benzoporphyrin-d and Necrosis

Photodynamic therapy with benzoporphyrin derivative monoacid ring A and red light (PDT-BPD) has been used to treat human choroidal hemangiomas, and may be useful for cutaneous vascular lesions. The potential for PDT-BPD to inhibit selectively vascular tumor growth was tested in a mouse angiosarcoma model, of which the tumor growth mimics the proliferative phase of hemangiomas. Vascular tumors arising after intradermal injection of immortalized murine endothelial cells were exposed to 50 to 150 J per cm2 of 690 nm laser light 15 min after intravenous injection of 1 mg per kg BPD. Tumor volume and gross response were followed after PDT-BPD and compared with control tumors receiving no treatment, light alone, or BPD alone. At 2 wk, hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling stained tumor sections was performed. There was a selective, fluence-dependent inhibition of tumor growth after PDT-BPD (p< or =0.05), typically with eradication of tumors exposed to higher fluences. A common effect was the replacement of tumor by small scar. Surrounding PDT-BPD exposed normal skin showed no changes. Based on these results, we conclude that PDT-BPD can lead to selective eradication of these tumors. Further studies investigating the efficacy of PDT-BPD for human hemangiomas are warranted.

Topics: Animals; Apoptosis; Cell Division; Cell Line, Transformed; Disease Models, Animal; Hemangiosarcoma; In Situ Nick-End Labeling; Light; Male; Mice; Mice, Nude; Necrosis; Photochemotherapy; Photosensitizing Agents; Porphyrins; Skin Neoplasms; Vascular Neoplasms

High intensity pulsed-laser light can be used to excite absorbing molecules to transient states in large proportions. The laser-induced spectral changes can be characterized by transient changes in light propagation; through the tissue provided the excited states of these molecules have altered absorption spectra. Characterization of these transient changes may then be used to exploit new mechanisms in photosensitization and/or to optimize photobiological effects. In this study, transmittance and reflectance were measured as a function of laser pulse energy, from tissue-simulating media as well as in rat muscle and liver slices, both with and without the photosensitizer benzoporphyrin derivative monoacid (BPD-MA) present. There was a transient decrease in absorption from the photosensitizer at peak pulse irradiance in the range of 100-1000 W cm(-2). The depth of photodynamic treatment-induced tissue necrosis was measured in a subcutaneous prostate cancer model in Copenhagen rats. A comparison between continuous wave irradiation and pulsed irradiation with the same average incident irradiance showed no statistically significant difference in the depth of necrosis at 48 h after irradiation. These results indicate that photosensitizer population-state changes are measurable in tissues and may provide a method for measuring triplet-state properties of photosensitizer in vivo, but for BPD-MA at clinically used concentrations these changes do not significantly affect the depth of photodynamically-induced tissue damage.

Topics: Absorption; Animals; Computer Simulation; Disease Models, Animal; Laser Therapy; Male; Necrosis; Photochemotherapy; Photosensitizing Agents; Porphyrins; Prostatic Neoplasms; Radiation-Sensitizing Agents; Rats; Rats, Inbred Strains

In an ideal world, photodynamic therapy (PDT) of abnormal tissue would reliably spare the surrounding normal tissue. Normal tissue responses set the limits for light and drug dosimetry. The threshold fluence for necrosis (TFN) was measured in normal skin following intravenous infusion with a photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA) Verteporin as a function of drug dose (0.25-2.0 mg/kg), wavelength of irradiation (458 and 690 nm) and time interval (0-5 h) between drug administration and irradiation. The BPD-MA levels were measured in plasma and skin tissue to elucidate the relationship between TFN, drug kinetics and biodistribution. The PDT response of normal skin was highly reproducible. The TFN for 458 and 690 nm wavelengths was nearly identical and the estimated quantum efficiency for skin response was equal at these two wavelengths. Skin phototoxicity, quantified in terms of 1/TFN, closely correlated with the plasma pharmacokinetics rather than the tissue pharmacokinetics and was quadratically dependent on the plasma drug concentration regardless of the administered drug dose or time interval between drug and light exposure. This study strongly suggests that noninvasive measurements of the circulating drug level at the time of light treatment will be important for setting optimal light dosimetry for PDT with liposomal BPD-MA, a vascular photosensitizer.

Topics: Animals; Drug Carriers; Female; Humans; Liposomes; Models, Biological; Necrosis; Photochemotherapy; Photosensitizing Agents; Porphyrins; Rabbits; Skin; Tissue Distribution

A comparative study, at both the macroscopic and microscopic level, of skin photosensitivity caused by four isomeric forms of benzoporphyrin derivative (BPD) has been carried out, and compared to effects of Photofrin. Animals injected intravenously with BPD analogues and exposed to light 3 h later showed extensive photosensitivity. Animals receiving the monoacid derivatives of BPD (BPD-MA and BPD-MB) showed markedly more photosensitivity than those receiving the diacid derivatives (BPD-DA and BPD-DB). Animals receiving BPD analogues which were exposed to light 24 h or more later showed only minimal reactivity. Histological examination of biopsies taken after photosensitizer injection and light exposure showed extensive changes in epidermis and dermis, including epidermal erosion, degranulation of the stratum granulosum, spongiosis, depletion in cellularity and mast cell degranulation. These changes were noted to be similar to changes caused by Photofrin.

Topics: Animals; Dose-Response Relationship, Radiation; Hematoporphyrin Derivative; Hematoporphyrins; Light; Male; Mice; Mice, Inbred DBA; Necrosis; Porphyrins; Radiation-Sensitizing Agents; Skin