Beta-adrenergic modulation of NNK-induced lung carcinogenesis in hamsters.
OBJECTIVE
Lung cancer is the leading cause of cancer death in industrialized countries. Pulmonary adenocarcinoma (PAC) is the most common histologic type of lung cancer, and it is reproducibly induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone (NNK) in laboratory rodents. We have recently shown that the growth of cell lines derived from human PACs is controlled by beta-adrenergic receptors, and that NNK is a high affinity agonist for this receptor family.


METHODS
In the current study, we have tested the relevance of these in in vitro findings for in vivo NNK-induced lung tumorigenesis, using a well-established hamster model of NNK-induced PAC.


RESULTS
Our experiments demonstrate a significant increase in NNK-induced PAC multiplicity in animals chronically exposed to the beta-adrenergic agonist epinephrine or theophylline which causes intracellular accumulation of the beta-adrenergic second messenger cAMP. On the other hand, our data show that administration of the beta-adrenergic antagonist propranolol prior to each NNK injection significantly inhibited the development of PACs.


CONCLUSIONS
Our findings support the hypothesis that the development of tobacco-associated PAC may be modulated by beta-adrenergic agents, and that the interaction of NNK with beta-adrenergic receptors contributes to the genesis of this histologic lung cancer type.
Schuller
H M
HM
Experimental Oncology Laboratory, College of Veterinary Medicine, University of Tennessee, Knoxville 37906, USA. hschulle@utk.edu
Porter
B
B
Riechert
A
A
D000230:Adenocarcinoma / Q000139:chemically induced* / Q000517:prevention & control*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000633:toxicity; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity; D006224:Cricetinae; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology / Q000633:toxicity; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D008647:Mesocricetus; D009602:Nitrosamines / Q000494:pharmacology* / Q000633:toxicity; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D013806:Theophylline / Q000494:pharmacology / Q000633:toxicity
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002273:Carcinogens; D009602:Nitrosamines; D011943:Receptors, Adrenergic, beta; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D011433:Propranolol; D013806:Theophylline; D004837:Epinephrine