Correlation between response to chemotherapy of human tumors in patients and in nude mice

Abstract

Human tumors serially heterotransplanted in nude mice have been tested for their response to chemotherapeutic agents. Fourteen melanomas, 14 colorectal carcinomas, and 14 breast carcinomas have been used. Each tumor originated in a different patient. The tumors were maintained by serial subcutaneous transplantation in nude mice. For the experiments in this study, each neoplasm was transplanted under the kidney capsule of 60 to 100 adult nude mice. The areas of the individual tumor implants were precisely measured immediately after insertion using a stereo microscope equipped with a micrometric ocular. The animals were then divided into groups of six to ten animals each. One group was injected daily with saline and served as controls. The mice in the remaining groups were injected daily for eight days with one of the following chemotherapeutic agents—Adriamycin (doxorubicin), 5-fluorouracil, methotrexate, Cytoxan (cyclophosphamide), Alkeran (melphalan), vincristine, vinblastine, methyl-CCNU, or BCNU—at optimum doses (the maximum dose tolerated that causes less than 10% weight loss). Treatment was initiated when the implants were well established, having roughly doubled their initial mass. The animals were then sacrificed and the tumors measured again. A drug was rated effective only if it inhibited growth of the tumor by 99% or more. The results so obtained were compared with the published results of various clinical trials. When the sensitivity of the human tumors in the mice was compared with the sensitivity of tumors of the same type that had been treated in human patients, a close correlation was found. The panel study detected nine of ten effective drugs, giving only two false-positive results. Our data strongly support the validity of heterotransplants of human tumors in the nude mouse as a predictive system for testing new anticancer agents and in determining optimal treatment schedules and combinations of known drugs.