JCT  Vol.5 No.1 , January 2014
The Acute Physiological Effects of the Vaso-Active Drug, L-NNA, a Nitric Oxide Synthase Inhibitor, on Renal and Tumour Perfusion in Human Subjects
Abstract: Purpose: To assess the baseline variation in global renal and tumour blood flow, blood volume and extraction fraction, and changes in these parameters related to the acute physiological effects of a single dose of a non selective inhibitor of nitric oxide synthase, L-NNA. Materials & Methods: Ethical approval and informed consent were obtained for this Phase I clinical study. Patients with advanced solid tumours refractory to conventional therapy were recruited and given L-NNA intravenously at two different dose levels. Volumetric perfusion CT scans were carried out at 1, 24, 48 & 72 hours post L-NNA. Blood pressures were taken at regular interval for 6 hours after LNNA. Results: L-NNA was well tolerated by the four patients who received it. Blood flow (BF) and blood volume (BV) in both tumour and kidney were reduced post L-NNA administration (renal BF—20%; renal BV—19.7%; tumour BF—16.9%; tumour BV—18.6%), though the effect was more sustained in tumour vasculature. A negative correlation was found between the change in systemic blood pressure and vascular supply to the tumour within 1 hour following L-NNA (p < 0.0001). Differences in response to L-NNA by separate target lesions in the same patient were observed. Conclusion: The differential effect of L-NNA on tumour and renal blood flow, and the absence of any significant toxicity in this small cohort of patients permit further dose escalation of L-NNA in future early phase trials. The predictive value of blood pressure change in relation to the acute effect of L-NNA on tumour vasculature deserves further evaluation.
Cite this paper: K. Yip, V. Goh, J. Gregory, I. Simcock, J. Stirling, N. Taylor, R. Kozarski, A. Mitchell, S. Bosopem, G. Halbert, R. Alonzi, D. Miles and P. Hoskin, "The Acute Physiological Effects of the Vaso-Active Drug, L-NNA, a Nitric Oxide Synthase Inhibitor, on Renal and Tumour Perfusion in Human Subjects," Journal of Cancer Therapy, Vol. 5 No. 1, 2014, pp. 44-52. doi: 10.4236/jct.2014.51006.

[1]   D. Fukumura, S. Kashiwagi and R. K. Jain, “The Role of Nitric Oxide in Tumour Progression,” Nature Reviews Cancer, Vol. 6, No. 7, 2006, pp. 521-534.

[2]   J. Muntane and M. D. la Mata, “Nitric Oxide and Cancer,” World Journal of Hepatology, Vol. 2, No. 9, 2010, pp. 337-344.

[3]   G. M. Tozer, V. E. Prise and K. M. Bell, “The Influence of Nitric Oxide on Tumour Vascular Tone,” Acta Oncologica, Vol. 34, No. 3, 1995, pp. 373-377.

[4]   S. Klahr, “The Role of Nitric Oxide in Hypertension and Renal Disease Progression,” Nephrology Dialysis Transplantation, Vol. 16, Suppl. 1, 2001, pp. 60-62. suppl _1.60

[5]   J. M. Valdivielso and R. C. Blantz, “Acute Renal Failure: Is Nitric Oxide the Bad Guy?” Antioxidants & Redox Signaling, Vol. 4, No. 6, 2002, pp. 925-934.

[6]   R. E. Klabunde, “Cardiovascular Physiology Concepts,” 2nd Edition, Lippincott Williams & Wilkins/Wolters Kluwer, Philadelphia, 2012, 243 p.

[7]   K. A. Saddi, C. Chefd’hotel and F. Cheriet, “Large Deformation Registration of Contrast-Enhanced Images with Volume-Preserving Constraint,” In: J. P. W. Pluim and J. M. Reinhardt, Eds., Medical Imaging 2007: Image Processing, 2007.

[8]   R. Goetti, et al., “Quantitative Computed Tomography Liver Perfusion Imaging Using Dynamic Spiral Scanning with Variable Pitch: Feasibility and Initial Results in Patients with Cancer Metastases,” Investigative Radiology, Vol. 45, No. 7, 2010, pp. 419-426.

[9]   C. S. Reiner, et al., “CT Perfusion of Renal Cell Carcinoma: Impact of Volume Coverage on Quantitative Analysis,” Investigative Radiology, Vol. 47, No. 1, 2012, pp. 33-40. 10.1097/RLI.0b013e31822598c3

[10]   J. M. Bland and D. G. Altman, “Statistical Methods for Assessing Agreement between Two Methods of Clinical Measurement,” Lancet, Vol. 1, No. 8476, 1986, pp. 307-310. S0140-6736(86)90837-8

[11]   S. M. Galbraith, et al., “Reproducibility of Dynamic Contrast-Enhanced MRI in Human Muscle and Tumours: Comparison of Quantitative and Semi-Quantitative Analysis,” NMR in Biomedicine, Vol. 15, No. 2, 2002, pp. 132-142.

[12]   S. Goel, et al., “Normalization of the Vasculature for Treatment of Cancer and Other Diseases,” Physiological Reviews, Vol. 91, No. 3, 2011, pp. 1071-1121. 00038.2010

[13]   A. Sandler, et al., “Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell Lung Cancer,” New England Journal of Medicine, Vol. 355, No. 24, 2006, pp. 2542-2550. NEJMoa061884

[14]   L. B. Saltz, et al., “Bevacizumab in Combination with Oxaliplatin-Based Chemotherapy as First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study,” Journal of Clinical Oncology, Vol. 26, No. 12, 2008, pp. 2013-2019.

[15]   B. Escudier, et al., “Bevacizumab plus Interferon Alfa-2a for Treatment of Metastatic Renal Cell Carcinoma: A Randomised, Double-Blind Phase III Trial,” Lancet, Vol. 370, No. 9605, 2007, pp. 2103-2111.

[16]   T. J. Perren, et al., “A Phase 3 Trial of Bevacizumab in Ovarian Cancer,” New England Journal of Medicine, Vol. 365, No. 26, 2011, pp. 2484-2496.

[17]   M. C. Chamberlain, “Bevacizumab for the Treatment of Recurrent Glioblastoma,” Clinical Medicine Insights: Oncology, Vol. 5, 2011, pp. 117-129.

[18]   J. D. Hood, et al., “VEGF Upregulates ecNOS Message, Protein, and NO Production in Human Endothelial Cells,” American Journal of Physiology, Vol. 274, No. 3, 1998, pp. H1054-H1058.

[19]   A. Bouloumie, V. B. Schini-Kerth and R. Busse, “Vascular Endothelial Growth Factor Up-Regulates Nitric Oxide Synthase Expression in Endothelial Cells,” Cardiovascular Research, Vol. 41, No. 3, 1999, pp. 773-780.

[20]   Y. Tsurumi, et al., “Reciprocal Relation between VEGF and NO in the Regulation of Endothelial Integrity,” Nature Medicine, Vol. 3, No. 8, 1997, pp. 879-886.

[21]   A. Lopez, et al., “Multiple-Center, Randomized, Placebo-Controlled, Double-Blind Study of the Nitric Oxide Synthase Inhibitor 546C88: Effect on Survival in Patients with Septic Shock,” Critical Care Medicine, Vol. 32, No. 1, 2004, pp. 21-30.

[22]   R. Kramp, P. Fourmanoir and N. Caron, “Endothelin Resets Renal Blood Flow Autoregulatory Efficiency during Acute Blockade of NO in the Rat,” American Journal of Physiology. Renal Physiology, Vol. 281, No. 6, 2001, pp. F1132-F1140.

[23]   N. W. Rajapakse, J. J. Oliver and R. G. Evans, “Nitric Oxide in Responses of Regional Kidney Blood Flow to Vasoactive Agents in Anesthetized Rabbits,” Journal of Cardiovascular Pharmacology, Vol. 40, No. 2, 2002, pp. 210-219.

[24]   E. Turkstra, B. Braam and H. A. Koomans, “Impaired Renal Blood Flow Autoregulation in Two-Kidney, One-Clip Hypertensive Rats Is Caused by Enhanced Activity of Nitric Oxide,” Journal of the American Society of Nephrology, Vol. 11, No. 5, 2000, pp. 847-855.

[25]   H. Kiyomoto, et al., “Effect of L-NG-Nitro-Arginine, Inhibitor of Nitric Oxide Synthesis, on Autoregulation of Renal Blood Flow in Dogs,” Japanese Journal of Pharmacology, Vol. 58, No. 2, 1992, pp. 147-155.

[26]   S. Racasan, et al., “NO Dependency of RBF and Autoregulation in the Spontaneously Hypertensive Rat,” American Journal of Physiology. Renal Physiology, Vol. 285, No. 1, 2003, pp. F105-F112.

[27]   Q. S. Ng, et al., “Effect of Nitric-Oxide Synthesis on Tumour Blood Volume and Vascular Activity: A Phase I Study,” Lancet Oncology, Vol. 8, No. 2, 2007, pp. 111-118.

[28]   O. Gallo, et al., “Role of Nitric Oxide in Angiogenesis and Tumor Progression in Head and Neck Cancer,” Journal of the National Cancer Institute, Vol. 90, No. 8, 1998, pp. 587-596.

[29]   L. L. Thomsen, et al., “Nitric Oxide Synthase Activity in Human Breast Cancer,” British Journal of Cancer, Vol. 72, No. 1, 1995, pp. 41-44.

[30]   S. Ambs, et al., “Frequent Nitric Oxide Synthase-2 Expression in Human Colon Adenomas: Implication for Tumor Angiogenesis and Colon Cancer Progression,” Cancer Research, Vol. 58, No. 2, 1998, pp. 334-341.

[31]   H. Zhu, et al., “Restoring Soluble Guanylyl Cyclase Expression and Function Blocks the Aggressive Course of Glioma,” Molecular Pharmacology, Vol. 80, No. 6, 2011, pp. 1076-1084.

[32]   O. Rixe, B. Billemont and H. Izzedine, “Hypertension as a Predictive Factor of Sunitinib Activity,” Annals of Oncology, Vol. 18, No. 6, 2007, p. 1117.

[33]   P. Bono, et al., “Hypertension and Clinical Benefit of Bevacizumab in the Treatment of Advanced Renal Cell Carcinoma,” Annals of Oncology, Vol. 20, No. 2, 2009, pp. 393-394.

[34]   A. Ravaud and M. Sire, “Arterial Hypertension and Clinical Benefit of Sunitinib, Sorafenib and Bevacizumab in First and Second-Line Treatment of Metastatic Renal Cell Cancer,” Annals of Oncology, Vol. 20, No. 5, 2009, pp. 966-967.

[35]   M. Scartozzi, et al., “Arterial Hypertension Correlates with Clinical Outcome in Colorectal Cancer Patients Treated with First-Line Bevacizumab,” Annals of Oncology, Vol. 20, No. 2, 2009, pp. 227-230.

[36]   Q. S. Ng, et al., “Acute Tumor Vascular Effects Following Fractionated Radiotherapy in Human Lung Cancer: In Vivo Whole Tumor Assessment Using Volumetric Perfusion Computed Tomography,” International Journal of Radiation Oncology, Biology, Physics, Vol. 67, No. 2, 2007, pp. 417-424.