Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or theophylline while the development of adenocarcinomas is promoted: implications for chemoprevention in smokers.

Lung cancer continues to be the leading cause of cancer death in developed countries. With smoking the major etiological factor for lung cancer, there is a great need for the development of chemopreventive treatments that inhibit the progression of initiated cells and premalignant lesions into overt lung cancer in smokers who quit. Although the major focus of chemoprevention research has been on agents that inhibit the metabolic activation of genotoxic chemicals contained in tobacco products, some of these agents may additionally modulate growth-regulating signal transduction. In turn, the function of such signaling pathways is highly cell type-specific, with a given pathway inhibiting the growth of one cell type while stimulating the growth of others. The current experiment has tested the hypothesis that green tea and the methylxanthine theophylline contained in tea inhibit the progression of neuroendocrine lung carcinogenesis in hamsters with hyperoxic lung injury and initiated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) while promoting the development of Clara cell-derived pulmonary adenocarcinomas initiated by NNK in healthy hamsters. This hypothesis is based on published evidence that human small cell lung cancer as well as the neuroendocrine hamster tumors are regulated via autocrine signaling pathways that activate Raf-1 and the mitogen-activated (MAP) kinase pathway whereas human pulmonary adenocarcinomas of Clara cell lineage and the hamster model of this cancer type are regulated by a beta-adrenergic pathway involving the activation of cyclic adenosine 3',5'-monophosphate (cAMP) and the arachidonic acid (AA) cascade. In turn, it was hypothesized that theophylline would inhibit Raf-1-dependent tumor progression while promoting cAMP-dependent tumor progression due to its documented ability to inhibit the enzyme cAMP-phophodiesterase. The experimental design simulated chemoprevention in former smokers in that treatments with tea or theophylline started after completion of a 10-week tumor induction period with NNK. Our data show that green tea as well as theophylline significantly inhibited lung tumor multiplicity in the neuroendocrine cancer model whereas identical chemopreventive treatments significantly promoted the lung tumor multiplicity in the adenocarcinoma model. These findings indicate that green tea and theophylline as well as other chemopreventive agents that modulate signal transduction may have opposite effects on cancers of different histolopathology and cell lineage. At the current state of knowledge such chemopreventive treatments should only be used as adjuvant to cancer therapy of cancers that have been fully characterized at the pathology and molecular level.