Clinical studies on a new screening assay for anticancer agents using nude mice and isotopic evaluation

Abstract

A new screening assay for anticancer agents was established using an in vivo nude mouse model. Assessment of the chemosensitivity of individual human tumors was determined by [3H]thymidine incorporation by the treated tumors. Three hundred and thirty tumors derived from cancer patients were transplanted into nude mice s.c. and treated with anticancer agents. Mitomycin C, 5-fluorouracil, cyclophosphamide, and doxorubicin were used in the present studies. In 270 of 330 cancers, chemosensitivity was evaluated by this method (evaluable rate, 81.8%). The rate of positive sensitivity against all tumors was 21.9% in mitomycin C, 12.2% in 5-fluorouracil, 27.4% in cyclophosphamide, and 23.6% in doxorubicin, respectively. The tumor sensitivity to anticancer agents varied according to the type of cancer. Retrospective and prospective clinical studies were performed to determine the usefulness of the nude mouse-isotope assay for the prediction of tumor sensitivity. The 24-month survival rates of 24 gastric cancer patients treated with tumor-sensitive agents was significantly higher than that of 28 patients treated with tumor-resistant agents. The end results after chemotherapy in far-advanced and inoperable terminal cases of gastrointestinal cancers was also investigated, prospectively. Out of 19 cases, the 50% survival time of 11 patients treated with tumor-sensitive agents was longer than that of eight patients treated with tumor-resistant agents. From prospective correlative studies carried out on 25 patients, this assay correlated with clinical responses (overall agreement, 76.0%; P less than 0.05) with specific agreements of sensitivity and resistance of 37.5 and 94.1%, respectively. From these results, it seems reasonable to conclude that nude mouse-isotope assay is a screening assay to identify appropriate agents for the treatment of patients with cancer. However, there is still a need to develop a better protocol in this assay, especially for antimetabolites, and to continue research in order to find more sufficient assays to predict clinical sensitivity to anticancer agents.