Carcinogenesis Advance Access published online on April 22, 2006
Carcinogenesis, doi:10.1093/carcin/bgl052
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1 Cellular and Molecular Toxicology Program, Alion Life & Environmental Sciences, Research Triangle Park, NC 27709, USA
* To whom correspondence should be addressed. 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/week for 4 weeks in regimen A. During the second and third week, mice received 6 mg total of B[a]P via gavage and after 16 weeks, they were sacrificed 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 euthanized 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 37-53 % in regimen A and 51% in regimen B, when compared to 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 shows that oltipraz is an effective agent for lung cancer prevention, when it is delivered directly to the target tissue as aerosolized particulates (Supported by NCI contract N01-CN-25112).
Received September 9, 2005
Revised March 27, 2006
Accepted April 13, 2006
CARCINOGENESIS
The chemopreventive efficacy of inhaled oltipraz particulates in the B[a]P-induced A/J mouse lung adenoma model
Sheela Sharma 1 *,
Pu Gao 1,
and
Vernon E. Steele 2
2 Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Sheela Sharma, E-mail: ssharma{at}alionscience.com
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