Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions.
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.
de Wilt
J H
JH
Department of Surgical Oncology, University Hospital Rotterdam/Daniel den Hoed Cancer Centre, Groene Hilledijk 301, Rotterdam, The Netherlands.
Manusama
E R
ER
van Etten
B
B
van Tiel
S T
ST
Jorna
A S
AS
Seynhaeve
A L
AL
ten Hagen
T L
TL
Eggermont
A M
AM
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006614:Hindlimb; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008558:Melphalan / Q000494:pharmacology* / Q000627:therapeutic use; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000517:prevention & control*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010477:Perfusion; D051381:Rats; D011914:Rats, Inbred BN; D011919:Rats, Inbred Strains; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008558:Melphalan; D019331:NG-Nitroarginine Methyl Ester