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Characterization of Early Pulmonary Hyperproliferation and Tumor Progression and Their Inhibition by Black Tea in a 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced Lung Tumorigenesis Model with A/J Mice¹

Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08854

The pathogenesis of pulmonary tumors induced by a tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and its inhibition by black tea have been characterized. Female A/J mice (6 weeks old) were treated with a single dose of NNK (103 mg/kg of body weight, i.p.) on day 0, and the cell proliferation index was measured by the incorporation of bromodeoxyuridine (BrdUrd) immunohistochemically. The number of BrdUrd-labeled cells increased in the bronchiolar epithelium from day 2 to day 14, with the highest proliferation rate observed on day 5. By day 35, the BrdUrd-labeling index returned to the level of the control group. Further examination of the day 35 samples revealed the presence of foci of hyperproliferative cells in the bronchiolar epithelium, particularly in the bronchiolalveolar regions. These proliferating bronchiolar epithelial cells (Clara cells) may be the initiated sites for pulmonary tumorigenesis. In this short-term model, administration of black tea polyphenols (0.3%) through the drinking water starting 24 h after NNK treatment significantly inhibited NNK-induced early bronchiolar cell proliferation on day 5. In long-term studies, adenomas were observed in 100% (15 of 15) of the mice at week 16, with 7.8 ± 0.8 tumors per mouse. At week 52, a malignant tumor incidence of 80% (41 of 51 mice) and a malignant tumor multiplicity of 2.39 ± 0.19 were observed. The growth patterns of the malignant tumors, which included solid, papillary, and mixed types, may be associated with the cellular origin of the tumor. The cell proliferation indices, as measured by proliferating cell nuclear antigen immunohistochemistry, were significantly higher in dysplasia within adenoma than in adenoma, and significantly higher in adenoma at week 52 than in adenoma at week 16. Administration of black tea, starting 16 weeks after a single dose of NNK, inhibited the progression of adenoma to adenocarcinoma as determined by both malignant tumor incidence and multiplicity. The cell proliferation rate in adenomas was also suppressed by black tea treatment. The present work demonstrates the antiproliferative activities of black tea and its polyphenols. Such activities, at the early and late stages of lung tumorigenesis, may be important for the cancer-chemopreventive activities of black tea.

¹ This work was supported by NIH Grant CA56673 and National Institute of Environmental Health Sciences Center Grant ES05022.

² Present address: Department of Dermatology, Columbia Presbyterian Hospital, 161 Fort Washington Avenue, New York, NY 10032-3784.

³ To whom requests for reprints should be addressed, at the Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Frelinghuysen Road, P. O. Box 789, Piscataway, NJ 08855-0789. PHone: (908) 445-5361; Fax: (908) 445-0687.

Received 11/20/96. Accepted 3/25/97.

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