Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study.
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. METHODS: Seven women and 11 men (12 with non...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2007
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| _version_ | 1797056845596065792 |
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| author | Ng, Q Goh, V Milner, J Stratford, MR Folkes, L Tozer, G Saunders, M Hoskin, P |
| author_facet | Ng, Q Goh, V Milner, J Stratford, MR Folkes, L Tozer, G Saunders, M Hoskin, P |
| author_sort | Ng, Q |
| collection | OXFORD |
| description | 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. 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. 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). 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. |
| first_indexed | 2024-03-06T19:28:13Z |
| format | Journal article |
| id | oxford-uuid:1c87b41f-69f0-4cd8-8041-72a52c922d15 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:28:13Z |
| publishDate | 2007 |
| record_format | dspace |
| spelling | oxford-uuid:1c87b41f-69f0-4cd8-8041-72a52c922d152022-03-26T11:06:02ZEffect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1c87b41f-69f0-4cd8-8041-72a52c922d15EnglishSymplectic Elements at Oxford2007Ng, QGoh, VMilner, JStratford, MRFolkes, LTozer, GSaunders, MHoskin, PBACKGROUND: 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. 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. 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). 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. |
| spellingShingle | Ng, Q Goh, V Milner, J Stratford, MR Folkes, L Tozer, G Saunders, M Hoskin, P Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study. |
| title | Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study. |
| title_full | Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study. |
| title_fullStr | Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study. |
| title_full_unstemmed | Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study. |
| title_short | Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study. |
| title_sort | effect of nitric oxide synthesis on tumour blood volume and vascular activity a phase i study |
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