Ineffective photodynamic therapy (PDT) in a poorly vascularized xenograft model

Abstract

Summary Haematoporphyrin derivative (HPD) photodynamic therapy (PDT) may have clinicial application in the management of patients with retinoblastoma. Heterotransplantation of retinoblastoma cells into the anterior chamber of the nude mouse eye and the subsequent growth of small tumour masses has provided a model for evaluation of various therapeutic modalities. Ninety-four evaluable xenograft tumours in 54 nude mice were randomized to receive one of the following treatments: cyclophosphamide (CPM) alone, HPD-PDT alone, CPM followed by HPD-PDT, HPD-PDT followed by CPM, or (White, 1983c). Although RB is highly curable by enucleation and/or radiotherapy, the morbidity of current treatment has made HPD-PDT an appealing prospect in the management of early, and particularly bilateral RB. The relatively easy access of light to the intraocular lesion (Gomer et al., 1984) and documented in-vitro responsiveness of RB to HPD-PDT (Sery, 1979) have encouraged further research.A xenograft model has been developed whereby human RB can be studied heterotransplanted into the anterior chamber of the nude (athymic) mouse eye (Gallie et al., 1977). Necrosis was documented histologically in very advanced tumours after HPD injection followed by PDT in the mouse (Benedict et al., 1980b). The model was adapted to allow the study of early, small tumours in situ and document changes in growth pattern as a measure of responsiveness (White et al., 1983a). Various chemotherapeutic agents have been successfully tested in this adapted model (White et al., 1983b). Cyclophosphamide (CPM) was the most effective of the currently available chemotherapeutic agents. Given this background, a series of experiments were performed to evaluate responsiveness of RB to HPD-PDT and the potential interaction between chemotherapy and HPD-PDT in the model. It became apparent that poor vascularization of the xenograft played an important role in determining response to HPD-PDT. Materials and methodsThe model A number of human RB cell lines have been established and maintained by the heterotransplantation of cells from enucleated eyes of children with RB (Benedict et al., 1980a). Cells in suspension (105 ml-1) were injected under microscopic visualization directly into the anterior chamber of the mouse eye (total volume injected less than 5 microlitres). Swiss background nude (athymic) mice of both sexes were utilized. The animals were maintained and treated in a protected, sterile environment and were allowed food and water ad libitum. Their weight was monitored weekly.

Correlation of photodynamic activity and fluorescence signaling for free and pegylated mTHPC in mesothelioma xenografts

“…Similar results have been described by other investigators who assessed the distribution of free and pegylated mTHPC in human adenocarcinoma xenografts [30]. The heterogeneous spatial distribution of free and pegylated mTHPC in xenografts may explain the findings of previous studies showing that for the same treatment conditions are applied, well-vascularized adenocarcinoma xenografts revealed a larger extent of mTHPC-PDT-related tumor necrosis than squamous cell carcinoma or mesothelioma xenografts which were poor in stroma and vessels [31,32]. Fluorescence intensity measurements after administration of free mTHPC (0.5 mg/kg) revealed no significant difference between tumor and skin whereas an equimolar dose of pegylated mTHPC resulted in significantly higher fluorescence intensity in tumors than in skin.…”

Antitumor Effects of Photodynamic Therapy Are Potentiated by 2-Methoxyestradiol

“…Hypoxic or anoxic conditions almost completely reduce the antitumor effectiveness of PDT in vitro (29). Moreover, PDT was shown to be ineffective in a poorly vascularized xenograft model (30) and chemotherapy-induced anemia leads to decreased effectiveness of PDT in mice (31). During photodynamic therapy, a photosensitizer absorbs light and crosses from its excited singlet state to the reactive triplet state.…”

Photodynamic therapy-induced alterations in interstitial fluid pressure, volume and water content of an amelanotic melanoma in the hamster

“…It has until now been generally accepted that the impairment of tumour microcirculation plays a critical role in tumour eradication by photodynamic therapy (PDT) (Henderson et al, 1985;Star et al, 1986;Reed et al, 1988;White et al, 1988;Wieman et al, 1988;Foster et al, 1991). Vascular effects which have been characterised in response to PDT include vasoconstriction, platelet aggregation, thrombi formation, microembolisation, release of eicosanoids and release of von Willebrand factor.…”