The limiting radiosensitisation of tumours by S-phase sensitisers

The aim of this study was to improve local control and survival of patients with radioresistant tumours by sensitising proliferating cells using halogenated analogues of thymidine, with emphasis on increasing the proportion of tumour cells that incorporate the sensitiser. It has been found clinically that 2 weeks of continuous infusion of IUdR at 1000 mg m-2 per day can be tolerated, followed after a gap by a third week of the same. The sensitising compound is taken up only into those cells which are in S-phase at the time of administration. It is assumed that if the same total dose of 3 g m-2 were administered spread evenly over a longer period, it would be tolerated at least as well, and a higher proportion of tumour cells would become sensitised (labelled with IUdR). The question then arises: is the reduced concentration of IUdR enough to cause significant radiosensitisation? This question was investigated in two contrasting lines of human colon cancer in vitro. It is essential that at least 90% of all clonogenic tumour cells should be labelled with the IUdR (that is 1 log), or else the sensitiser enhancement ratio (SER) cannot be expected to exceed 1.1. Similarly, to reach an SER of 1.2, we should label 99% of cells (2 logs labelled). To achieve such proportions labelled, infusions would have to be 5 or 10 times longer than the population doubling time of clonogenic cells Tpot that is of several weeks duration. The infusion should be either continuous or perhaps better-by repeated small boluses at intervals of less than T (duration of DNA synthesis), so that no proliferating cells escape being exposed to the IUdR. It is shown that LIs (labelling indices) of 94% can be obtained with SERs ranging from 1.5 to 3.0 and 99% with SERs from 1.2 to 2.4, in the two most contrasting human colon cancer cell lines for which data are available. Longer, lower dose infusions than previously used should be considered so as to emphasise the importance of not allowing any potentially clonogenic tumour cells to pass through S-phase without labelling.