MECHANISM OF ACTION OF PSORALENS - ISOBOLOGRAM ANALYSIS REVEALS THAT ULTRAVIOLET-LIGHT POTENTIATION OF PSORALEN ACTION IS NOT ADDITIVE BUT SYNERGISTIC

The combination of psoralens and ultraviolet light (UVA, 320-400 nm), referred to as PUVA, inhibits proliferation of a variety of cell types. In the present studies, we used S-180 cells to investigate the mechanism underlying the antiproliferative actions of PUVA. We found that inhibition of growth of S-180 cells by PUVA was dependent on the concentration of psoralen as well as the dose of UVA light. Neither the psoralens nor UVA light by themselves inhibited cell growth. Several clinically important psoralen analogs inhibited cell growth. The potent phototoxin 4,5',8-trimethylpsoralen was the most active psoralen analog tested, followed by 5-methoxypsoralen and 8-methoxypsoralen. The angular furocoumarin, 5-methylangelicin, was the least active inhibitor of growth. Multivariate (isobologram) analysis of the growth-inhibition curves revealed that combinations of psoralens and UVA light were not simply additive but synergistic. Similar results were observed when inhibition of DNA synthesis was used as an endpoint for the biological effects of PUVA. These studies are the first to demonstrate that psoralens and UVA light act synergistically. Our results suggest that the synergism between the psoralens and UVA light may be an important property of PUVA that contributes to its therapeutic efficacy in proliferative diseases.