TITLE:
The Acute Physiological Effects of the Vaso-Active Drug, L-NNA, a Nitric Oxide Synthase Inhibitor, on Renal and Tumour Perfusion in Human Subjects
AUTHORS:
Kent Yip, Vicky Goh, Jane Gregory, Ian Simcock, J. James Stirling, N. Jane Taylor, Robert Kozarski, Andrew Mitchell, Sam Bosopem, Gavin Halbert, Roberto Alonzi, David Miles, Peter Hoskin
KEYWORDS:
L-NNA; Cancer; Imaging; Vascular; Perfusion; Nitric Oxide
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.5 No.1,
January
8,
2014
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.