Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions.

Abstract

Nitric oxide (NO) is an important molecule in regulating tumour blood flow and stimulating tumour angiogenesis. Inhibition of NO synthase by L-NAME might induce an anti-tumour effect by limiting nutrients and oxygen to reach tumour tissue or affecting vascular growth. The anti-tumour effect of L-NAME after systemic administration was studied in a renal subcapsular CC531 adenocarcinoma model in rats. Moreover, regional administration of L-NAME, in combination with TNF and melphalan, was studied in an isolated limb perfusion (ILP) model using BN175 soft-tissue sarcomas. Systemic treatment with L-NAME inhibited growth of adenocarcinoma significantly but was accompanied by impaired renal function. In ILP, reduced tumour growth was observed when L-NAME was used alone. In combination with TNF or melphalan, L-NAME increased response rates significantly compared to perfusions without L-NAME (0-64% and 0-63% respectively). An additional anti-tumour effect was demonstrated when L-NAME was added to the synergistic combination of melphalan and TNF (responses increased from 70 to 100%). Inhibition of NO synthase reduces tumour growth both after systemic and regional (ILP) treatment. A synergistic anti-tumour effect of L-NAME is observed in combination with melphalan and/or TNF using ILP. These results indicate a possible role of L-NAME for the treatment of solid tumours in a systemic or regional setting.

• Authors: J H de Wilt, E R Manusama, B van Etten, S T van Tiel, A S Jorna, A L Seynhaeve, T L ten Hagen, A M Eggermont
• Journal: British journal of cancer (Br J Cancer) Vol. 83 Issue 9 Pg. 1176-82 (Nov 2000) ISSN: 0007-0920 [Print] England
• PMID: 11027431 (Publication Type: Journal Article)
• Copyright: Copyright 2000 Cancer Research Campaign.

Chemical References

• Antineoplastic Agents, Alkylating
• Tumor Necrosis Factor-alpha
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Melphalan
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology, therapeutic use)
• Blotting, Western
• Drug Synergism
• Drug Therapy, Combination
• Hindlimb
• Immunohistochemistry
• Kidney (drug effects, enzymology, pathology)
• Male
• Melphalan (pharmacology, therapeutic use)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Neoplasm Transplantation
• Neoplasms, Experimental (enzymology, prevention & control)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Nitric Oxide Synthase Type II
• Perfusion
• Rats
• Rats, Inbred BN
• Rats, Inbred Strains
• Time Factors
• Tumor Necrosis Factor-alpha (pharmacology, therapeutic use)