PDT has been reported to induce cancer cell expression of cytokines, such as IL-6 and TNF-␣, but it has been unclear whether cytokine expression by cancer cells is directly related to the antitumor effect of PDT. We treated Lewis lung carcinoma (LLC) cells with a new photosensitizer, mono-Laspartyl chlorin e6 (NPe6) and light from a diode laser and found that expression of the mRNA of IL-2, IL-6, and TNF-␣ was increased by NPe6-mediated-PDT 6 hr later. To elucidate the mechanism of the direct anti-tumor effect of cytokine expression, we examined the photosensitivity of cytokine- To enhance the potential of PDT and to extend its clinical applications, a second generation of photosensitizers is now being assessed, and it is important to elucidate their mechanism of action in PDT. Mono-L-aspartyl chlorin e6 (NPe6) is a water-soluble substance, and NPe6-mediated-PDT has been shown to have an antitumor effect in several experimental models and is currently undergoing clinical evaluation in Japan.Granville et al. 3 reported that PDT induces apoptosis in various tumor cell lines. PDT also induces nonspecific and specific immune responses against tumors in vitro and in vivo. Krosl et al. 4 reported that the antitumor efficacy of PDT is improved by the administration of macrophage activating factors such as granulocyte-macrophage colony activating factor (GM-CSF), whereas Gollnick et al. 5 demonstrated that PDT alters expression of IL-6 and IL-10 in vivo. The immune mechanisms of PDT have never been clarified, however, and it is unknown whether cytokine expression is involved in the antitumor effects of PDT. To elucidate the immune response and the mechanisms of action involved in NPe6-mediated PDT, we examined the effects of cytokine overexpression on PDT by using cytokine gene transfected cells and we have characterized the apoptotic mechanism. MATERIAL AND METHODS Laser light delivery systemA new high-power red laser diode system (Matsushita Industrial Equipment Co., Osaka, Japan), with potential for use in photodynamic therapy (PDT) with NPe6, was employed. This system has a power output of 10 -500 mW/cm 2 at the fiber tip. The irradiation mode is continuous wave (CW), and the delivered energy can be adjusted from 1-1,000 J/cm.2 . 2 Although it runs on 100 V current, the system is 49 ϫ 20 ϫ 40 cm in size, weighs 20 kg, and is easy to take into a sickroom. The power of the laser is easily adjusted, the wavelength of the light is stable (within 0.2 nm), and it is delivered through a quartz fiber. The full width at half maximum is less than 2 nm, which enables uniform, high-density photoradiation, and the power density distribution of the laser, analyzed by a charge-coupled device (CCD) camera, is uniform throughout the photoradiated field. In our study, the diode laser wavelength was adjusted to 664 nm to match the absorption bands of NPe6. PHOTOSENSITIZERCompound NPe6 is an effective photosensitizer that possesses properties such as chemical purity and a major absorption band at 664 nm, features that are potentiall...
Abstract. 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 ATXs10-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 wildtype Bcl-2 or Bcl-2Δ33-54 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.
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.
The authors performed photodynamic therapy (PDT), avoiding any hyperthermic effects, using a newly developed diode laser and photosensitizer, mono-L-aspartyl chlorin e6 (NPe6), of Meth-A fibrosarcoma implanted in mice and achieved tumor therapeutic benefit. The photodynamic light treatment was performed 5 h following the photosensitizer administration. With 5.0 mg/kg NPe6 and light doses of 50, 100, 150 and 200 J/cm2, the tumor cure rates were 20, 50, 70 and 90%, respectively. With 100 J/cm2 laser exposure and NPe6 doses of 1.25, 2.5, 5.0, 7.5 and 10.0 mg/kg, the tumor cure rates were 0, 20, 50, 70 and 90%, respectively. A charge-coupled device (CCD) camera system was employed to measure the NPe6 fluorescence intensity correlating with the residual amount of the photosensitizer at deferent depth from the tumor surface. The ratios of the NPe6 fluorescence intensity at 3 mm from the tumor surface following 50, 100, 150 and 200 J/cm2 laser exposure to no laser exposure were 0.73, 0.36, 0.22 and 0.16, respectively. With samples sectioned at 1 mm depth, after 50 J/cm2 and the same photosensitizer dose (5 mg/kg) this ratio was 0.19. These results suggest that a certain increase in the tumor tissue level of NPe6 and a certain increase of laser light dose reaching deeper layer of tumor caused an increase in percent cure. In addition, the effectiveness of PDT depends on the total laser dose reaching deeper layers of tumors. Furthermore, the effectiveness of PDT tends to correlate with the amount of NPe6 photobleaching by PDT.
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