EVIDENCE FOR DIFFERENT MECHANISMS OF EMT-6 TUMOR NECROSIS BY PHOTODYNAMIC THERAPY WITH DISULFONATED ALUMINUM PHTHALOCYANINE OR PHOTOFRIN - TUMOR-CELL SURVIVAL AND BLOOD-FLOW

A comparison was made of photodynamic therapy (PDT) mediated by two ph otosensitizers, the disulfonated aluminium phthalocyanine (AlPcS(2)) a nd Photofrin(circle) (PII) with regard to their mechanism of action on murine tumours. Balb/c mice bearing intradermally growing EMT-6 tumor s were injected intravenously with either 1 mu mol kg(-1) body weight of AlPcS(2) or 5 mg/kg of PII 24 h prior to red light irradiation from a Xenon lamp (650-700 nm, 200 mW cm(-2), for AlPcS(2) and 600-650 nm, 400 J cm(-2) for PII. Tumor cell survival following in vivo PDT was d etermined by an in vitro clonogenicity assay on the dissociated tumors . Immediately after the completion of light irradiation, a reduction o f similar to 72% in the number of clonogenic cells was seen with AlPcS (2)-treated tumor versus similar to 24% of that for PII-treated tumor. Further loss of clonogenic cell survival progressed as a function of time following PDT, and was considered to be the consequence of indire ct PDT action, however, the decline in cell viability was steeper in t he first 6 h with PII-PDT than with AlPcS(2)-PDT. 24 h after PDT, the clonogenic capacity of both AlPcS(2)- and PII-PDT treated tumor fell t o similar to 3% of the control tumor. The PDT effect on tumor blood fl ow as a measure of the tumor vascular damage was monitored by the rete ntion of Tc-99m-MIBI in the tumor. Little effect on tumor blood flow w as seen with AlPcS(2)-PDT at 0 h after the completion of light treatme nt. Thereafter the blood flow declined slowly and remained at similar to 50% the level of the control by 24 h post-PDT. In contrast, PII pro voked a similar to 40% reduction of tumor blood flow immediately after the completion of photo irradiation, which then fell to similar to 20 % within 2 h and similar to 7% by 24 h post-PDT. These results indicat e the involvement of both direct and indirect mechanisms in the PDT in duced tumor necrosis. However, AlPcS(2)-PDT exerted a larger direct tu mor cell phototoxic effect, whereas PII-PDT induced tumor cell death t o a greater extent via an indirect effect that parallels the extensive damage to the tumor vasculature.