Carcinogenesis, Vol 18, 491-496, Copyright © 1997 by Oxford University Press
A Castonguay and N Rioux
The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone (NNK) is a potent lung carcinogen in mice and is most likely
involved in the aetiology of tobacco-induced lung cancer. Two protocols
using NNK and A/J mice have been developed. In the single-dose protocol,
each mouse was injected once with 2 mg of NNK. In the 7-week protocol, each
mouse received 9.1 mg of NNK in drinking water during 7 weeks. Mice were
killed 16 weeks after NNK treatment. We observed a near-Gaussian
distribution in the number of tumours per mouse in the single protocol, but
not in the 7-week protocol. In the 7-week protocol, a significant number
(8.6%) of mice had more than 20 tumours/mouse. In the single-dose protocol,
no mouse had more than 20 tumours. Sulindac at a dose of 123 mg/kg of diet
inhibits lung tumourigenesis in the 7-week protocol, but not in the
single-dose protocol. We observed that the inhibition of tumourigenesis in
the 7- week protocol was proportional to the logarithm of the dose of
sulindac between 15 and 123 mg/kg of diet. Treatment of mice for 7 weeks
inhibits the primary humoral response to sheep red blood cells by 70%. This
observation is particularly significant considering that NNK is present in
tobacco smoke and that tobacco smoking suppresses both the specific and
non-specific humoral and cellular immunity. Single injections of 2.0, 3.5
or 5.0 mg of NNK had no effect on this response. Our results suggest that
the immunosuppressive effects of NNK contribute to its high carcinogenic
potency particularly in sustained or life-time exposure models. We
hypothesize that sulindac promotes the recovery of immune system from the
NNK-mediated suppression observed in the 7-week protocol. This study
illustrates the importance of selecting the most appropriate protocol of
carcinogen treatment in investigating the efficacies of cancer
chemopreventive agents.
ARTICLES
Inhibition of lung tumourigenesis by sulindac: comparison of two experimental protocols
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada.
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