Effect of dietary green tea extract and aerosolized difluoromethylornithine during lung tumor progression in A/J strain mice.

Chemoprevention strategies to prevent the development of lung cancer in at-risk individuals are a key component in disease management. In addition to being highly effective, an ideal chemopreventive agent will require low toxicity as patients are likely to require treatment for several years before their risk of cancer is lowered to background levels. In principle, a combination of safe agents that work through distinct mechanisms will improve efficacy while simultaneously maintaining a favorable safety profile. Here, we describe the use of the decaffeinated green tea extract Polyphenon E (Poly E) (1% in diet) and aerosolized difluoromethylornithine (DFMO) (20 mg/kg/day, 5 days/week) in a mouse lung cancer chemoprevention study using a progression protocol. Female A/J mice were injected with benzo[a]pyrene (B[a]P) at 8 weeks of age and precancerous lesions allowed to form over a period of 21 weeks before chemoprevention treatment for an additional 25 weeks. Poly E treatment did not significantly inhibit average tumor multiplicity but reduced per animal tumor load. Analysis of tumor pathology revealed a specific inhibition of carcinomas, with the largest carcinomas significantly decreased in Poly E-treated animals. Aerosolized DFMO did not have a significant effect on lung tumor progression. Magnetic resonance imaging of B[a]P-induced lung tumors confirmed the presence of a subset of large, rapidly growing tumors in untreated mice. Our results suggest a potential role for green tea extracts in preventing the progression of large, aggressive lung adenocarcinomas.

A method of producing carcinoma in upper aerodigestive tree and esophagus of the Syrian golden hamster using wounding and instillation of N-methylnitrosourea.

Details of a method for producing carcinoma of the aerodigestive tree of the Syrian golden hamster and the use of this model to evaluate putative agents for chemoprevention of these carcinomas are described. The method produces a majority of squamous carcinomas of the trachea and glottis that follow squamous metaplasia of respiratory epithelium. In addition, seen are adenocarcinomas arising in glands of the respiratory tree. Squamous carcinomas of the digestive epithelium arise in primary squamous epithelium. These tumors of digestive epithelium have a growth pattern that differs from that of the respiratory epithelium in that they grow and invade without filling the epithelial layer with tumor cells.

Chemoprevention of cancer of the upper respiratory tract of the Syrian golden hamster by aerosol administration of difluoromethylornithine and 5-fluorouracil.

Research aimed at identifying effective chemopreventive compounds active against carcinogenesis of the upper respiratory tract (URT) has been largely unsuccessful. We are addressing this problem by efforts at agent identification and by using aerosol delivery. Two compounds, difluoromethylornithine (DFMO) and 5-fluorouracil (5-FU) were investigated. DFMO is an irreversible inhibitor of ornithine decarboxylase, an enzyme important in cell proliferation. It has been used widely by oral administration for chemoprevention. 5-FU is a pyrimidine analog used extensively as a chemotherapeutic agent. It is generally administered i.v. and can cause considerable toxicity. However, aerosol administration for therapy of lung cancer in humans has been reported to be without adverse effects (Tatsumura et al., Br J Cancer 1993;68:1146-9). The experimental model used herein entailed six intratracheal administrations of methylnitrosourea (MNU) to hamsters. Each of the test agents was started about 1 week after MNU and was continued for 29 weeks with DFMO. Infiltrating squamous cell carcinomas of the URT occurred in 92% of the controls and were reduced by 50% in animals receiving DFMO (P = 0.0001). The experiment with 5-FU was of shorter duration being terminated 20 weeks after MNU. Thirty percent of the controls had infiltrating carcinomas and were reduced by 60% in animals receiving 5-FU (P = 0.0274). Both compounds resulted in a significant increase in the percent of cancer-free animals. These two agents may have selected use in subjects at high risk of cancer of the URT.

A dominant-negative c-jun mutant inhibits lung carcinogenesis in mice.

Lung cancer is the leading cause of cancer mortality in the United States and worldwide. The identification of key regulatory and molecular mechanisms involved in lung tumorigenesis is therefore critical to increase our understanding of this disease and could ultimately lead to targeted therapies to improve prevention and treatment. Induction of members of the activator protein-1 (AP-1) transcription factor family has been described in human non-small cell lung carcinoma. Activation of AP-1 can either stimulate or repress transcription of multiple gene targets, ultimately leading to increased cell proliferation and inhibition of apoptosis. In the present study, we show induction of AP-1 in carcinogen-induced mouse lung tumors compared with surrounding normal lung tissue. We then used a transgenic mouse model directing conditional expression of the dominant-negative c-jun mutant TAM67 in lung epithelial cells to determine the effect of AP-1 inhibition on mouse lung tumorigenesis. Consistent with low AP-1 activity in normal lung tissue, TAM67 expression had no observed effects in adult mouse lung. TAM67 decreased tumor number and overall lung tumor burden in chemically induced mouse lung tumor models. The most significant inhibitory effect was observed on carcinoma burden compared with lower-grade lesions. Our results support the concept that AP-1 is a key regulator of mouse lung tumorigenesis, and identify AP-1-dependent transcription as a potential target to prevent lung tumor progression.