tetra(4-n-methylpyridyl)porphine and Necrosis

Photodynamic therapy (PDT) is based on the cytotoxic effect induced by a photosensitizer in the presence of light and molecular oxygen, with production of reactive oxygen species which cause cell death and tumor destruction. Here we describe the response of the murine mammary adenocarcinoma, LM3, to repeated PDT treatments using the synthetic porphyrin derivative, meso-tetra (4-N-methylpyridinium) porphine (TMPyP). Intradermal LM3 tumors in BALB/c mice were left untreated, only treated with light, only injected with 0.9% NaCl solution, or with TMPyP alone (10 microg in 0.1 ml of 0.9% NaCl). For PDT, the intratumoral TMPyP injection was followed 1 h later by blue-red light irradiation for 50 min (80 mW/cm2 total dose: 240 J/cm2). In all cases, control and PDT treatments were performed on the depilated and glycerol-covered skin over the tumor of anesthetized mice and repeated four times (every two days). In a pilot experiment, no significant differences were found in the growth rate of untreated tumors (n=4) and tumors only treated with light (n=4), 0.9% NaCl (n=3) or TMPyP (n=3). PDT-treated tumors (n=3) showed transitory regression and growth delay. In a second approach, the average diameter (mean, mm +/- SEM) of control (drug alone, n=15) vs PDT tumors (n=17) was 2.13+/-0.11 vs 2.02+/-0.10 at day 0, and 4.00+/-0.17 vs 0.20+/-0.07 at day 9, p<0.0001. At day 37 the average diameter of tumors from control vs the PDT group was 10.98+/-0.59 vs 6.31+/-0.82, p<0.0001. PDT caused partial regression of tumors in one from a total of 17 mice, long-term regression in 15, and cure in one animal. Significant differences in the survival and tumor size at death were found between control and PDT-treated mice. Histopathological analysis of LM3 tumors one day after a unique PDT treatment showed extensive hemorrhage and necrotic areas. These results indicate the considerable potential of intratumoral injection of photosensitizers and repeated PDT protocols.

Topics: Animals; Cell Proliferation; Female; Glycerol; Hemorrhage; Male; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Models, Chemical; Necrosis; Neoplasm Transplantation; Oxygen; Photochemotherapy; Photosensitizing Agents; Porphyrins; Time Factors

The meso-substituted cationic porphyrin, meso-tetra(4N-methyl-pyridyl)porphine (T4MPyP) appears to be a selective tumour localizer on the basis of pharmacokinetic studies. Irradiation (at 600-680 nm) of an intramuscularly implanted MS-2 fibrosarcoma in Balb/c mice at 24 h after injection of T4MPyP causes tumour necrosis: histological and ultrastructural analyses of tumour specimens taken at different times after phototherapy indicate slowly-appearing tissue damage which involves both malignant cells and the vascular endothelium. At the subcellular level, the membranous systems and nuclei are the main targets of the photoprocess. The tumour necrosis is particularly extensive upon injection of 4.1 mg kg-1 T4MPyP.

Topics: Animals; Endothelium, Vascular; Female; Fibrosarcoma; Mesoporphyrins; Mice; Mice, Inbred BALB C; Microscopy, Electron; Necrosis; Photochemotherapy; Porphyrins; Time Factors