STUDIES OF PHOTOTHERAPY AND FREE RADICAL LYMPHOKINE RELATIONSHIPS

我们实验室继续进行光动力疗法的研究

Our laboratory has continued its investigation of photodynamic therapy (PDT) by sensitization of malignant cells with dihematoporphyrin ether followed by illumination by 630 nm light. Since October 1990, we have established an in vitro, in vivo model of PDT for cells transformed with the k-ras oncogene which is frequently activated in lung cancer. The model was found to exhibit (1) classic sensitizer retention characteristics of other models, and (2) predictable tumor regression with PDT. The model have been used to investigate the use of monoclonal antibody conjugated to the sensitizer, and superior PDT effects as well as greater sparing of normal tissue has been demonstrated. A murine model of solid peritoneal carcinomatosis, investigating sensitizer delivery, and maximal tolerated dose of PDT was published. A large animal model of PDT investigating the effects on intrathoracic organs revealed that focal PDT up to 40 Joules/cm2 was tolerated by heart, esophagus, chest wall, and lung. A Phase I human trial which combines radical debulking to 5 mm thickness of pleural malignancies followed by intrathoracic-intraoperative delivery of PDT for incurable, localized thoracic malignancies has been ongoing. Light dose escalation in cohorts of three patients has been performed from 15 Joules/cm2 to 32.5 Joules/cm2. We continue to treat patients with obstructing endobronchial malignancies with PDT delivered by bronchoscopy. As a followup on studies revealing PDT induction of tumor necrosis factor, our laboratory has demonstrated that free radical stress itself with hydrogen peroxide or superoxide can induce macrophages to produce TNF, and that radical-inducing chemotherapies can increase TNF production. Moreover, we have demonstrated that SOD-mimics can, at least, in vitro, abrogate TNF cytotoxicity. Investigations of other compounds which may be useful in protecting against cytokine toxicity is continuing in our section with in vitro and in vivo models.