A predictive clinically-useful in vitro test of drug response is a critical need in cancer chemotherapy. Toward this end we have developed a three-dimensional, gel-supported, primary culture system that allows all types of solid human tumors to grow and maintain their native tissue structure in vitro (Freeman, A.E. and Hoffman, R.M. Proc. Natl. Acad. Sci., USA 83, 2694-2698, 1986). With the use of autoradiographic techniques to measure DNA synthesis in individual cells of the cultured tumor tissues, we have developed a drug-response assay on the tumors grown in our system which has been used on 18 different solid tumor types (Vescio, R.A., Redfern, C.A., Nelson, T.J., Ugoretz, S., Stern, P.H. and Hoffman, R.M. Proc. Natl. Acad. Sci., USA 84, in press, 1987). The assay is of high resolution with regard to distinguishing the drug response of different cell types within individual tumors and scoring rare resistant cells. In vitro drug responses are similar to the clinical situation and in early studies are predictive of clinical response. We propose here to 1) continue a retrospective validation of the ability of drug-response assay to correlate to clinical outcome 2) further validate the assay by carrying out a prospective correlative clinical trial to determine the efficacy of the drug-response assay to predict breast cancer response to doxorubicin as a single agent 3) further increase the resolution and clinical usefulness of the drug- response assay, by measuring microspectrophotometrically the DNA content of cells within the cultured tumors as an indicator of malignancy and relating these data to autoradiographic measurements of cell proliferation to determine the drug responses of the most malignant cells of each tumor. At the end of this grant period, the drug-response assay should be clinically validated and available to patients throughout the United States on a commercial basis.
