Mariana S. De Lorenzo1, Kotha Subbaramaiah1, Nasser K. Altorki1, Madhu Mazumdar3, Levy Kopelovich2, Krista M. La Perle4, Andrew J. Dannenberg1, Jeffrey L. Port1; 1CT Surgery, Weill Cornell, New York, NY; 2NCI, Bethesda, MD; 3Dept. of Biostatistics Weill Cornell, New York, NY; 4Dept. of Comparative Pathology Weill Cornell, New York, NY
Objective: The use of nonsteroidal anti-inflammatory drugs (NSAIDs), prototypic inhibitors of cyclooxygenase (COX), has been associated with a reduced incidence of gastrointestinal cancers. While it is known that NSAIDs can block tumor promotion and progression, little is known about the effects of this widely used class of drugs on tumor initiation. In this study, we investigated whether administration of sulindac, a dual inhibitor of COX-1 and COX-2, or celecoxib, a selective COX-2 inhibitor, during the initiation phase of carcinogenesis suppressed benzo[a]pyrene (B[a]P)-induced neoplasia.Methods: CD2 mice (n=100) were randomly assigned to four groups: I sham (n=10), 2 B[a]P (n=30), 3 B[a]P + celecoxib (1000 ppm, n=30), and 4 B[a]P + sulindac (320 ppm, n=30). Celecoxib and sulindac were administered in AIN76 diet beginning 1 week prior to the administration of B[a]P and continued for a total of 4 weeks. Animals in groups 2-4 received B[a]P by gavage (125mg/kg in 0.5 mL corn oil) on 5 consecutive days. Sham animals (group 1) received corn oil by gavage. Sacrifice was performed 41 weeks following the last dose of B[a]P. At the time of sacrifice, the esophagus, forestomach, lung, thymus, spleen and colon were harvested for pathologic analysis. Comparisons between groups were made with non-parametric Fishers-exact test and P-values are adjusted using the False Discovery Rate multiple comparison procedure in Proc Multtest in SAS with 5% familywise rate.
Results: 14 of the original 100 mice died during the course of the experiment. A total of 86 mice were sacrificed and evaluated. B[a]P caused neoplastic changes only in the forestomach and lung. Accordingly, a further analysis was performed for these two organ sites as follows: 1) Sham versus B[a]P; 2) B[a]P versus B[a]P + Celecoxib; 3) B[a]P versus B[a]P + Sulindac; (Table)
Conclusion: Collectively, these data demonstrate that the administration of NSAIDs during the initiation phase of chemical carcinogenesis can suppress tumor formation.
Table
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