Abstract
A commonly used technique for evaluating potential bioreductive drugs is the determination of hypoxic cytotoxicity ratios in vitro. This experimental model, however, does not accurately mimic the tumour microenvironment, as other factors (such as reduced pH, poor nutrient status, low cell proliferation rates and high catabolite concentrations) are not incorporated into the design of the assay. Plateau-phase monolayer cultures possess many of these characteristics, and this study compared the response of plateau-phase and exponentially growing human colon carcinoma cells (DLD-1) with a series of standard and bioreductive compounds. All drugs tested were added directly to conditioned medium and three patterns of chemosensitivity were observed. In the case of doxorubicin, vinblastine and 5-fluorouracil, exponentially growing cells were significantly more responsive than plateau-phase cultures. ThioTEPA and MeDZQ (2,5-diaziridinyl-1, 4-benzoquinone) were equally cytotoxic to both populations of cells. Tirapazamine (SR4233), RSU 1069, mitomycin C and EO-9, however, were preferentially toxic towards plateau-phase compared with exponentially growing cells. While the exact mechanisms responsible for these observations in each case are not known, this study suggests that plateau-phase cultures may prove to be a useful experimental model in the evaluation of drugs designed to work preferentially within the tumour microenvironment.
Highlights
In the case of EO-9, DLD- 1 cells progressively became more sensitive as cultures matured into plateau phase (Figure 2B)
ThioTEPA and MeDZQ were effective against plateau-phase cells as exponentially growing cells (Figure 3B)
EO-9, mitomycin C, tirapazamine and RSU 1069 were preferentially cytotoxic towards plateau-phase cultures compared with exponentially growing cells (Figure 3C)
Summary
In order to validate this proposed screening strategy, the principal aim of this study is to determine whether or not the sensitivity of DLD- I human colon carcinoma cells at different stages of the growth curve can distinguish between a series of standard anti-cancer agents and known bioreductive drugs using the selection criteria outlined above. The principal objective of this study was to develop a novel cellbased screening assay that could be used to identify drugs that are activated under conditions which mimic the tumour microenvironment
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