Identification of biomarkers to predict anticancer drug sensitivities by means of transgene experiments

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All of the classical antineplastic agents, with the exception of vinca alkaloids and taxanes, work on DNA metabolism in cells and can therefore be categorised as 'DNA metabolism inhibitor'. Cellular sensitivity against these drugs largely depends on various activities in DNA metabolism. Thymidylate synthase (TS), which regulate the limiting step of thymidylate synthesis, has long received attention as a determinant of cellular sensitivity against the most widely used anticancer agent, 5-fluorouracil (5-FU). However, this possibility has thus far been studied by retrospective, i.e. inductive, approaches, with few exceptions, and has not been concluded yet. In order to approach this problem a priori, a TS-expression plasmid vector has been introduced into a human colorectal cancer cell line, DLD-1. In this system, the expression of the TS transgene is under the control of tetracycline-dependent promoter and inducible by depletion of the antibiotics in the culture media. Ten TS-expressing transformants were isolated and established as a cellline. In one, the dynamic range of TS expression was over ten-fold. Using this transformant cell line, the 5-FU sensitivity at diverse levels of TS expression are now being approached from various angles.