Identifying lead drug candidates or appropriate tumor cell lines for xenograft studies can be expensive and time-consuming — it takes months to get a result and requires large numbers of mice. Although faster, in vitro 3D cell proliferation assays also present challenges because it is not possible to evaluate the movement and distribution of drug compounds.
The in vivo Hollow Fiber Model bridges these two types of study by conducting cell proliferation assays in mice. As described in a new, non-peer-reviewed white paper from ProQinase, a division of Reaction Biology Corp, the Hollow Fiber Model allows researchers to quickly evaluate numerous drug candidates or identify the best tumor cell lines.
The technique uses straw-shaped fibers with semi-permeable membranes. Each fiber contains a different tumor cell line suspension; three fibers are inserted at two locations, subcutaneously and intra-peritoneally, allowing three tumor cell lines to be tested in a single mouse.
The semi-permeable membrane keeps the cells within the fibers but allows the influx of oxygen, nutrients and drugs, and the efflux of waste and CO2. Within the fibers, the cells naturally aggregate into spheroids resembling tumor architecture: viable cells on the outside have ready access to nutrients and oxygen whereas those inside in hypoxic zones become quiescent — or necrotic in the very center.
Model advantages
Because six datapoints are obtained for each mouse, the Hollow Fiber Model reduces the total number of mice needed. For example, a study using 48 mice permits researchers to test 14 drug candidates, with 3 mice replicates per drug and 6 control mice. Mice suffer less because tumor cell growth is restricted to the fibers. Compared with xenograft studies, which can take months to deliver results, drug treatments using the Hollow Fiber Model allow researchers to obtain results in as little as two weeks.
Mice are treated with drug compounds for a standard period of two weeks after the fibers are inserted. The compound is administered and can contact the serum and other potentially inhibitory or binding factors. Conducting the assay in vivo permits researchers to assess how drug compounds move and are distributed throughout the mice’s bodies. After the treatment period, the fibers are removed and the cells are examined using standard cell viability assays or other analyses such as Western blot, ELISA, or flow cytometry.
Several studies have evaluated the efficacy and predictive value of the Hollow Fiber Model for subsequent xenograft studies. The National Cancer Institute, which originally developed the model1, conducted a study using 690 compounds and found that of the 93 compounds that showed high activity in the Hollow Fiber Model, 55% also showed activity in at least one xenograft model2. Another study that used 20 standard tumor cell lines and four anti-cancer agents found a 92% predictive accuracy for resistance in the xenograft assay3. And a case study, described in the white paper, compared the performance of crizotinib with matching results in the Hollow Fiber Model and respective xenograft models.
The Hollow Fiber Model can gather pharmacodynamic and pharmacokinetic data and test therapy combinations and dosing schedules — in less time and using fewer animals than conventional methods. Ultimately, it can reduce the time and money researchers need to spend on drug efficacy studies.
For more information on the Hollow Fiber Model, read the white paper here.