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 selec-tive inhibitor of nitric oxide synthase, L-NNA. 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. L-NNA was well tolerated by the four patients who received it. Blood flow (BF) and blood vo-lume (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 tu-mour 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. 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.
- nitric oxide
Yip, K., Goh, V., Gregory, J., Simcock, I., Stirling, J. J., Taylor, N. J., Kozarski, R., Mitchell, A., Bosopem, S., Halbert, G., Alonzi, R., Miles, D., & Hoskin, P. (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. Journal of Cancer Therapy, 5(1), 44-52. . https://doi.org/10.4236/jct.2014.51006