HISTOCULTURE AND THE IMMUNODEFICIENT MOUSE COME TO THE CANCER CLINIC - RATIONAL APPROACHES TO INDIVIDUALIZING CANCER-THERAPY AND NEW DRUG-EVALUATION (REVIEW)

Originating from the experiments of Alexis Carrel, tissues in culture were originally grown in three dimensions and maintained important in vivo-like structural and functional properties. However, in modem times, monolayer cell culture methods have become predominant despite losses of structural and functional properties of the cells. Strangeways, Fell, Leighton, Sutherland and others have designed various methods of three-dimensional culture using cellulose supports, mesh supports, collagen gel or sponge supports and floatation that allow tissues to maintain many in vivo-like properties such as native architecture, differentiated functions, gene regulation, invasive properties and drug sensitivities which are very different than cells in monolayer cultures. Collagen-sponge-gel-supported histoculture has been shown to support the growth and native three-dimensional architecture of both tumor and normal tissue, often for long periods of time. This method of histoculture was utilized to develop a chemosensitivity assay for individual cancer patients by assessing the effects of drug on the patients' histocultured tumor. Various end points to measure drug response have been utilized in histoculture, including [H-3]thymidine incorporation measured by histological autoradiography and the use of vital dyes to indicate cell viability. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) end point was applied to the histoculture assay in an attempt to increase in vitro-in vivo correlation. The chemosensitivities of 16 human tumor lines were determined in vitro by the histoculture assay, and retrospectively correlated to their in vivo chemosensitivity as xenografts in nude mice. The overall correlation rate of the efficacy results of the drug-response assay to in vivo chemosensitivities was 89.8%, with 90.0% true-positive and 89.7% true-negative rates, 81.7% sensitivity and 94.6% specificity, thereby indicating potential clinical use for tumor histoculture with the MTT end point. The data reviewed and analyzed here thus indicate that three-dimensional culture systems offer much more realistic model systems for evaluating potential new cancer agents and individualized treatment such as predictive drug-response testing. The 'MetaMouse' model developed in our laboratory allows direct 'onplantation' of intact patient surgical cancer specimens orthotopically to athymic 'nude' mice with high-level expression of local growth on the target organ and high metastatic potential. Eight MetaMouse human cancer models are reviewed including those for the colon, bladder, lung, stomach, prostate, ovary, pancreas and head and neck. The human tumors growing and metastasizing in the mice reflect the clinical situation and should be useful for new drug evaluation and development of strategies for individual treatment. The combined technologies of histoculture and MetaMouse thus offer an integrated in vitro-in vivo system for preclinical evaluation of experimental and standard cancer therapy.