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T Okunaka

Publications and source records attributed to T Okunaka.

At least 19 recordsLinked to original sources
PubMed2001

Increased cytotoxic effects of photodynamic therapy in IL-6 gene transfected cells via enhanced apoptosis.

PDT has been reported to induce cancer cell expression of cytokines, such as IL-6 and TNF-alpha, 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-L-aspartyl chlorin e6 (NPe6) and light from a diode laser and found that expression of the mRNA of IL-2, IL-6, and TNF-alpha 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-gene-transfected cells, namely LLC-IL-2, LLC-IL-6, and LLC-TNF-alpha cells, by MTT assay. The IL-6 gene transfected, LLC-IL-6 cells were significantly more sensitive to cytotoxic effects than the parent LLC cells and other cytokine gene-transfected cells. This finding indicates that IL-6 expression modulates cellular sensitivity to PDT and that IL-2 and TNF-alpha expressions does not. In addition, the apoptosis of LLC-IL-6 cells induced by NPe6-PDT was greater than in the other cells as determined by DNA fragmentation and staining of apoptotic nuclei. Because IL-6 has been reported to induce apoptosis by downregulating expression of Bcl-2, we analyzed the expression of apoptosis-related Bcl-2, Bax, and cytochrome C by Western blot analysis. Decreased expression of Bcl-2 and cytochrome C was observed in both LLC cells and LLC-IL-6 cells. Bax protein increased in a time-dependent manner, and the ratio of Bax to Bcl-2 rose markedly after PDT in LLC-IL-6 cells. These results suggest that the increased sensitivity of LLC-IL-6 cells to PDT-induced cytotoxicity results from the high ratio of Bax to Bcl-2 in the IL-6-dependent apoptotic pathway. In conclusion, IL-6 expression plays a role in cellular sensitivity to PDT, and combination of IL-6 and PDT may provide a new strategy for cancer treatment.

Animals↗
PubMed2001

[Preoperative PDT for early stage lung cancer accompanied with infiltration to the central airway].

For the treatment of central type lung cancers, it is often necessary to perform bronchoplasty or bi-lobectomy even in early stage cases in which tumor invasion is found at the bronchial bifurcation. To solve this contradictory situation, we applied PDT for central type early stage lung cancer to reduce the extent of superficial infiltration, enabling a simple surgical technique or decreasing the amount of resected lung parenchyma. Among 7 patients, the simplification of surgical technique and reduction of the range of resection were possible in 2 cases each respectively. However, these objectives were not satisfied in the remaining 3 cases and the operations performed were those that had been originally scheduled before PDT. The current problems are the establishment of appropriate laser irradiation technique and accurate assessment for extension of invasion.

Adult↗
PubMed2000

Localization of experimental submucosal esophageal tumor in rabbits by using mono-L-aspartyl chlorin e6 and long-wavelength photodynamic excitation.

BACKGROUND AND OBJECTIVE: To increase the applicability of photodynamic diagnosis with regard to deep-seated tumor, we illuminated tumors with a long-wavelength laser beam after photosensitization with mono-L-aspartyl chlorin e6 (NPe6). STUDY DESIGN/MATERIALS AND METHODS: Rabbits with VX2 esophageal tumors were divided into four groups. The control group was not treated, and the other three groups were injected with 1, 2.5, and 5 mg/kg mono-L-aspartyl chlorin e6 (NPe6), respectively. After excitation with a 664-nm laser beam (10 mW, 10 seconds), the fluorescence image and the relative fluorescence intensity (tumor/normal tissue) were recorded every 2 hours up to 8 hours by a newly developed diode laser endoscopic fluorescence imaging system. The tissue concentration of NPe6 was examined by high performance liquid chromatography at 2, 4, and 6 hours after injection with 1 and 5 mg/kg NPe6. RESULTS: The diode laser endoscopic fluorescence imaging system was able to selectively detect fluorescence from submucosal tumor by comparison with the surrounding normal mucosa after NPe6 injection. The fluorescence intensity correlated with NPe6 dose, selectively accumulated in the tumor tissue and relative intensity peaked at 6 hours after injection. No fluorescent images were detected in controls. CONCLUSION: Given intravenously, NPe6 at a dose of 5 mg/kg and excited with a 664-nm wavelength laser beam 6 hours later can define experimentally induced deep-seated esophageal carcinoma in rabbits, by using an endoscopic fluorescence imaging system.

Animals↗
PubMed2000

[Bronchofiberscopy].

New diagnostic modalities have been used in conjunction with endoscopy for early detection of lung cancer. Videoendoscope is routinely used instead of fiberoptic bronchoscope. Fluorescence diagnosis has been proved to be useful in detecting subtle lesions which might be invisible by conventional endoscopy in central airway. Also, a number of small peripheral lesions has increased by the helical CT. CT guided transbronchial lung as well as needle cytology are indicated for definitive diagnosis of such lesions. Endobronchial Ultrasonography is employed to evaluate the depth of cancer invasion of the bronchus and lymph node swelling around the bronchus. It should be helpful in staging of lung cancer and selecting therapy.

Bronchoscopy↗
PubMed1998

The effects of serum on cellular uptake and phototoxicity of mono-L-aspartyl chlorin e6 (NPe6) in vitro.

Previous reports showed that the photosensitizer mono-L-aspartyl chlorin e6 (NPe6) binds to serum proteins. However, the influence of this binding on the cellular uptake and photodynamic therapy (PDT) phototoxicity of NPe6 is still undefined. In this paper, we studied how serum in medium affected the P388 cellular uptake and PDT phototoxicity of NPe6 in vitro. This was assessed by (1) detection of the red shift (654 nm Q band peak of absorption) induced by protein binding NPe6; (2) detection of intracellular concentration of NPe6 by HPLC and (3) measurements of the cell survival ratio after PDT by MTT assay. The 654 nm Q band peak of NPe6 shifted to 665 nm after binding of NPe6 and serum proteins. The protein-bound NPe6 cannot be uptaken by cells, thus there was no PDT phototoxicity. Nevertheless, phototoxicity recovered when the concentration of NPe6 excessed the serum protein binding ability or there was free serum protein in the medium. These data suggested that the cellular uptake of NPe6 is inhibited by serum components in the medium, and that only free NPe6 is accumulated by P388 cells even during relatively long incubations. The cytotoxicity of PDT mainly depends on the free NPe6 level in the medium.

Animals↗
PubMed1997

[Photodynamic therapy for bronchogenic carcinoma].

Laser endoscopic surgery has now achieved a status as effective therapeutic modality for lung cancer. Especially increasing attention has been focused on photodynamic therapy (PDT) using Photofrin and excimer dye laser. PDT obtained government approval in October 1994 and finally obtained national insurance reimbursement status in April 1996. Over the past decade, 248 patients (296 lesions) with central type lung cancers have been treated in our hospital. Overall complete remission was obtained in 42.5% of the 125 lesions, partial remission in 56.8% and no remission was obtained in 1.0%. Indications of PDT are follows, 1. Early stage lung cancer as a curative purpose: among 104 early stage lesions CR was obtained in 87 (83.7%) and 61 cases were disease free at 2 to 178 months. 2. Advanced lesions for opening of bronchi: overall, "effective" opening of bronchi was achieved in 61 out of 81 lesions (75%) for the PDT group, as opposed to 143 of 177 (81%) for the Nd-YAG laser therapy group. 3. Preoperative laser irradiation for the propose of increasing operability and reducing the extent of resection area: the initial purpose of PDT, i.e., either reduction of extent of resection of conversion of inoperable disease to operable status, was achieved in 21 out of 21 patients treated. 4. Multiple primary lung cancer. The success from clinical trials using PDT for treatment of cancers offers encouragement for its future use. More stable, definitive and more successful results will be obtained if new dyes which distribute more equally in the tumor tissue and deeper tissue penetration by longer wavelength beams are used.

Aged↗
PubMed1996

Photodynamic therapy for early stage bronchogenic carcinoma.

Photodynamic therapy utilizing Photofrin has proved to be an effective modality that can be used in the treatment of a wide variety of solid tumors and luminal cancers. The effectiveness of photodynamic therapy (PDT) was demonstrated in our institution in 1980 for the treatment of lung cancers, and increasing attention has been focused on this new treatment technique. Over the past decade, 240 patients (283 lesions) with central type lung cancers have been treated in our hospital. Overall complete remission was obtained in 39.6% of the 112 lesions, partial remission in 59.4%, and no remission was obtained in 1.0%. However, among 95 early stage lesions, CR was obtained in 79 (83.2%) and 71 cases were disease free at 3 to 176 months. We conclude that PDT is efficacious in the treatment of superficial lung cancer where complete remission may be achieved.

Adenocarcinoma↗
PubMed1996

Photodynamic therapy with a diode laser for implanted fibrosarcoma in mice employing mono-L-aspartyl chlorin E6.

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.

Animals↗
PubMed1996

[Photodynamic therapy for multiple primary lung cancer].

In recent years, multiple primary lung cancers have been reported with greater frequency, partly as a result of technologic advances in the detection of lung cancer and therapeutic achievements in its management. As for the treatment of multiple primary lung cancer, operative excision is usually difficult for all lesions due to problems of pulmonary function. PDT is a good therapeutic modality in the treatment of multiple primary lung cancer, especially central type lung cancer, for preservation of lung function. Since 1980, 27 patients of multiple primary lung cancers have been treated with PDT at Tokyo Medical College. Fourteen of these 27 patients were synchronous with the rest, metachronous. Seven of 27 patients with multiple tumors had early-stage lesions and were treated with endoscopic PDT alone. In other 20 cases, PDT was used to treat accessible early-stage foci although operative excision was required for advanced lesions. Mean survival after PDT, alone or in combination with surgery, was 52 months (range, 5 to 162 months) and 16 patients remain alive to date. PDT is useful in extending the therapeutic options for, and improving the prognosis of patients with, multiple primary bronchogenic carcinomas.

Adenocarcinoma↗
PubMed1996

[Photodynamic therapy for early stage lung cancer].

Since 1980, 225 patients with lung cancers have been treated with photodynamic therapy (PDT) at Tokyo Medical College. These were 212 males and 13 females, and the median age was 65.2 years (range 36 to 85). Clinical stages were 72 early stage, 33 stage I, 11 stage II, 84 stage III and 25 stage IV. In 72 cases (91 lesions) of early stage lung cancers, complete remissions were obtained in 75 cases (82.4%) and partial remission in 16 cases. Mean survival after PDT was 52 months and 53 cases were disease free in 5 to 176 months. PDT is useful in the treatment for early stage lung cancer.

Adult↗
PubMed1996

[Laser photodynamic therapy for central-type lung cancer].

Laser endoscopic surgery is recognized as an effective treatment for lung cancer. Attention has increasingly been focused on photodynamic therapy (PDT) with dihermatoporphyrin ethers. The Japanese government approved the use of this therapy in October 1995, and reimbursement through the national health insurance system began in April 1996. Over the past decade, 140 patients (283 lesions) with central type lung cancers have been treated at our hospital. Overall complete remission was obtained in 39.6% of 112 lesions, partial remission in 59.4% and no remission in 1.0% The indications for PDT are as follows: 1. Early stage lung cancer curative; among 95 early stage lesions complete remission was obtained in 79 (83.2%), and 71 patients were disease free at 3 to 176 months. 2. Advanced lesions opening of bronchi; overall, "effective" opening of bronchi was achieved in 61 of 81 lesions (75%), in the PDT group, and in 143 of 177 (81%) in the Nd-YAG laser therapy groups. 3. Preoperative laser irradiation to increase operability and reduce the extent of operation; the extent of resectin was reduced, or inoperable lesions were made operable in 21 of 24 patients treated. 4. Multiple primary lung cancer. The success of clinical trials of PDT for treatment of lung cancers bodes well for its future use. More stable, definitive, and successful treatment will become possible with the use of new dyes that distribute more evenly in tumor tissue, and with the deeper tissue penetration made possible by longer-wavelength beams.

Adenocarcinoma↗
PubMed1995

Photofrin photosensitization. Correlation of Photofrin:erythrocyte binding processes with photolysis.

Unilamellar suspensions of dimyristoylphosphatidylcholine (DMPC) can be utilized to remove Photofrin from the erythrocyte. This enables correlation of the Photofrin membrane-binding processes with Photofrin-sensitized photolysis. The observed rates of erythrocyte biding as well as the observed rates of removal of PHotofrin from the erythrocyte membrane suggest the existence of two Photofrin species that differ in their rates of exchange between the erythrocyte and buffer phases. Selective depletion and readdition of these Photofrin species to the erythrocyte membrane permits evaluation of their separate and joint photolytic efficiencies. These rapidly and slowly exchanging membrane-bound Photofrin species are separately much less efficient photosensitizers than the two species together. The two Photofrin species exhibit essentially identical fluorescence emission spectra in the presence of DMPC. Nevertheless, models consistent with the results involve partitioning by chemically distinct Photofrin components or partitioning of chemically similar Photofrin components into distinct membrane environments, or a combination of these.

Dihematoporphyrin Ether↗
PubMed1995

[Laser bronchoscopic therapy of lung cancer].

Laser endoscopic therapy has now achieved status as an effective treatment modality for lung cancer. The usefulness of Nd-YAG laser as palliative treatment for obstructive tracheobronchial tumors has been recognized. Our experience consisted in 205 YAG laser cases, including 184 obstructive tracheobronchial tumors, and the airway gauge was improved in 88.3%. On the other hand, the effectiveness of photodynamic therapy (PDT) using photofrin as a photosensitizer was demonstrated in our institution in 1979 for the treatment of lung cancers, and increasing attention has focused on this new treatment technique. Over the past decade, 211 patients with central lung cancers, including 66 cases of early-stage lesions, have been treated at Tokyo Medical College Hospital, and a complete remission rate of 65.2% was achieved. We gave an overview of laser endoscopic therapy, including Nd-YAG laser treatment and photodynamic therapy, for lung cancer as well as an evaluation of the effectiveness of these therapies.

Bronchoscopy↗
PubMed1994

Photodynamic therapy using a diode laser with mono-L-aspartyl chlorin e6 for implanted fibrosarcoma in mice.

We have developed a new high-power red (664 nm) laser diode system for photodynamic therapy (PDT) with mono-L-aspartyl chlorin e6 (NPe6). Meth-A fibrosarcoma cells (1 x 10(6)) were implanted subcutaneously in the right hind leg of 4-week-old BALB/c female mice. One week later, diode laser irradiation was applied 5 h after the intravenous administration of NPe6 to each tumor-bearing mouse. In the first study, the time course of intratumor temperature increase during PDT was measured by using a 23-guage thermocouple hypodermic needle at a depth of 2 mm from the tumor surface. In the second study, 6 groups of 10 to 17 tumor-bearing mice were treated with the diode laser 5 h after intravenous administration of NPe6 at the dose of 1.25, 2.5, 5.0 or 7.5 mg/kg i.v. per mouse. Total photoirradiation ranged from 0 to 150 J/cm2 and the dose rate was adjusted to 100 mW/cm2. Percentages of cures were determined from numbers of mice apparently disease-free 50 days after treatment. The results showed that this diode laser is effective in PDT of implanted fibrosarcoma after NPe6 administration. It also confirmed that the therapeutic effects of PDT were not due to hyperthermia. Moreover, the diode laser beam was demonstrated by CCD technology to be uniform in intensity throughout the photoirradiated field.

Animals↗
PubMed1993

A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan Lung Cancer Photodynamic Therapy Study Group.

PURPOSE: A phase II study was conducted between June 1989 and February 1992 to evaluate the activity and toxicity of photodynamic therapy (PDT) with photofrin II in centrally located early-stage lung cancer and to determine the complete response (CR) rate as the primary end point. PATIENTS AND METHODS: Patients had histologically proven lung cancer and endoscopically superficial thickening or small protrusions. All lesions were located in subsegmental or larger bronchi. All patients had a performance status (PS) of 0 to 2 and arterial oxygen pressure tension (PaO2) > or = 60 mm Hg. No lymph node or distant metastases were present. All patients received photofrin II (2 mg/kg) intravenously 48 hours before PDT. Tumor lesions were superficially photoradiated by an argon dye laser or an excimer dye laser. RESULTS: Of 54 patients with 64 carcinomas, 51 with 61 carcinomas were eligible for toxicity evaluation and 49 with 59 carcinomas were assessable for response. Of the 59 assessable carcinomas, 50 (84.8%; 95% confidence interval, 73.0% to 92.8%) showed a CR after initial PDT. The median duration of CR was 14.0+ months (range, 2.0+ to 32.4+). The multiple regression model indicates that estimated length of longitudinal tumor extent was the only independent prognostic factor for CR (P = .002). Five carcinomas that had a CR had a local recurrence at 6, 10, 12, 16, and 18 months after initial PDT, respectively. Toxicity assessment (World Health Organization [WHO] grade 2) showed transient elevation of ALT (1.9%), pulmonary toxicity (7.7%), and allergic reaction (7.7%), as well as sunburn (1.9%). CONCLUSION: PDT with photofrin II has an excellent effect on patients with centrally located early-stage lung cancer who have limited tumor invasion extending over a small area (< or = 1 cm).

Aged↗
PubMed1993

[Photodynamic therapy (PDT) in roentgenographically occult lung cancer by photofrin II and excimer dye laser].

UNLABELLED: Patients (pts) with hilar type early lung cancer from 5 hospitals served as the subjects to assess the complete response rate and toxicity of PDT with Photofrin II (PHE) and excimer dye laser (PDT EDL-1). ENTRY CRITERIA: 1. Histologically proven lung cancer with endoscopically superficial thickening or small protrusion. 2. All lesions that were located proximally from the subsegmental bronchus, were visible to the distal margin of the lesions. 3. N0M0. METHOD: All pts received PHE (2 mg/kg) i.v., 48 hours before PDT. Tumor lesions superficially photoradiated by an excimer dye laser via flexible bronchoscope. RESULTS: From September 1990 to March 1992, 39 pts with 46 carcinomas (CA) were enrolled. Thirty-three pts with 40 CA were evaluable. 1. RESPONSE: Thirty-five in 40 CA showed a complete response (CR) (87.5%, 95% confidence limit: 73.2-95.8%). All 32 cases of CA equal to or less than 1 cm of tumor length were CR, but 3 CA relapsed locally. Thirty-three of 35 CA visible to the distal margin were CR (91.7%, 95% confidence limit: 77.5-98.3%). 2. Toxicity (> WHO grade 2): Three pts (7.7%) had transient dermatitis and sunburn, while another pt (2.6%) had symptoms due to obstructive pneumonitis. CONCLUSIONS: Tumors equal to or less than 1 cm in length and visible to the distal margin are curable by PDT.

Aged↗
PubMed1992

Correlation between photodynamic efficacy of differing porphyrins and membrane partitioning behavior.

The ability of a photosensitizer to partition into membrane is determined by its structure and physical properties. Partitioning behavior can be quantitated as the partition coefficient (Kp) for a particular drug. This property may be an important determinant of cytocidal efficacy in photodynamic therapy. The Kp of five photoactive drugs--13,17-ditetraammonium protoporphyrin (PH1008), photofrin II (PII), hematoporphyrin (Hp), benzoporphyrin derivative monoacid (BPD-MA), coproporphyrin (Cp), and uroporphyrin (Up)--was determined using a simple liposome system composed of sonicated egg phosphatidylcholine single bilayer vesicles. The cytocidal efficacy of each drug was compared by determining the concentration of drug resulting in 50% maximal lysis (C50) obtained by measuring the hemoglobin absorbance at 414 nm released from lysed human red blood cells. The percentage lysis at 1 microM final drug concentration was also determined. An argon-dye laser was used to administer light of 630-nm wavelength for a total exposure of 5 J/cm2. Porphyrins with a greater tendency to partition into phosphocholine bilayer membranes demonstrated a greater lytic efficacy in the rbc system utilized. The comparison of physical properties with lytic ability may be useful in understanding the mechanism by which PDT exerts its effects and in predicting the clinical efficacy of different drugs.

Cell Membrane↗