed indices of vascular stiffness, including central aortic augmentation index (CAIx) and aortic pulse wave velocity (APWV), at baseline and after 3 weeks of therapy and measured serum factors known to be involved in the pathogenesis of hypertension.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Eligibility
Eligible patients were at least 18 years of age with histologically confirmed metastatic solid tumors that were refractory to standard therapy or for which no approved effective therapy was available. Patients were required to have measurable disease defined according to the modified WHO Tumor Response Criteria.¹¹ Eligibility criteria also included an Eastern Cooperative Oncology Group performance status of 0 to 1; adequate bone marrow (neutrophils 1,500/µL and platelets 100,000/µL), renal (serum creatinine 1.5x the upper limit of normal), and hepatic (serum bilirubin < 1.0x the upper limit of normal and AST/ALT 2.5x the upper limit of normal, unless with known liver metastases when AST/ALT should be < 5x the upper limit of normal) function; no active brain metastasis; and no serious uncontrolled medical disorder or active infection that would impair the ability of the patient to receive the study treatment. The study was approved by the institutional review board of the University of Pennsylvania. All patients received information on the purpose and conduct of this study and provided written informed consent.

Pretreatment Evaluation and Follow-Up
Pretreatment evaluation consisted of a history and physical examination, CBC, prothrombin time, activated partial thromboplastin time, serum electrolytes, creatinine and liver function tests, urinalysis, ECG, baseline imaging study, and assessment of Eastern Cooperative Oncology Group performance status. BP and heart rate (HR) were measured during each visit (usually in the morning) after 5 to 10 minutes of rest in the sitting position using an automated BP cuff (Dinamap; Criticon Inc, Tampa, FL). A large adult cuff was used for patients whose arm circumference exceeded the capacity as marked on the standard adult Dinamap cuff. Patients were examined before every course of therapy. Lesions noted at baseline that were measured or evaluated by radiographic scan or x-ray were reviewed every 12 weeks for response according to the modified WHO Tumor Response Criteria. Responding patients ( 25% regression) were observed with radiographic evaluation every 12 weeks. Stable patients (< 25% regression or progression) were randomly assigned to either BAY 43-9006 or placebo and were evaluated for subsequent radiographic progression every 6 weeks. Patients were evaluated every 3 weeks for adverse events and toxicity. Patients whose disease progressed at any time during the first 12 weeks were discontinued from the study. When the BP increase was sustained and felt to represent a risk for short-term consequences, antihypertensive medications were initiated.

Study Design and Drug Administration
This study was conducted on a subset of patients enrolled onto a phase II randomized discontinuation clinical trial. The purpose of this trial was to investigate the incidence, severity, and potential mechanisms of BP elevation among patients treated with BAY 43-9006. BAY 43-9006 was administered continuously at a dose of 400 mg twice daily for 12 weeks. Doses were delayed or reduced for clinically significant hematologic and other toxicities related to study drug. Treatment after 12 weeks was determined by response evaluations as described earlier. Patients who experienced progressive disease at any time after random assignment were unblinded and allowed to resume BAY 43-9006 therapy if they had been receiving placebo. Patients experiencing progressive disease who were randomly assigned to BAY 43-9006 were taken off study medication.

Evaluation
Toxicity during each treatment cycle was assigned according to the National Cancer Institute Common Toxicity Criteria, version 2.0 (Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD). Response was defined according to the modified WHO Tumor Response Criteria.

Measurement of Humoral Factors
Measurements of circulating concentrations of VEGF, total catecholamines, epinephrine, norepinephrine, endothelin I, urotensin II, renin, and aldosterone were performed at baseline (within 2 weeks of the initiation of therapy) and again after 3 weeks of therapy and obtained in the sitting position from direct phlebotomy (not an indwelling intravenous line) between 2 and 6 hours after the morning medication dose. VEGF was measured by standard enzyme-linked immunosorbent assay (Quest Diagnostics Laboratory, Lyndhurst, NJ). Measurements of endothelin I and urotensin II were performed by radioimmunoassay (Interscience Institute, Inglewood, CA). Total catecholamines were measured by high-performance liquid chromatography, and renin and aldosterone were measured by radioimmunoassay in the core laboratory of the General Clinical Research Center at the University of Pennsylvania using a commercially available kit for direct renin assay (Nichols Institute Diagnostics, San Clemente, CA) and aldosterone (Diagnostic Products Corporation, Los Angeles, CA).

APWV and CAIx
Patients underwent noninvasive assessment of APWV and CAIx at baseline, after 3 to 6 weeks of therapy with the study drug, and again after 9 to 10 months of therapy. For measurement of APWV, pulse wave analyses with a high-fidelity Millar tonometer (Millar Instruments, Houston, TX) at the carotid and femoral arteries with simultaneous electrocardiographic gating were performed using the SphygmoCor SCOR-PVx device (AtCor, West Ryde, Australia). The time delay (t) was measured between the feet of the carotid and femoral waveforms. The distance (D) covered by the waves was assimilated to the distance measured between the two recording sites. APWV was calculated as follows: APWV = D (meters)/t (seconds).¹² CAIx represents a ratio of the augmentation portion of the central aortic pressure (that is a result of pressure waves reflected from the periphery retrograde to the heart) to the measured pulse pressure. For estimation of CAIx, pulse wave analysis at the radial artery was performed as described earlier. This information was converted to an estimated CAIx with a computerized algorithm based on the measured SBP and diastolic BP (DBP).¹³

Statistical Analysis
Data was stored in a password-protected laptop computer using Microsoft Excel (Microsoft Corporation, Redmond, WA). All statistical tests were performed using JMP IN statistical software version 4 (SAS Institute, Cary, NC). Mean values and SEMs were calculated for all values. The mean of each variable was compared between baseline and repeated measurements (eg, 3 weeks) using paired student's t tests when directionality of change was not predictable, as was the case with measured humoral factors. One-sided student's t tests were performed when directionality was predictable, as was the case with BP, HR, and indices of vascular stiffness. Data lacking a normal distribution (VEGF levels) were analyzed with a Wilcoxon rank sum test. Also, we assessed possible correlations between the independent variables of measured humoral factors or indices of vascular stiffness and the dependent variables of SBP, DBP, and HR using bivariate fit analyses.

	RESULTS

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Patient Characteristics
A total of 20 patients (13 males and seven females) with metastatic renal cell carcinoma (19 patients) and adenocarcinoma of unknown primary (one patient) and good performance status were entered onto this study. The demographic characteristics of the patients are listed in Table 1. All patients were assessable for toxicity, 19 and 17 patients where assessable for BP assessments at 6 and 18 weeks, respectively, after beginning BAY 43-9006. One patient was unable to complete the study because of death from progressive disease, and in one patient, no pulse wave velocities could be measured because of scarring in the soft tissue overlying the carotid arteries as a result of prior surgeries.

View larger version (12K): [in this window] [in a new window]   Fig 1. Changes in mean systolic (upper curve) and diastolic (lower curve) blood pressures during 18 weeks of therapy with BAY 43-9006. Dotted lines are drawn at baseline values of systolic and diastolic blood pressure for clarity.

View larger version (13K): [in this window] [in a new window]   Fig 2. Correlation of change in heart rate with change in systolic blood pressure after 3 weeks of therapy with BAY 43-9006. (P = .02).

Changes in Humoral Factors
There were no statistically significant changes in total catecholamines, epinephrine, norepinephrine, endothelin I, urotensin II, plasma renin, and aldosterone after 3 weeks of therapy with the study drug (Table 3). The distribution of VEGF was not normal, and the comparison of baseline versus week 3 values was performed with the Wilcoxon rank sum test and was statistically significant (P = .045; Table 3). There was no significant correlation between SBP and any of these factors at baseline. The r values for the correlation with SBP at baseline were –0.18 for VEGF, 0.31 for total catecholamines, 0.18 for epinephrine, 0.30 for norepinephrine, 0.44 for endothelin I, –0.07 for urotensin II, –0.11 for renin, and 0.05 for aldosterone. Also, there was no significant correlation between changes in SBP and changes in individual factors, except total catecholamines (see below) after 3 weeks of treatment with BAY 43-9006. The r values for the correlation of the changes in SBP at week 3 compared with baseline with the changes in the same humoral factors at week 3 compared with baseline were –0.46 for VEGF, –0.35 for endothelin I, –0.14 for urotensin II, 0.04 for renin, and –0.19 for aldosterone. Patients with greater increases in VEGF levels during treatment tended to have less BP increase, but the correlation was not statistically significant (P = .11, r = 0.45). However, there was a statistically significant inverse relationship between changes in total catecholamines and changes in SBP after 3 weeks of treatment with BAY 43-9006, as depicted in Figure 3 (P = .03, r = –0.58). There was also a statistically significant inverse relationship between changes in epinephrine and changes in SBP after 3 weeks of treatment (P = .03, r = –0.5), and there was a trend towards a significant inverse relationship between changes in norepinephrine and changes in SBP after 3 weeks of treatment (P = .077, r = –0.44).

View larger version (14K): [in this window] [in a new window]   Fig 3. Correlation of change in total catecholamines with change in systolic blood pressure after 3 weeks of therapy with BAY 43-9006. (P = .03).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

We found that treatment with single-agent BAY 43-9006 is associated with a significant increase in BP that is evident within 3 weeks of beginning therapy and persists for at least 18 weeks. Only two patients required either the addition or an increase in dose of antihypertensive medications.

A considerable body of evidence suggests a link between hypertension and impaired angiogenesis. Specifically, some authors have suggested that hypertension results from depressed angiogenesis at the microcirculation level, as is reflected by the phenomenon of rarefaction, which is a reduction in the density of microvessels.⁷ Rarefaction is a normal component of the aging process that has been demonstrated to occur to a greater degree in hypertensive adults,¹⁵ even in those with mild or borderline hypertension,¹⁶ as well as in normotensive young adults with a genetic predisposition for hypertension.¹⁷ The resultant diminution of vascular surface area leads to increased peripheral vascular resistance. Furthermore, animal models have shown that the process of vascular rarefaction can occur rapidly (within a few days).¹⁸ Nevertheless, it is unclear whether rarefaction is the cause or the result of hypertension.¹⁹

Further evidence of the link between hypertension and impaired angiogenesis stems from research pertaining to VEGF. As mentioned previously, a prevalent adverse effect in clinical trials of the chemotherapeutic agent bevacizumab, an anti-VEGF monoclonal antibody, is hypertension.^1,2 It is interesting to note that investigators have shown that VEGF exerts its angiogenic effects by enhancing the transcription and activity of endothelial nitric oxide synthase.²⁰ This observation suggests that VEGF could rapidly induce a hypotensive response even before angiogenesis has occurred. Indeed, impressive reductions in BP were demonstrated with intracoronary and intravenous infusions of VEGF in the VEGF in Ischemia for Vascular Angiogenesis Trial.²¹ Surprisingly, high levels of VEGF have been reported in hypertensive patients.⁶ Thus, it has been suggested that these paradoxically elevated levels may be a compensatory response to increased mechanical stretch, tissue ischemia/hypoxia, or endothelial dysfunction with peripheral resistance to VEGF and may also be a marker of platelet activation.¹⁹ Indeed, when hypertensive patients were aggressively treated, levels of VEGF decreased after 6 months of therapy.⁶

In this study, we did not directly measure the degree of inhibition of angiogenesis. However, we did measure levels of VEGF and observed no significant changes in levels of VEGF after 3 weeks of therapy, even though the most impressive hypertensive effects occurred in this short period. Furthermore, there was no correlation between VEGF values at baseline or after 3 weeks of therapy and changes in BP. These results suggest that the hypertensive effect of BAY 43-9006 may be independent of its inhibition of VEGF receptors. Alternatively, we can postulate that the effect is mediated through inhibition of VEGFR without affecting the concentration of VEGF itself. The RAF inhibition associated with BAY 43-9006 may inhibit the local production of VEGF, as has been shown in preclinical models.⁸ It is also possible that the small number of patients analyzed and/or the timing of measurement may account for our inability to detect potentially significant changes in VEGF.

There was no significant change in HR or serum total catecholamines, epinephrine, or norepinephrine after 3 weeks of therapy. Furthermore, there was a significant inverse correlation between the change in HR and the change in SBP, as well as between the change in total catecholamines or epinephrine and the change in SBP. Also, there was a trend towards a similar negative correlation between norepinephrine and SBP. These observations lessen the likelihood of an adrenergic etiology for the elevation in BP. Although these findings are consistent with a reduction in adrenergic activity perhaps as a consequence of the increase in BP, it is also possible that changes in vascular sensitivity to adrenergic stimuli and local tissue effects of catecholamines that we cannot detect in a circulating assay could also be present; thus, our findings do not rule out a role for adrenergic activity as a mechanism of increased BP with this therapy.

Other vasoactive substances that are emerging as important contributors to the pathogenesis of hypertension are endothelin I and urotensin II. Endothelin I is a potent vasoconstrictor that plays an important role in vascular remodeling, particularly in resistance arteries.²² Studies conducted in several models of experimental hypertension have shown that endothelin I induces vascular hypertrophy and BP elevations. Another vasoactive peptide is urotensin II, which is eight- to 110-fold more potent than endothelin I.²³ In our patients, there were no changes in levels of endothelin I or urotensin II after 3 weeks of treatment with BAY 43-9006. Also, no correlations between changes in these factors with changes in SBP were observed.

During treatment with BAY 43-9006, there were no changes in serum creatinine, serum aldosterone, or plasma renin concentrations, and the mean weight decreased by 1.7 kg after 3 weeks. These observations indicate that significant renal dysfunction was an unlikely explanation for the increase in BP. We cannot be sure that we have excluded a sodium retention mechanism because, even though the patients lost, rather than gained, weight, it is possible that a greater weight loss was masked by a subtle sodium retention. The lack of significant changes in renin and aldosterone also reduces the likelihood of a renal parenchymal or renovascular etiology for the observed increase in BP.

Another important factor contributing to hypertension and independently predicting cardiovascular risk is aortic stiffness, as measured from aortic APWV and CAIx.²⁴ It has been hypothesized that impairment of angiogenesis at the level of vasa vasorum of large and/or muscular arteries could lead to an increase in vascular stiffness associated with hypertension.²⁵ We observed a 30% increase in the CAIx (from 23% to 29%, representing an absolute mean increase of 7%) after a mean of 34 days of treatment with BAY 43-9006, and we observed a 9% increase in APWV (from 8.9 m/sec to 9.7 m/sec, representing an absolute mean increase of 0.8 m/sec). These changes persisted after 9 to 10 months of therapy. We did not observe any correlation between changes in APWV or CAIx and changes in SBP. Because increased vascular stiffness can be demonstrated in any group of hypertensive patients, we cannot determine whether our observed increase in vascular stiffness is the direct result of BAY 43-9006 or whether it is the consequence of hypertension and only indirectly caused by the study drug.

There are several limitations in this study. First, the sample size is small. However, the BP elevations were highly statistically significant (P < .001) and sustained through the 18 weeks of follow-up. Also, we only measured selected humoral factors. Nevertheless, there is sound evidence for these factors as causative factors in human and animal models of hypertension.

In conclusion, treatment with BAY 43-9006 is associated with a significant and sustained increase in BP. Our results do not support a humoral mechanism whereby BAY 43-9006 causes hypertension. Moreover, we found no evidence of sodium retention or renovascular physiology. Although we noted a significant increase in indices of vascular stiffness, these were present at the time of established BP increase, and we could not determine a cause or effect relationship. We suspect that BAY 43-9006 exerts its hypertensive effects directly at the level of the vasculature through processes such as vascular rarefaction, endothelial dysfunction, and/or altered nitrous oxide metabolism. Further studies are necessary to assess these mechanisms.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Conception and design: Ari Mosenkis, Keith T. Flaherty, James P. Stevenson, Raymond R. Townsend, Peter J. O'Dwyer

Administrative support: Maryann Gallagher

Provision of study materials or patients: Ari Mosenkis, Keith T. Flaherty, Maryann Gallagher, James P. Stevenson, Peter J. O'Dwyer

Collection and assembly of data: Maria Luisa Veronese, Ari Mosenkis, Maryann Gallagher, Raymond R. Townsend

Data analysis and interpretation: Maria Luisa Veronese, Ari Mosenkis, Keith T. Flaherty, Raymond R. Townsend, Peter J. O'Dwyer

Manuscript writing: Maria Luisa Veronese, Ari Mosenkis, Keith T. Flaherty, James P. Stevenson, Raymond R. Townsend, Peter J. O'Dwyer

Final approval of manuscript: Maria Luisa Veronese, Keith T. Flaherty, Raymond R. Townsend, Peter J. O'Dwyer

	NOTES

 
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Hurwitz HH, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004[Abstract/Free Full Text]

2. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003[Abstract/Free Full Text]

3. Thomas AL, Morgan B, Drevs J, et al: Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK222584. Semin Oncol 30:32-38, 2003 (suppl 6)[Medline]

4. Fiedler W, Serve H, Dohner H, et al: A phase I study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105:986-993, 2005[Abstract/Free Full Text]

5. Koch-Weser J: Correlation of pathophysiology and pharmacotherapy in primary hypertension. Am J Cardiol 32:499-510, 1973[CrossRef][Medline]

6. Feldemen DC, Spencer CGC, Belgore FM, et al: Endothelial damage and angiogenesis in hypertensive patients: Relationship to cardiovascular risk factors and risk factor management. Am J Hypertens 16:11-20, 2003[CrossRef][Medline]

7. Struijker Boudier HAJ, Le Noble JLML, Messing MWJ, et al: The microcirculation and hypertension. J Hypertens 10:S147-S156, 1992 (suppl 7)

8. Alavi A, Hood JD, Frausto R, et al: Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301:94-96, 2003[Abstract/Free Full Text]

9. Ahmad T, Eisen T: Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res 10:6388s-6392s, 2004[CrossRef][Medline]

10. Ratain MJ, Flaherty KT, Stadler WM, et al: Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT). J Clin Oncol 22:382s, 2004 (suppl, abstr 4501)

11. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, Offset Publication No. 48, 1979

12. Wilkinson IB, Fuchs SA, Jansen IM, et al: Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis. J Hypertens 16:2079-2084, 1998[CrossRef][Medline]

13. Siebenhofer A, Kemp CRW, Sutton AJ, et al: The reproducibility of central aortic blood pressure measurements in healthy patients using applanation tonometry and sphygmocardiography. J Hum Hypertens 13:625-629, 1999[CrossRef][Medline]

14. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976[Medline]

15. Greene AS: Microvascular regulation and dysregulation, in Izzo JI, Black HR (eds): Hypertension Primer (ed 3). Baltimore, MD, Lippincot Williams and Wilkins, 2003, pp 183-185

16. Sullivan JM, Prewitt RL, Josephs JA: Attenuation of the microcirculation in young patients with high-output borderline hypertension. Hypertension 5:844-851, 1983[Abstract/Free Full Text]

17. Noon JP, Walker BR, Webb DJ, et al: Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 99:1873-1879, 1997[Medline]

18. Hansen-Smith FM, Morris LW, Greene AS, et al: Rapid microvessel rarefaction with elevated salt intake and reduced renal mass hypertension in rats. Circ Res 79:324-330, 1996[Abstract/Free Full Text]

19. Sane DC, Anton L, Brosnihan KB: Angiogenic growth factors and hypertension. Angiogenesis 7:193-201, 2004[CrossRef][Medline]

20. Hood JD, Meininger CJ, Ziche M, et al: VEGF upregulates eNOS message, protein, and NO production in human endothelial cells. Am J Physiol 274:H1054-H1058, 1998[Medline]

21. Henry TD, Annex BH, McKendall GR, et al: The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 107:1359-1365, 2003[Abstract/Free Full Text]

22. Amiri F, Virdis A, Fritsch M, et al: Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation 110:2233-2240, 2004[Abstract/Free Full Text]

23. Douglas SA, Ohlstein EH: Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease. Trends Cardiovasc Med 10:229-237, 2000[CrossRef][Medline]

24. Safar ME, Levy BI, Struijker-Boudier H: Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 107:2864-2869, 2003[Free Full Text]

25. Stefanadis CI, Karrayannacos PE, Boudoulas HK, et al: Medial necrosis and acute alterations in aortic distensibility following removal of the vasa vasorum of canine ascending aorta. Cardiovasc Res 27:951-956, 1993[Abstract/Free Full Text]

Submitted March 17, 2005; accepted November 1, 2005.

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				T. E. Hutson, R. A. Figlin, J. G. Kuhn, and R. J. Motzer Targeted Therapies for Metastatic Renal Cell Carcinoma: An Overview of Toxicity and Dosing Strategies Oncologist, October 1, 2008; 13(10): 1084 - 1096. [Abstract] [Full Text] [PDF]

				N. S. Azad, E. M. Posadas, V. E. Kwitkowski, S. M. Steinberg, L. Jain, C. M. Annunziata, L. Minasian, G. Sarosy, H. L. Kotz, A. Premkumar, et al. Combination Targeted Therapy With Sorafenib and Bevacizumab Results in Enhanced Toxicity and Antitumor Activity J. Clin. Oncol., August 1, 2008; 26(22): 3709 - 3714. [Abstract] [Full Text] [PDF]

				M. H. Chen, R. Kerkela, and T. Force Mechanisms of Cardiac Dysfunction Associated With Tyrosine Kinase Inhibitor Cancer Therapeutics Circulation, July 1, 2008; 118(1): 84 - 95. [Full Text] [PDF]

				N. Steeghs, H. Gelderblom, J. o. t Roodt, O. Christensen, P. Rajagopalan, M. Hovens, H. Putter, T. J. Rabelink, and E. de Koning Hypertension and Rarefaction during Treatment with Telatinib, a Small Molecule Angiogenesis Inhibitor Clin. Cancer Res., June 1, 2008; 14(11): 3470 - 3476. [Abstract] [Full Text] [PDF]

				J.-S. Lee, S.-H. Song, J.-M. Kim, I.-S. Shin, K. L. Kim, Y.-L. Suh, H.-Z. Kim, G. Y. Koh, J. Byun, E.-S. Jeon, et al. Angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor Cardiovasc Res, June 1, 2008; 78(3): 572 - 580. [Abstract] [Full Text] [PDF]

				J.-J. Mourad, G. des Guetz, H. Debbabi, and B. I. Levy Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation Ann. Onc., May 1, 2008; 19(5): 927 - 934. [Abstract] [Full Text] [PDF]

				S. A. Laurie, I. Gauthier, A. Arnold, F. A. Shepherd, P. M. Ellis, E. Chen, G. Goss, J. Powers, W. Walsh, D. Tu, et al. Phase I and Pharmacokinetic Study of Daily Oral AZD2171, an Inhibitor of Vascular Endothelial Growth Factor Tyrosine Kinases, in Combination With Carboplatin and Paclitaxel in Patients With Advanced Non-Small-Cell Lung Cancer: The National Cancer Institute of Canada Clinical Trials Group J. Clin. Oncol., April 10, 2008; 26(11): 1871 - 1878. [Abstract] [Full Text] [PDF]

				B. L. Frei and S. A. Soefje A Review of the Cardiovascular Effects of Oncology Agents Journal of Pharmacy Practice, April 1, 2008; 21(2): 146 - 158. [Abstract] [PDF]

				L. Moreno-Vinasco, M. Gomberg-Maitland, M. L. Maitland, A. A. Desai, P. A. Singleton, S. Sammani, L. Sam, Y. Liu, A. N. Husain, R. M. Lang, et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension Physiol Genomics, April 1, 2008; 33(2): 278 - 291. [Abstract] [Full Text] [PDF]

				A. Saad, R. Beto, J. Abraham, and S. C. Remick Cardiovascular Safety and Toxicity Profile of New Molecularly Targeted Anticancer Agents ASCO Educational Book, January 1, 2008; 2008(1): 428 - 434. [Abstract] [Full Text] [PDF]

				M. J. Ratain and R. H. Glassman Biomarkers in Phase I Oncology Trials: Signal, Noise, or Expensive Distraction? Clin. Cancer Res., November 15, 2007; 13(22): 6545 - 6548. [Full Text] [PDF]

				L. W. Jones, M. J. Haykowsky, J. J. Swartz, P. S. Douglas, and J. R. Mackey Early Breast Cancer Therapy and Cardiovascular Injury J. Am. Coll. Cardiol., October 9, 2007; 50(15): 1435 - 1441. [Abstract] [Full Text] [PDF]

				A. A. M. van der Veldt, A. J. M. van den Eertwegh, K. Hoekman, F. Barkhof, and E. Boven Reversible cognitive disorders after sunitinib for advanced renal cell cancer in patients with preexisting arteriosclerotic leukoencephalopathy Ann. Onc., October 1, 2007; 18(10): 1747 - 1750. [Full Text] [PDF]

				L. Dirix, H Maes, and C Sweldens Treatment of arterial hypertension (AHT) associated with angiogenesis inhibitors Ann. Onc., June 1, 2007; 18(6): 1121 - 1122. [Full Text] [PDF]

				B. I. Rini Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma: Current Status and Future Directions Clin. Cancer Res., February 15, 2007; 13(4): 1098 - 1106. [Abstract] [Full Text] [PDF]

				K. T. Flaherty Sorafenib in Renal Cell Carcinoma Clin. Cancer Res., January 15, 2007; 13(2): 747s - 752s. [Abstract] [Full Text] [PDF]

				O. Mir, L. Mouthon, J. Alexandre, J.-M. Mallion, G. Deray, L. Guillevin, and F. Goldwasser Bevacizumab-Induced Cardiovascular Events: A Consequence of Cholesterol Emboli Syndrome? J Natl Cancer Inst, January 3, 2007; 99(1): 85 - 86. [Full Text] [PDF]

				A. Morabito, E. De Maio, M. Di Maio, N. Normanno, and F. Perrone Tyrosine Kinase Inhibitors of Vascular Endothelial Growth Factor Receptors in Clinical Trials: Current Status and Future Directions Oncologist, July 1, 2006; 11(7): 753 - 764. [Abstract] [Full Text] [PDF]

				D. A. Sica Angiogenesis Inhibitors and Hypertension: An Emerging Issue J. Clin. Oncol., March 20, 2006; 24(9): 1329 - 1331. [Full Text] [PDF]

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