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© 1987 Oxford University Press

research-article

Evaluation of the Interaction of Three Genotoxic Agents in Eliciting Sister-Chromatid Exchanges Using Response Surface Methodology

RICHARD P. SOLANA*, VERNON M. CHINCHILLI*,{ddagger}, JOHN D. WILSON{dagger}, WALTER H. CARTER, JR{ddagger} and RICHARD A. CARCHMAN*,{ddagger},1

*Department of Pharmacology and toxicology Box 32 MCV Station, Medical Colllege of Virginia, Richmond, Verginia 23298 {ddagger}Department of Biostatistics Box 32 MCV Station, Medical College of Virginia, Richmond, Virginia 23298 {dagger}Department of Radiology Box 32 MCV Station, Medical College of Virginia, Richmond, Virginia 23298

Chinese hamster cells (V79) were treated with ethylnitrosourea (ENU), bischloroethylnitrosourea (BCNU), and cis-diamminedichloroplatinum(II) (DDP) alone and in combination. Sister chromatid exchanges (SCEs) were quantitated as measures of genotoxicity of the three agents. The combination experiment employed a factorial design in which cells were treated, in various concentration combinations, with all agents simultaneously. Response surface methodology using a polynomial model in treatment variables to approximate the mean the distribution of SCE events was employed for analysis of the interactions of the three genotoxic agents. Due to unequal variances of the number of SCEs in the various treatment groups, a weighted leastsquares analysis was used to estimate the parameters of the dose-response relationship. The single-agent results suggest that the DDP concentration-response curve has a much steeper slope than the ENU and BCNU curves, and is concave downward as compared to the relatively linear concentration-response curves of ENU and BCNU. The combination results suggest that ENU and DDP are involved in a negative interaction. The BCNTJ/DDP interaction, the ENU/BCNU interaction, and the three-factor interaction are not statistically significant. The analysis of these data demonstrates the usefulness of a statistical procedure for evaluating the biological effects resulting from exposure to multiple cytotoxic agents. The methodology can be used with many other types of endpoints and is not limited by the number of treatment agents.


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