Novel photodynamic therapy against biliary tract carcinoma using mono-L: -aspartyl chlorine e6: basic evaluation for its feasibility and efficacy.

BACKGROUND: Recently, a second-generation photosensory agent for photodynamic therapy (PDT), mono-L: -aspartyl chlorine e6 (NPe6), which degrades rapidly in vivo, has been developed. We evaluated its feasibility and efficacy for treatment in biliary tract carcinoma. METHODS: A transmittance of semiconductor laser light (664 nm), sensitivity of a human biliary tract carcinoma cell line, and disorder to normal tissue including Glissonian constructs and adjacent hepatocytes were investigated. RESULTS: The transmittance of the laser was 85-91% through yellow clear bile and that of the bile including 50 microg/ml NPe6 was 17-48%. The effective concentration of NPe6 which showed LD50 for a cell line was 12.5 microg/ml, and that of LD95 was 25 microg/ml. NPe6 in the supernatant reduced laser transmissiveness, but it had little influence on the antitumor effect in supernatant with or without NPe6. The NOZ cell-tumor volume was reduced significantly 14 days after irradiation in the PDT group (PDT 69.9 +/- 44.6 mm(3) vs control 296.3 +/- 239.9 mm(3) P < 0.05). No severe hepatic disorder including Glisson components was observed by the histological findings. CONCLUSION: NPe6 PDT was effective in carcinomas even in the presence of bile, and causes no serious complication for the liver and Glisson structure. Therefore, NPe6 PDT will be a useful candidate as a new therapy for biliary tract carcinomas.

Lysosomal cathepsin initiates apoptosis, which is regulated by photodamage to Bcl-2 at mitochondria in photodynamic therapy using a novel photosensitizer, ATX-s10 (Na).

ATX-s10 is a novel and second-generation photosensitizer for photodynamic therapy (PDT). In order to conduct clinical trials of ATX-s10-PDT and/or extend its clinical applications, it is very important to elucidate the mechanisms of the action of ATX-s10-PDT. We examined the apoptic response against ATX-s10-PDT using a Bcl-2 or Bcl-2 mutant overexpressing cells. Using fluorescent microscopy, ATX-s10 localized not only to mitochondria but also to lysosomes and possibly other intracellular organelles, but not to the plasma membrane or the nucleus. These results suggest that ATX-s10-PDT can damage mitochondria and lysosomes. By Western blot analysis, ATX-s10-PDT damaged Bcl-2, which localized preferentially at mitochondrial membranes, and caused Bcl-2 to cross-link immediately after laser irradiation. However, ATX-s10-PDT was not able to rapidly induce morphologically typical apoptosis (i.e. chromatin condensation and fragmentation) as PDT using mitochondria targeted photosensitizers, such as phthalocyanine 4 (Pc 4). Pharmacological inhibitions of lysosomal cytokine protease cathepsins, such as cathepsin B and D, protected MCF-7c3 cells (human breast cancer cells expressing stably transfected procaspase-3) from apoptosis caused by ATX-s10-PDT. Overexpression of wild-type Bcl-2 or Bcl-2Delta33-54 resulted in relative resistance of cells to ATX-s10-PDT, as assessed by the degree of morphological apoptosis or loss of clonogenicity. We conclude that lysosomal damage by ATX-s10-PDT can initiate apoptotic response and this apoptotic pathway can be regulated by photodamage to Bcl-2 via mitochondrial damage.

Photodynamic therapy for peripheral lung cancer.

Photodynamic therapy (PDT) has now achieved the status of a standard treatment modality for centrally located early-stage lung cancer. In the last decade, CT screening for lung cancer has attracted much attention for its ability to detect early peripheral lung cancer. Extremely recently, treatment using PDT has been introduced for the first time in patients with peripheral lung cancer, who did not meet the previous criteria for surgery. The procedure was carried out with local anesthesia with xylocain infiltrated into the chest wall, 48 h after Photofrin administration. Needles (19 gauge) containing an internal catheter were inserted percutaneously under CT guidance. The needles were then extracted and a diffuser fiber with a 2 cm long tip for light delivery was positioned in the tumor through the catheter. Of the nine patients enrolled in this trial, seven achieved partial remission (PR). No serious complications, except for two cases of pneumothorax, were noted. As an increasing number of patients consider quality of life after therapy, the indications for PDT are expected to expand. We conclude that PDT is a promising new technique for curative treatment of localized, peripheral lung cancer less than 1cm in size in patients who are unfit for surgery or radiotherapy.