Bernard C. Szirth

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

Haematoporphyrin derivative (HPD) photodynamic therapy (PDT) may have clinical 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 saline control. Responses were demonstrated after CPM treatment in all three relevant groups. However, HPD-PDT was found to be ineffective either alone or as a contributor in the double modality treatment groups. The small tumour masses treated can be demonstrated histologically to be avascular. It is proposed that although the same retinoblastoma cells in different circumstances are responsive to HPD-PDT, no clinical response is demonstrable utilizing this model, due to the absence of tumor vascularity.

Hematoporphyrin derivative photoradiation induced damage to normal and tumor tissue of the pigmented rabbit eye

Cytotoxicity induced by hematoporphyrin derivative (HpD) photoradiation in both normal and experimental tumor tissue of pigmented rabbit eyes has been examined. In addition, documentation of HpD induced fluorescence in ocular structures has also been obtained. Acute normal ocular tissue toxicity studies demonstrated that HpD (1-10 mg HpD/kg) followed 48 hours later by a transpupil irradiation of red light (635 nm, 36-90 J/cm2) resulted in demarcated areas of retinal damage. Long term (chronic) toxicity studies have shown that the initial damage to the retina was permanent but that no damage to the cornea, lens or vitreous could be observed during a 16 month follow-up. Visual and histological documentation have been obtained, following HpD photoradiation therapy (PRT), in rabbit eyes having heterotransplanted single nodule amelanotic melanomas. A toxic effect characterized by tumor blanching, edema and hemorrhage was observed within 24 hours of treatment. Histological examination obtained 24 hours following HpD PRT illustrated massive tumor tissue necrosis and vascular disruption. HpD PRT at clinically relevant doses was also shown to be effective in selectively curing the highly malignant amelanotic iris melanoma. It is concluded that HpD PRT may prove to be an effective modality for treating certain ocular tumors.

Evaluation of response to chemotherapy in retinoblastoma heterotransplanted to the eyes of nude mice

SummaryThe role of chemotherapy in the treatment of retinoblastoma (RB) is unsatisfactory and clinical research is severely limited. A xenograft model for testing chemotherapeutic and other atents has been developed by the heterotransplantation of human RB cells into the anterior chamber of the nude mouse eye. A grading system for visually monitored tumor growth was designed to allow serial observations and documentation of the response to therapy in the model. This method of monitoring compared favorably with histopathologic, photographic, or other criteria in the reproducible, sequential evaluation of tumor status. Six chemotherapeutic agents [vincristine (VCR), doxorubicin (DOX), actinomycin D (ACT-D), dimethyltriazeno-imidazole carboxamide (DTIC), cyclosphosphamide (CMP), and diaziquone (AZQ)] were then tested in the model against a patient-derived xenograft line. Results were expressed as the delay in tumor progression judged by serial grading. CPM produced a consistent response in all treated tumors, as did DTIC to a lesser, more variable extent. In 3 of 10 tumors treated with CPM and in 1 of 18 treated with DTIC, complete responses were maintained for at least 20 weeks. VCR, DOX, and ACT-D were ineffective, producing patterns of tumor progression no different from those in the control group. AZQ was most effective, producing responses far exceeding those of conventional agents. The model allows quantitative documentation of the response to therapy in heterotransplanted human RB. Further testing of new agents and combinations is warranted. AZQ may be active against RB.

Preclinical Examination of Ocular Photoradiation Therapy

Hematoporphyrin derivative photoradiation therapy is an effective therapeutic modality for several types of solid tumors 1,2. One area of recent clinical interest is the exploitation of HpD PRT for the treatment of ocular malignancies 3,4. New therapies which can provide effective tumor destruction and minimal normal ocular tissue damage are needed since the current modalities used for treating eye tumors (external beam radiation, radioisotope plaques, photocoagulation and cryotherapy) are not totally satisfactory 5,6. HpD PRT may provide a modality which can be utilized for the treatment of both retinoblastoma and uveal melanoma. In addition, this procedure may be useful as both a primary modality in selective instances as well as a secondary modality following recurrence.

Preclinical Evaluation of Hematoporphyrin Derivative for the Treatment of Intraocular Tumors: A Preliminary Report

Treatment modalities such as external beam radiation therapy, cobalt plaques, photocoagulation or cryotherapy for preservation of useful vision in patients with ocular tumors offer only limited success. In many cases enucleation is necessary in order to prevent tumor spread (1). The accessibility of intraocular tumors to visible light and the excellent optical properties of the eye suggest that hemato-porphyrin derivative photoradiation therapy (HPD PRT) may prove to be an important advancement in the successful management of intraocular and periocular malignancies. Due to the extreme sensitivity of the eye to light and the possible loss of vision resulting from non-repairable damage to normal ocular structures, we are performing preclinical studies designed to evaluate the efficacy of HPD PRT as a primary clinical modality for treating ocular tumors.

Cellular And Preclinical Examination Of Photodynamic Therapy

In-vitro studies have been performed to compare the mode of action of porphyrin induced photodynamic therapy and hyperthermia. Parent and temperature resistant clones of Chinese hamster and mouse fibrosarcoma cells were treated with either PDT or hyperthermia. Quantitative survival curves obtained from these experiments indicate that temperature resistant cells are not cross resistant to PDT even though both treatments induce the synthesis of stress proteins. In-vivo studies were performed to evaluate the photosensitizing efficiency to mono-l-aspartyl chlorin e 6 (NPe6). Tumor response and normal skin response were determined using a murine tumor system. The studies indicate that NPe6 is an extremely effective tumor photosensitizer with rapid in-vivo clearance properties which may eliminate the side effects of prolonged and systemic skin photosensitivity.