Improvement of tumor response to photodynamic therapy by manipulation of tumor oxygenation in an in-vivo model system

Abstract

Photodynamic therapy (PDT) requires molecular oxygen during light irradiation in order to generate reactive oxygen species. Tumor hypoxia, either pre-existing or induced by PDT, can severely hamper the effectiveness of PDT treatment. Lowering the light irradiation dose rate or fractionating a light dose may improve cell kill of PDT induced hypoxic cells, but will have no effect on pre-existing hypoxic cells. In this study, hyper-oxygenation technique was used during PDT to overcome hypoxia. C3H mice with transplanted mammary carcinoma tumors were injected with 12.5 mg/kg Photofrmn and irradiated with 630 nm laser light 24 hours later. Tumor oxygenation was manipulated by subjecting the animals to 3 alp hyperbaric oxygen or normobanc oxygen during PDT light irradiation. The results show a significant improvement in tumor response when PDT was delivered during hyper-oxygenation. With hyper-oxygenation, up to 80% of treated tumors showed no re-growth after 60 days. In comparison, only 20% of tumors treated while animals breathed room air did not re-grow. To explore the effect of hyperoxygenation on tumor oxygenation, tumor PO2 was measured with microelectrodes positioned in pre-existing hypoxic regions before and during the PDT. The results show that hyperoxygenation may oxygenate pre-existing hypoxic cells and compensate for oxygen depletion induced by PDT light irradiation. In conclusion, hyper-oxygenation may provide effective ways to improve PDT treatment efficiency by oxygenating both pre-existing and treatment induced cell hypoxia.