Towards in-vitro prediction of an in-vivo cytostatic response of human tumor cells with a fast chemosensitivity assay

The objective of this study is to evaluate a novel approach to chemosensiti vity testing with respect to its predictive value in the selection of clini cally effective cytostatic drugs to optimize the therapeutic treatment of c ancer. The chemosensitivity assay, which we used in this study, has its roo ts in pharmaceutical drug screening and the surrounding intellectual proper ty is protected by various patent applications and trademarks. Therefore, w e will refer to this test in the following pages as ChemoSelect(R). ChemoSe lect(R) is a sensor-chip based diagnostic test, which permits the functiona l and continuous real-time measurement of induced tumor cell cytotoxicity f ollowing the administration of chemotherapeutic drugs. Chemosensitivity is measured through the reduction of the excretion of lactic and carbonic acid s-by-products of the metabolic processes of glycolysis and respiration and a parameter for cell vitality-generated specifically by ATP hydrolysis and lactic acid production. We used this test to study the applicability of thi s assay for tumor cells based on the analysis of tumor cell lines and tumor specimens. In this preliminary study, this test was studied in predicting chemoresistance and chemosensitivity in cell lines and tumor specimens for which the result was already predetermined by the properties of the cell li ne or the tumor specimen used in the experiment. The applicability in a cli nical setting was studied by confirming the trends on selected drug sensiti vity and drug resistance with an interim analysis of an ongoing clinical st udy in selected patients with breast cancer undergoing neoadjuvant chemothe rapy. The minimum detection limit of cells and biologic cell responses, an important variable determining the applicability of the test in routine cli nical use, was also assessed. ChemoSelect(R) avoids many of the limitations of existing chemoresistance assays and provides more comprehensive informa tion and output, as it has a 24-h turnaround time, is applicable to the maj ority of solid tumors and available cytostatic drugs, does not need more th an 10(5) cells in total, cultivated tumor cells, provides dynamic monitorin g of cellular responses through on-line data read-out during the perfusion with drugs and can be extended to the analysis of novel therapeutic modalit ies such as biologics. (C) 2001 Elsevier Science Ireland Ltd. All rights re served.