These lesions, however, are likely to be relatively easily repaired (McNair et al, 1997). Considering that MMR seems not to be affected by PDT, it is reasonable to assume that PDT-induced DNA damage remains of low clinical importance. Indeed, the risk of PDT generating secondary cancer is known to be very small (Moan and Berg, 1992). In order to ensure that PDT acts similarly in MMR-proficient selleck catalog and -deficient tumour cells, the subcellular photosensitiser distribution and kinetics of drug uptake (i.e. relative values representing changes in drug concentrations) have been estimated using fluorescence microscopy. As demonstrated in Figures 3 and and4,4, both, drug uptake kinetics and drug distribution, were similar in MMR-proficient and -deficient cells.

This finding further supports the idea that PDT-mediated cell killing is fully independent of MMR. Furthermore, the pattern of the subcellular photosensitiser distribution and the kinetics of drug uptake in HCT116 cells are in good agreement with previous findings of this laboratory in MCF-7 and V-79 cells that are known to be proficient in MMR (Hornung et al, 1997). The addition of mitomycin C has been shown to enhance the PDT effect (Nahabedian et al, 1988). Recently, it has been reported that loss of MMR is specifically associated with hypersensitivity to mitomycin C (Fiumicino et al, 2000). Although mechanistic studies are needed to fully elucidate the biochemical events involved, these findings are interesting because they may suggest a means of selectively eliminating cells that have lost their ability to perform MMR.

In conclusion, our results demonstrate that: (i) PDT is as efficient in MMR-deficient cells as in MMR-proficient cells; (ii) repetitive treatments with PDT do not result in loss of MMR; and (iii) MMR-deficient cells show similar m-THPC distribution and kinetics of drug uptake as cells proficient in MMR. Thus, our results suggest the use of PDT as a strategy for circumventing resistance due to loss of MMR. Acknowledgments The authors are grateful to Dr J Jiricny (Institute of Medical Radiobiology of the University of Zurich, Switzerland) for providing the antibodies and Aida Kurmanaviciene for technical support. We also thank Drs CR Boland and M Koi for kindly providing the cell lines. This work has been supported in part by a grant from the Swiss National Science Foundation (No.

31-52531.97) and by Scotia Pharmaceuticals Ltd. (Stirling, UK).
Endothelins (ETs) 1, 2 and 3 are a family of 21 amino-acid peptides that mediate a variety of physiological functions, including cell growth and death. ETs are produced from inactive intermediates that are cleaved to yield active peptides by ET-converting enzyme Cilengitide (ECE), a zinc metalloprotease, specifically responsible for this key step (Shimada et al, 1995; Yanagisawa et al, 1998).