Phylonix uses zebrafish model to target cancers

CAMBRIDGE, Mass.—If results published in the latest issue of Angiogenesis are anything to go by, lab mice may have competition in modeling human cancer, as scientists at Phylonix Pharmaceuticals success­fully modeled various stages of tumor develop­ment in zebrafish. The researchers were able to show that melanoma, colorectal and pancreatic cell lines not only proliferated but also stimulated angiogenesis in these small aquarium fish.

"Although the mouse has been the model-of-choice for human cancer cell research and drug screening for more than 25 years, the time required to perform xenotransplantation studies in mice ranges from several weeks to months, and it has been difficult to generate mouse models that exhibit tumor metastasis," says Patricia McGrath, Phylonix president and CEO, who also co-authored the paper.

In the current research, however, the scientists showed that not only did the zebrafish embryos not reject the human cancer cells, there was clear evidence of tumor cell mass formation and angio­genesis. Furthermore, the fish actually incorpo­rated their own cells into the human tissues.

According to McGrath, the researchers initially transplanted a highly metastatic melanoma cell line, which migrated and formed masses. They then assessed the general usefulness of the method by transplanting colorectal and pancreatic cancer cell lines, which also formed mass­es. To ensure that the cell behavior wasn't the result of transplanta­tion, however, they introduced healthy human fibroblast cells. As hoped, this cell line migrated but did not form masses.

Given their small size, short generation time, and relative transparency during embryo­genesis, zebrafish offer scientists the opportunity to monitor in vivo responses in drugs or tumor development in a high-throughput setting. In a 2002 paper, National Institutes of Health researcher Dr. Josephine Briggs examined how embryo transparency greatly facil­itated detailed in vivo analysis.

"Individual living cells and even cellular organelles can be observed directly with no staining and little preparation of the fish and no tools other than a good microscope," she wrote. "With the use of an optical sectioning technique, usually dif­ferential interference contrast or Nomarski, it is possible to visual­ize many structures, even subcel­lular organelles, with exceptional clarity."

And because the fish swim in very small volumes of water, drug studies can be conducted with micromolar amounts of many compounds. In mouse studies, the company suggests, these amounts are more typically in the mil­limolar range. With so little test compound, researchers can screen a larger spectrum of compounds, thereby increasing the likelihood of successful lead generation.

The Phylonix researchers are quick to admit, however, that zebrafish are by no means perfect analogues for humans. For one thing, swimming in a drug solu­tion does not necessarily correlate with other modes of drug adminis­tration. Similarly, few studies have been done that compare ADME characteristics of zebrafish and humans, so any results must be accepted with caution. They are nonetheless enthusiastic about the future impact of the study.