Carcinogenesis Advance Access originally published online on April 22, 2006
Carcinogenesis 2006 27(8):1721-1727; doi:10.1093/carcin/bgl052
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The chemopreventive efficacy of inhaled oltipraz particulates in the B[a]P-induced A/J mouse lung adenoma model
Cellular and Molecular Toxicology Program, Alion Life & Environmental Sciences Research Triangle Park, NC 27709, USA
1 Division of Cancer Prevention, National Cancer Institute NIH, Bethesda, MD 20892, USA
*To whom correspondence should be addressed at: Alion Science & Technology, PO Box 12313, Research Triangle Park, NC 27709, USA. Tel: +1 919 406 2225; Fax: +1 919 549 9058; Email: ssharma{at}alionscience.com
This study explored the efficacy of oltipraz, a dithiolthione to prevent lung cancer by delivering it directly to the lung as inhaled particulates to obtain maximum efficacy with no toxicity. Two exposure regimens were used to compare the efficacies of early (Regimen-A) versus late (Regimen-B) intervention in prevention of lung tumorigenesis in A/J mice. Female A/J mice were exposed to 10, 30 and 100 mg/m3 exposure concentrations of oltipraz for 1.0 h a day for 5 days per week for 4 weeks in Regimen A. During the second and third week, mice received totally 6 mg of B[a]P via gavage and after 16 weeks, they were killed for tumor counting and pathology. In Regimen B, mice were treated first with B[a]P and, after a gap of 4 weeks, exposed to oltipraz at 100 mg/m3 for 16 additional weeks. At 22 weeks, animals were killed and necropsied for tumor scoring. The spontaneous tumors were few in untreated A/J mice (0.7 tumors/lung), whereas there was an average of 16.5 tumors per lung in the B[a]P group (20-fold induction). Evaluation of lung tumor multiplicity following exposure to oltipraz showed that oltipraz inhibited the tumor development in a dose-dependent manner (10–100 mg/m3) with inhibition ranging from 37 to 53% in Regimen A and 51% in Regimen B, when compared with the B[a]P group. Analysis of the tumor incidence showed that 81.5% of the animals had 10 or more tumors in the B[a]P group, whereas, in oltipraz exposure groups, there was a significant decrease in Regimen A (24–36%) and in Regimen B (42%). The data from this study show that oltipraz is an effective agent for lung cancer prevention, when it is delivered directly to the target tissue as aerosolized particulates.
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