Sensitivity of parasites to free radical damage by antiparasitic drugs

Amphotericin B (AmB) is known to bind to ergosterol in fungal cell membranes, but the precise mechanism of its toxicity to cells is as yet poorly understood. AmB autooxidizes, and it is possible that its antifungal effects could result from oxidative damage. Exposure of protoplasts of Candida albicans to AmB under hypoxic conditions reduced protoplast lysis by as much as 80% compared with incubations in air. Protoplasts were protected from AmB-induced lysis by exogenous catalase and/or superoxide dismutase (SOD). Whole cells of C. albicans were protected by exogenous catalase from AmB-induced leakage of [3H]leucine and from killing by AmB. Cells grown on medium inducing high levels of endogenous catalase were resistant to AmB-induced growth inhibition. In contrast, AmB-induced K+ leakage was not hindered under hypoxic conditions or in the presence of catalase or SOD. Thus the lethal and lytic effects of AmB on C. albicans cells and protoplasts, but not prelethal AmB-induced K+ leakage, are mediated by oxidative damage.

Photoradiation therapy (PRT) was performed in 13 lung cancer cases and in one case of severely atypical squamous metaplasia following administration of hematoporphyrin derivative (HpD). The HpD is activated by visible red light (630 nm, 90 to 400 mW) from an argon dye laser. The cytocidal effects were due to the activation of the HpD, since 400 mW of power has in itself no effect on normal epithelium, even with long-term exposure. HpD is retained longer by malignant tissue than by normal tissue. Therefore, the lesions were irradiated with the red laser beam, delivered by a quartz fiber inserted through the instrumentation channel of the fiberoptic bronchoscope, 48 hours or more after intravenous injection of 2.5 to 4.0 mg/kg of HpD. A total of 14 cases received PRT. In one, two small, smooth-surfaced, squamous cell carcinoma tumors in the right B2b of a 74-year-old man who had refused surgery disappeared three days after HpD-photoradiation, and the patient remained disease-free 16 months after the treatment. In 12 cases of centrally located lung cancer local effects were obtained in all. However, there was no significant improvement in survival, attributable to the fact that all were advanced-stage cases. One patient with severely atypical squamous metaplasia requested treatment, and complete disappearance of metaplastic atypic was obtained.