Photodynamic therapy (PDT) of cancer is based on tumor-specific accumulation of a photosensitizer, followed by irradiation with light of appropriate wavelength, which induces cell death. Photosensitizer currently used in the clinic have afforded some success in the treatment of lung, esophageal, cervical, bladder and gastric tumors, but present with a number of limitations. Therefore, synthesis and characterization of novel photosensitizers with higher increased photon absorption at longer wavelengths, improved tissue retention, rapid clearance from surrounding normal tissues, high quantum yield of reactive oxygen species, and minimal toxicity in the dark represent areas of active research. In this study we evaluated the photo-toxic activity of a number of meso di- and tetra-aryl substituted porphyrin derivatives, synthesized in our laboratory, to identify new synthetic compounds suitable for PDT. Their effects were assessed in the human colon carcinoma cell line HCT116 and the results compared with those obtained with Photofrin and with the tetra-(m-hydroxyphenyl)-chorine, both approved for clinical use. Cytotoxicity studies, performed by MTT assay following 24h exposure to the compounds, 2h irradiation and 24h in drug-free medium, showed that some of the 5,15-diaryl compounds are more effective than both 5,10,15,20-tetraarylporphyrins and reference compounds. None of the compounds tested exhibited significant toxicity in the dark. Flow cytometric analysis of HCT116 cells treated with the more active compounds in the panel showed a relevant increase in apoptotic cell death; this effect was associated with a significant increase in peroxides levels and cell cycle alterations. The involvement of NO in the cytotoxic effect of the more active sensitizers was also investigated: following treatment, a significant increase in nitrite levels was observed in HCT116 culture medium, confirming a role for NO in PDT-induced apoptosis. Taken together, our observations suggest that the new di-aryl derivatives included in this study could represent a promising alternative to the photosensitizers already used in cancer therapy.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]