Validation studies: tegafur



Among its proof-of-concept studies, HµREL® was used to test the cancer chemotherapeutic pro-drug tegafur. Tegafur itself is inactive, and requires metabolic activation by cytochrome P450 enzymes present in the liver to generate the cancer cell-killing metabolite 5’-fluorouracil (5-FU).

Both tegafur and, separately, 5-FU were tested in a HµREL device containing hepatocytes cultured in the liver compartment and colon cancer cells cultured in the "target tissue" compartment. For comparison, both tegafur and, separately, 5-FU were also tested on colon cancer cells using a conventional, static cell-based assay.

With the HµREL system, both tegafur and 5-FU were found to be cytotoxic to colon cancer cells in a dose-dependent fashion. However, tegafur was ineffective when tested using the traditional static assay. Moreover, although 5-FU triggered cell death in the traditional assay, HµREL demonstrated cytotoxicity much more rapidly and strongly with either 5-FU or tegafur than the traditional assay did with 5-FU.

As a control experiment to demonstrate that the HµREL liver compartment was necessary for bio-activation of tegafur, HµRELs were seeded with colon cancer cells only (i.e., no hepatocyte culture was included). In the absence of a functional liver compartment tegafur had no effect on the colon cancer cells, whereas 5-FU caused significant cell death. This result confirms that tegafur is metabolized to an active drug in the HµREL liver compartment and that the metabolites are cytotoxic to the target cancer cells.