Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Mechanism of differential effects of diclofenac and naproxen in NDEA-induced lung tumorigenesis

KL Khanduja PhD, S Jnagal PhD

Postgraduate Institute of Medical Education and Research, Chandigarh, India,

AIMS: Non-steroidal anti-inflammatory drugs(NSAID’s) are among the most widely prescribed drugs which are used for many years. The aim of the present study was to investigate their(naproxen and diclofenac) role in carcinogenesis. METHODS: Lung tumors were induced in mice by oral administration of three doses of N-nitrosodiethylamine(NDEA), 80 mg/kg body weight with a gap of 4 weeks between the two administrations. RESULTS: It was found that diclofenac feeding at a dose of 375 ppm was able to inhibit (NDEA)-induced lung carcinogenesis in mice by acting on initiation and post-initiation phases of carcinogenesis. However naproxen at 1500ppm stimulated the promotional phase without modulating the initiation phase. To look into the mechanism(s) involved for the different action of the two NSAID's, various assays were done. Ornithine decarboxylase enzyme, which is the first and rate limiting enzymes in the steps of polyamine biosynthesis required for tumor promotion and self proliferation, was inhibited by diclofenac , but was stimulated by naproxen. Prostaglandin E2 release was decreased to a variable degree; diclofenac being the strongest and naproxen being the weakest inhibitors. Since prostaglandins are involved in stimulating the process mediated by reactive oxygen species, the antioxidative properties of NSAID’s and their role in modulating the antioxidant defense system was studied. Diclofenac arrested the microsomal lipid peroxidation, whereas naproxen at a concentration of 10mM stimulated the process initiated by NADPH. It seems that besides being antioxidant, enzymatic metabolism of naproxen forms reactive intermediates/ free radicals. However, the feeding of NSAID’s inhibited the process of lipid peroxidation through stimulation in tissue antioxidant system. CONCLUSIONS: In conclusion, there is no parallel relationship in ODC and prostaglandin levels. Increased tumorigenesis and levels of ODC by naproxen need clinical evaluation for its safety for the long term treatment.

KEY WORDS: diclofenac, naproxen, prostaglandin E2, ornithine decarboxylase, antioxidants, lung carcinogenesis.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on chemotherapy.