Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung tumor formation by FGN-1 (sulindac sulfone).
The sulfone derivative of the non-steroidal anti-inflammatory drug (NSAID), sulindac, has been reported to inhibit mammary and colon tumor formation in rodent models of chemically-induced carcinogenesis. Unlike its parent compound, this metabolite lacks cyclo-oxygenase inhibitory activity. A tumor induction protocol, consisting of NNK administration in the drinking water over several weeks to model chronic human exposure, was used to test whether the sulfone (called FGN-1) could inhibit the formation of primary lung tumors in mice. A total of 150 female, AIN76A-fed, A/J mice received 9 mg of NNK each. Concentrations of FGN-1 that had been previously determined not to affect body weight gain were added to the food at levels of 0, 250, 500 and 750 mg/kg of diet (30 mice/group) starting 2 weeks before NNK administration and continuing for 22 weeks. At that time pleural surface tumors were counted. Tumor incidence decreased significantly from 96 % in the control diet and 93% in the 250 FGN-1 mg/kg diet to 63 and 67% in the 500 and 750 mg FGN-1/kg diet groups, respectively (P < 0.001 by chi-square analysis). Lung tumor multiplicity decreased from 18.1+/-3 tumors/ mouse (mean+/-SEM, control diet) to 12.3+/-3 (250), 5.3+/-1 (500) and 2.1+/-1 (750) (P < 0.0005 by post hoc ANOVA). In previous studies using this carcinogenesis protocol, the maximum tolerated dose of sulindac inhibited lung tumor multiplicity by no more than 50% with no effect on incidence. This dose-dependent reduction in tumorigenesis by a non-toxic dose of FGN-1 indicates a strong chemopreventive activity against experimental induction of lung carcinogenesis. The greater potency of the sulfone over sulindac and its lack of toxic side effects because of its inability to affect cyclo-oxygenase activity suggests that clinical testing in individuals at high risk for lung cancer should be considered.
Malkinson
A M
AM
Department of Pharmaceutical Sciences, School of Pharmacy and Colorado Cancer Center, University of Colorado Health Sciences Center, Denver 80262, USA. al.malkinson@uchsc.edu
Koski
K M
KM
Dwyer-Nield
L D
LD
Rice
P L
PL
Rioux
N
N
Castonguay
A
A
Ahnen
D J
DJ
Thompson
H
H
Pamukcu
R
R
Piazza
G A
GA
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002273:Carcinogens; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines; D013467:Sulindac / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D002273:Carcinogens; D009602:Nitrosamines; D013467:Sulindac; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C025463:sulindac sulfone