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Hollow fiber assay adopted as prerequisite for xenograft studiesIn 1995, DTP implemented a solid tumor efficacy model based on cell growth inside biocompatible hollow fibers.1,2 The hollow fiber assay, which was developed by Dr. Melinda Hollingshead, chief, Biological Testing Branch, has the ability to provide quantitative indices of drug efficacy in heterogeneous tumors with minimal expenditures of time and materials. It is currently being used as the initial in vivo experience for agents found to have reproducible activity in the in vitro anticancer drug screen. The hollow fiber assay has several advantages over standard animal efficacy models. First, demonstrating that potential anticancer agents have in vivo efficacy in one or more animal models of neoplastic disease can require considerable investments in terms of laboratory animals and quantity of test compound. Second, conducting studies in animal models requires substantial amounts of time and resources for the testing procedure itself. Even when such studies can be conducted, it is possible that the experimental agent or series of agents will exhibit only minimal antitumor activity. Third, cancer treatments that appear promising in tissue culture are often less effective in solid tumors, in part because of the proliferative and microenvironmental heterogeneity that develops in these tumors as they grow.3 The hollow fiber assay at full capacity allows screening of 50 or more compounds per week in a 10-day assay. In addition to requiring less than two weeks to complete, it requires at most only 450 mg of material, as opposed to the multigram quantities required for xenograft studies. Compounds that retard the growth of the selected tumor cell lines are recommended for the next level of testing. Methodology: 1 Biological Testing Branch, Developmental Therapeutics Program. Primary anti-cancer drug screening activities. 2 National Cancer Institute. Drug Discovery at the National Cancer Institute: Questions and Answers. 3 Hollingshead MG, Alley MC, Camalier RF, Abbott BJ, Mayo JG, Malspeis L, Grever MR. In vivo cultivation of tumor cells in hollow fibers. Life Sci 1995;57:131141. Links: In vivo cultivation of tumor cells in hollow fibers. Growth
and chemotherapeutic response of cells in a hollow-fiber in vitro solid
tumor model. |
The assay has demonstrated the ability to provide quantitative initial indices of in vivo drug efficacy and is currently being used as the initial in vivo experience for agents found to have reproducible activity in the in vitro anticancer drug screen. Drugs showing activity with unique mechanisms of action are being further developed as potential clinical candidates or have already made the transition from bench to bedside. Some examples are Velcade, 17-AAG, and dimethanesulfonate. |