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The A/J mouse lung as a model for developing new chemointervention strategies
S A Belinsky1, S A Stefanski, M W Anderson
1Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Abstract:
The use of the A/J mouse lung as a model for developing new chemo-intervention strategies was investigated by first inducing lung tumors with a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Lungs were then staged for tumor development and intervention therapy was initiated 42 weeks after carcinogen treatment. At this time point, an average of 7 pulmonary lesions were present on a standard histological section and the relative frequency of lesions was distributed as alveolar hyperplasias (38%), adenomas (40%), and adenocarcinomas (22%). Mice were treated for 4 or 8 weeks with cis-platinum alone or in combination with either indomethacin, an inhibitor of prostaglandin synthesis, metoclopramide, an inducer of poly(ADP) ribosylation, or nifedipine, a calcium channel blocker. The effect of indomethacin, metoclopramide, and nifedipine on tumor growth was also determined. The most dramatic effects were observed in lungs from mice treated for 8 weeks. cis-Platinum treatment caused a 37% reduction in the size of carcinomas, while tumor mass was reduced by 50 to 60% with cis-platinum in combination with metoclopramide and/or indomethacin. The inclusion of indomethacin therapy in conjunction with cis-platinum significantly enhanced the effectiveness of cis-platinum for inhibiting the growth of adenocarcinomas. In contrast, nifedipine appeared to ameliorate any of the inhibitory growth effects seen with cis-platinum treatment. Although none of the therapeutic combinations affected the size of adenomas, morphological differences were observed among treatment groups. A moderate to marked decrease in cytoplasm was observed in adenomas from mice treated with cis-platinum in combination with indomethacin or metoclopramide, cis-platinum plus metoclopramide and indomethacin, or metoclopramide plus indomethacin. Taken together, the results from these studies demonstrate that the A/J mouse lung can be used as a model to study the effectiveness of new intervention therapies for controlling malignant tumor growth. This model should also be applicable for studying the effectiveness of cancer prevention therapies on the progression of pulmonary hyperplasia.
Insights
This study shows the A/J mouse lung is a viable model for testing lung cancer chemo-intervention strategies. Combining cis-platinum with indomethacin or metoclopramide effectively reduced tumor growth.
Area of Science:
- Oncology
- Pharmacology
- Preclinical Research
Background:
- The A/J mouse lung is a model for studying lung cancer.
- Lung tumors were induced using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
- Tumor development was staged 42 weeks post-carcinogen treatment.
Purpose of the Study:
- To investigate the A/J mouse lung as a model for chemo-intervention strategies.
- To evaluate the efficacy of cis-platinum alone and in combination with other agents.
- To assess the impact of indomethacin, metoclopramide, and nifedipine on tumor growth.
Main Methods:
- Induction of lung tumors in A/J mice.
- Treatment with cis-platinum, indomethacin, metoclopramide, or nifedipine for 4 or 8 weeks.
- Histological analysis of pulmonary lesions and tumor growth.
Main Results:
- Eight weeks of cis-platinum treatment reduced carcinoma size by 37%.
- Combinations of cis-platinum with metoclopramide and/or indomethacin reduced tumor mass by 50-60%.
- Indomethacin significantly enhanced cis-platinum's efficacy against adenocarcinomas; nifedipine diminished these effects.
Conclusions:
- The A/J mouse lung model is effective for evaluating lung cancer intervention therapies.
- Combination therapies, particularly with indomethacin, show promise for controlling malignant lung tumor growth.
- This model can also assess cancer prevention therapies for pulmonary hyperplasia.