Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study

SummaryBackgroundNitric oxide has been implicated in tumour angiogenesis and in the maintaining of vasodilator tone of tumour blood vessels. The tumour vascular effects of inhibition of nitric-oxide synthesis have not been investigated in patients with cancer.MethodsSeven women and 11 men (12 with non-small-cell lung cancer, five prostate cancer, and one cervical cancer) were recruited onto a phase I dose-escalation study and received a single dose of the nitric oxide synthase inhibitor, N-nitro-L-arginine (L-NNA). Dose escalation was done by a modified Fibonacci scale with three patients at each dose level, starting with 0·1 mg/kg. Changes in dynamic contrast-enhanced CT measures of tumour relative blood volume and transfer constant (K) were measured at 1 h and 24 h after L-NNA administration.FindingsIn the 18 patients, toxic effects were self-limiting cardiovascular changes: three patients had Common Toxicity Criteria version 2.0 grade 1 hypertension; two had grade 1 sinus bradycardia; and one had grade 1 palpitation. L-NNA area under the curve (AUC) increased linearly with dose from 163 μmol min−1 L−1 at 0·1 mg/kg L-NNA to 2150 μmol min−1 L−1 at 0·9 mg/kg L-NNA. In eight patients that underwent dynamic CT scanning, tumour blood volume decreased 1 h after L-NNA treatment (mean 42·9% [range 12·0–62·1]; paired t test p=0·0070), which was sustained for up to 24 h (mean 33·9% [range 6·5–64·9]; p=0·035). This decrease in blood volume was associated with an increase in the number of non-perfused pixels from 7·3% (SD 5·5) at baseline to 25·1% (15·3; p=0·0089) at 1 h, and 18·2% (12·9; p=0·050) at 24 h. There was a significant correlation between L-NNA plasma AUC and the reduction in tumour blood volume at 24 h after L-NNA (r=0·83; p=0·010).InterpretationWe have shown in vivo in patients with cancer that nitric oxide has a role in maintaining tumour blood supply, and we provide early clinical evidence that inhibition of nitric-oxide synthesis has tumour antivascular activity.