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Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study.
- Source :
-
The Lancet. Oncology [Lancet Oncol] 2007 Feb; Vol. 8 (2), pp. 111-8. - Publication Year :
- 2007
-
Abstract
- Background: Nitric 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.<br />Methods: Seven 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.<br />Findings: In 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 micromol min(-1) L(-1) at 0.1 mg/kg L-NNA to 2150 micromol 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).<br />Interpretation: We 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.
- Subjects :
- Adult
Aged
Blood Pressure drug effects
Carcinoma, Non-Small-Cell Lung blood supply
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung metabolism
Dose-Response Relationship, Drug
Female
Heart Rate drug effects
Humans
Lung Neoplasms drug therapy
Lung Neoplasms metabolism
Male
Middle Aged
Nitric Oxide metabolism
Ovarian Neoplasms drug therapy
Ovarian Neoplasms metabolism
Prostatic Neoplasms drug therapy
Prostatic Neoplasms metabolism
Regional Blood Flow drug effects
Blood Volume drug effects
Enzyme Inhibitors pharmacology
Lung Neoplasms blood supply
Nitric Oxide Synthase antagonists & inhibitors
Nitroarginine pharmacology
Ovarian Neoplasms blood supply
Prostatic Neoplasms blood supply
Subjects
Details
- Language :
- English
- ISSN :
- 1470-2045
- Volume :
- 8
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Lancet. Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 17267325
- Full Text :
- https://doi.org/10.1016/S1470-2045(07)70001-3