The ability to predict the response of an individual tumor to subsequent chemotherapy would offer obvious clinical advantages in cancer treatment. We have previously shown that for the treatment of established tumor cell lines with specific chemotherapeutic agents, drug-induced sister chromatid exchanges (SCEs) are correlated with drug-induced cell kill. The goal of this proposal is to investigate the use of the SCE assay as a model for predicting the response of primary human tumor cell cultures to specific antineoplastic drugs. These studies will involve ranking the drug sensitivities of primary cultures according to their SCE dose-responses and, or probably greater significance, evaluating the heterogeneity in drug sensitivity existing among the tumor cell subpopulation through the generation of SCE frequency histograms (number of cells versus SCEs/chromosomes). SCE dose-response curves will be generated after treatment of primary cultures of human tumor cells with cis-platinum, BCNU or melphalan and the relative sensitivities as predicted by the SCE and a survival assay compared. The heterogeneity in cis-platinum, BCNU and melphalan response existing in primary tumor cell cultures will be investigated through the construction of SCE frequency histograms. Drug- induced SCE frequency histograms will also be used to investigate intraneoplastic diversity in intrinsic radiation response. The detection of this form of heterogeneity will be based on the modification of drug- induced SCE frequency histograms by prior X-irradiation. These proposed studies should aid in evaluating the potential application of SCE analysis as a predictive assay and may provide insight into the heterogeneity in antineoplastic response existing within human tumors.
