Summary We have examined the effectiveness of photodynamic therapy against R3230AC rat mammary adenocarcinoma and human mesothelioma as xenografts in the same host. The results demonstrate that the xenografted human tumour is significantly more responsive to photodynamic treatment than the rodent mammary tumour. Studies also showed that the mesothelioma xenograft was fluence rate-and fluencedependent while the rat tumour exposed to the same conditions demonstrated neither of these dependencies. This disparity in response was not attributable to a difference in either whole-tumour uptake or subcellular distribution of the porphyrin photosensitiser. Analysis of the effects of visible irradiation on cytochrome c oxidase activity, measured in mitochondria prepared from tumours borne on hosts injected with photosensitiser, demonstrated that photoradiation-induced enzyme inhibition was significantly greater in mesothelioma than in R3230AC mammary tumour preparations. However, in parallel studies conducted in vitro, when photosensitiser and light were delivered to previously unperturbed mitochondria, rates of enzyme inhibition were not significantly different. Both tumours were established in long-term cell culture. While the uptake of porphyrin photosensitiser was equivalent in both cell lines, the R3230AC cells displayed a significantly greater photosensitivity than the mesothelioma cells. The data presented here demonstrate that the mechanisms that govern response to photodynamic therapy are complex, but in the case of these two xenografted tumours host response to therapy is not likely to play a significant role.Diffuse malignant mesothelioma (DMM) occurs on the serosal surfaces of the body. Induction of DMM is associated with prolonged exposure to asbestos fibres, followed by a latency period of 15-30 years before appearance of symptoms that support its diagnostic confirmation (Wagner et al., 1960;McDonald & McDonald, 1980;Muscat & Wynder, 1991 (Gomer & Dougherty, 1979;Woodburn et al., 1992). The light is usually delivered via fibre optics coupled to the output of a tuned dye laser. The resulting electronic excited state of the porphyrin retained in tumours initiates a photochemical reaction, which in turn forms the toxic oxygen species, singlet oxygen ('02) (Weishaupt et al., 1976;Gibson et al., 1984;Keene et al., 1986). Intracellular oxidative damage induced by '02 occurs in lipid-rich cellular structures, such as the plasma, mitochondrial and ribosomal membranes, where accumulation of PPS is greatest because of the hydrophobic nature of its 'active' components (Moan et al., 1982;Kessel & Cheng, 1985;Dougherty & Mang, 1987). The '02-induced damage leads to reduced cellular metabolism, morphological alterations, cytotoxicity and tumour necrosis (Hilf et al., 1986(Hilf et al., , 1987Berg & Moan, 1988 (1990) found that mesothelioma cells in culture were sensitive to PDT using PPS. Employing meta-tetrahydroxyphenylchlorin (mTHPP), Ris et al. (1993) found that a 3 day interval between sensitiser administration and...