Is the induction of pyrimidine cyclobutane dimers relevant for the high cytotoxic effect of 7-methylpyrido[3,4-c]psoralen plus UV-A?

Recently, it was shown that the photoactivation of 7-methylpyrido[3,4-c]psoralen (MPP), a highly phototoxic monofunctional compound, as well as leading to the direct cycloaddition of the molecule to pyrimidine bases, also induces the dimerization of adjacent pyrimidines in DNA in vitro (Moysan et al., 1988). For other psoralens, e.g., 8-methoxypsoralen (8-MOP), such a formation of pyrimidine dimers does not occur (Costalat et al., 1989). The relatively low number of pyrimidine dimers which one can estimate from such in vitro results to be formed in vivo in cell DNA after highly lethal MPP photosensitization does not indicate that these dimers have important direct biological consequences. They could, however, interact with MPP adducts and eventually greatly potentiate their action. In order to test this hypothesis, experiments were designed to mimic the photosensitization by MPP. CV-1 TC-7 cells were irradiated at 254 nm, to produce pyrimidine dimers, and subsequently treated with 8-MOP or angelicin plus 365-nm light, to produce psoralen adducts. The clonogenicity of these cells was compared to that of cells damaged only by irradiation at 254 nm or by psoralens plus 365-nm light. It was observed that, for the same amount of induced adducts, the lethal effect of photosensitization by MPP remains much higher than that of photosensitization by 8-MOP coupled to a large excess of pyrimidine dimers induced with 254-nm light. In fact, with both 8-MOP and angelicin, close to additive effects were observed between pyrimidine dimers and psoralen adducts.(ABSTRACT TRUNCATED AT 250 WORDS)