Carcinogenesis Advance Access published online on November 21, 2003
Carcinogenesis, doi:10.1093/carcin/bgh022
© 2003 by Oxford University Press
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CARCINOGENESIS
1 AMC Cancer Research Center, Denver, CO 80214
* Corresponding author. E-mail: hanausekm{at}amc.org.
Received 24 June 2003
; revised 29 October 2003
; accepted 4 November 2003
Screening of newly synthesized organic peroxides for tumor initiating/promoting activity would be greatly facilitated if predictive methodologies could be developed using topical exposures shorter than those required for definitive tumor assessment in mouse skin models. Nine organic peroxides [benzoyl peroxide (BZP), di-t-butyl peroxide (DTBP), t-butyl peroxybenzoate (TBPB), p-t-butyl isopropylbenzene hydroperoxide (TBIBHP), cumene hydroperoxide (CHP), dicetyl peroxydicarbonate (DPD), dicumyl peroxide (DCP), methyl ethyl ketone peroxide (MEKP), and O,O-t-butyl-O-(2-ethylhexyl) monoperoxycarbonate (TBEC)] were evaluated for their ability to increase biomarkers of tumor promotion in mouse skin, i.e., sustained epidermal hyperplasia, dermal inflammation, and oxidative DNA damage. Evaluations were performed using SENCAR mice exposed topically for 4 weeks. The organic peroxides varied in their effects on these biomarkers. BZP, TBPB, and TBIBHP exhibited significant increases in all three biomarkers associated with tumor promoting activity, CHP produced increases only in sustained epidermal hyperplasia and dermal inflammation, MEKP and DCP produced increases only in sustained epidermal hyperplasia, and TBEC produced an increase only in dermal inflammation. DTBP and DPD had no effect on the three parameters studied. TBPB and TBIBHP were selected for further examination of their ability to produce mutations in codons 12, 13, and 61 of the c-Ha-ras protooncogene, i.e., those mutations known to be involved in the initiation of mouse skin tumors, because they were the only peroxides to exhibit significant positive results in all assays except the Ha-ras mutation following 4 weeks of exposure. Evaluations were performed using SENCAR mice dosed topically for 8 or 12 weeks in a complete carcinogenesis protocol or 16 weeks in an initiation/promotion protocol using 7,12-dimethylbenz[a]anthracene (DMBA), urethane, benzo[a]pyrene (B[a]P), and N-methyl-N'-nitro-N-nitrosoquanidine (MNNG) as positive controls. Neither TBPB nor TBIBHP produced detectable mutations in the c-Ha-ras protooncogene, indicating that they are not likely to possess tumor initiating or complete carcinogenic activity.
organic peroxides, mouse skin, epidermal hyperplasia, tumor initiation, tumor promotion, Ha-ras proto-oncogene mutation
Exposure of mouse skin to organic peroxides: subchronic effects related to carcinogenic potential
2 Great Lakes Chemical Corporation, West Lafayette, IN 47906 (formerly of Akzo Nobel Chemicals, Inc., Dobbs Ferry, NY 10522)
3 ATOFINA Chemicals, Inc., Philadelphia, PA 19103
4 Dermigen, Inc., Smithville, TX 78957
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