It has been thirty years since the laser made its debut, during which period laser technology has achieved remarkable advances and today one may find its applications in truly manifold fields. Medical applications, among other instances utilizing of laser energy, have always magnetized the attention of the people concerned, ever since lasers came into the world. Laser applications in this field were premature when laser technology itself in the cradle but they were given powerful momentum for a leap forward by the developing of various lasers and advent of practical optical fibers.
Representative medical applications of lasers include Ar lasers for photocoagulation of the eyeground, CO₂ laser blade and Nd: YAG laser endscopes. These innovations use laser energy as heat. New laser technology for surgery and medicine provides great expectations because the technology of shortening wavelength in lasers has make progress.
Medical applications of laser beams can be discuss in terms of energy. The photon energy level of laser beams can vary according to the kind of laser. Interactions between photon energy and biotissue, therefore, may be identified by this variation. This phenomenon is exactly the same as that in the case of laser wavelength. In this context, studying how photon energy interacts with biotissue will become a very interesting topic for medical laser research as a whole.

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Some physical concepts of laser-tissue interactions that occur in 308nm excimer laser angioplasty are addressed. Monte Carlo numerical computations were used to analyze the light fluence rate distributions resulting from finite diameter laser beams incident on tissue, as applied by fiber optic light delivery catheters. The fluence rate at the inside part of the tissue surface from a 0.2mm diameter fiber emitting 308nm light, is increased more than twice relative to the incident power density. The light fluence rate distribution inside the tissue spreads very little outside the incident beam diameter. Therefore, the distributions from different fibers in multifiber catheters will not overlap unless the fibers are very close together. The maximum fluence rate decreases with decreasing beam diameters, Ablation of tissue by a 308nm excimer laser delivery system in contact with the tissue resulted in a damage zone adjacent to the crater wall due to expansion of the gaseous debris trapped under the tip of delivery system. In case of contact irradiation, the ablation was much more efficient than in case of non contact irradiation. Direct temperature measurements during excimer laser ablation by an IR camera showed that temperature accumulation will occur when a sequence of pulses is applied at frequencies of at least 5Hz. The temperature rise above ambient under circumstances simulating clinical conditions is measured to be 66±7°C.

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Localized prostatic carcinoma is defined as a malignant prostatic disease limited to the gland without evidence of lymph node involvement or distant metastases. Theoretically it should be possible to cure these patients with local procedures provided that suitable techniques were available. Radical prostatectomy, transurethral resection, radiotherapy and radioactive implants have been practiced for years, but non of these methods has gaind common acceptance as routine procedures.
Combined treatment with TUR and the subsequent Neodymium-YAG laser irradiation was introduced in our department in 1981 as a method for radical treatment in patients with localized prostatic carcinoma.
This treatment is founded on the following considerations: Prostatic cancer nodes often arise and are situated near to the capsule or in the apical area of the gland. Even extended transurethral resection will frequently leave remnants of tumor tissue close to the capsule.
The Neodymium-YAG laser light is only slightly absorbed by water and hemoglobin, and penetrates the tissue to a depth of about 5mm. The considerable forward (20-30%) and backward scattering (30-40%) of the laser energy reduces the penetration depth, but heats a larger tissue volume around the point of impact. This property makes the Neodymium-YAG laser suited for deep termal volume coagulation. The development of heat occurs rather slowly, and it is therefore possible to perform coagulation under controlled conditions without carbonization or vaporization of the tissue. As the beam can be conducted in flexible fibers, the Neodymium-YAG laser is ideal for endoscopic coagulation in the urinary tract.
Our experiences and preliminary results have previously been presented in the literature (Sander and Beisland 1984), (Beisland and Sander 1986), The present paper gives results updated to 1990.

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There are some cases of biliary stones difficult to treat with conventional therapy. Nd-YAG laser is suitable modality for those cases. For non-contact method, intensity of YAG laser needs up to 70W, while only 15W for contact method. Bullet shaped ceramic head is effective for contact method. Laser fragmentation of biliary calculi is somewhat invasive because of percutaneous transhepatic biliary drainage or endoscopic papillotomy is needed before the laser treatment. but direct and reliable way to treat biliary stones. Advantages and problems of laser treatment for biliary stone are discussed in this paper.

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Defected guinea pig skin was treated with the He-Ne and CO₂ lasers at same energy densities of 4.5 J/cm² Four biochemical assay systems revealed accelated degradative and reproductive enzyme activities of collagen at initial and healing stages, respectively, for He-Ne laser but not for CO₂ laser at all.
These result indicate that nature of wave length of two lasers should be important for wound healing proces

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We have performed in vitro experiments of laser irradiation on osteoblastic cells to investigate the effect on cell differentiation and calcification. Clonal osteoblastic cells (MC3T3-E1) were exposed to Helium-Neon laser beam at various energy densities. ⁴⁵Ca accumulation was enhanced by laser irradiation at 1.0 J/cm2, with four sessions of irradiation resulting in a 46%increase as compared with the control. In contrast, no significant increase in alkaline phosphatase activity was produced by laser irradiation. Electron microscopic observation revealed a tendency of enlargement of the Golgi apparatus in the laser-treated cells. In clinical use, laser therapy was given to eight patients with fractures, and we obtained good results. These findings suggest that laser irradiation photoactivates osteoblastic cells, accelerates osteoblastic calcification as well as cell proliferation, and therefore, could promote bone regeneration. Laser therapy might be of therapeutic value as a promising modality for fractures.

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Recently, low-power lasers have been attracting a lot of attention. They are effective in promoting recovery from various diseases and states. Their use fulness is also becoming more recognized in the field of plastic reconstructive surgery.
Our earlier report concluded that flap survival was significantly improved as blood flow within the pedicle plap increased due to the effect of diode laser irradiation.
In the present study, the effects of lowpower He-Ne laser irradiation on wound healing were then evaluated. Round skin defects 2.5cm were made on both ears of rabbits. They were then divided into three groups, with two groups receiving He-Ne laser irradiation at 1.3 J/cm2. The one group was under point irradiation, and the other, scanning irradiation. Irradiation with a He-Ne laser promotes the wound healing process and suppress excessive inflammation. Furthermore, it has a systemic effect

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The sutureless approximation technique using Nd: YAG laser had already been reported before by the authors. This study was conducted to clarify the characteristics of wound healing process using this laser new technique as comparison with a conventional interrupted suture technique.
For this purposes, Hematoxylin-Eosin staining and cell-maceration/scanning electron microscope (SEM) method were used to observe the wound on the post operative day 7, 21 and 42. The cell-maceration/SEM method study revealed the signs of earlier reproduction of collagen fibers and smaller wound cleft in the laser suture technique than in the conventional suture technique.
These findings seems to be the reason why lower scar formation and faster wound healing are achieved in the laser technique than in the conventional technique.

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When we carried out the light irradiation to accelate wound healing, the polarization of light was very important factor. Linear and right circular polarization had positive effect over non-polarized light.
We applied the linear polarized light of the iluminating diode and low power diode Laser to seven patient who had chemical skin injury at the injection site of anti-cancer drugs.
All patients were relieved from pain and inflammation early and they had the accelated wound healing without heavy scar formation and motor disturbance.
We supposed that the light irradiation gave the early washing out of the anti-cancer drugs from the local wound. The improved venous return would give benifits.

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Spontaneously ultraweak light (biophoton) from wound surface of mouse was detected by two-dimensional photon counting system. Biophoton emission from the wound changed with the post operative time. The initial emission during the first day was not specific to the wound, but a clear wound shape discerned about two days later. The most intensive emission part of the wound moved from the edge to the center in the process of wound healing. We proposed that biophoton emission and its changes are related the external stimulus (wounding) and containd important biochemical and medical imformation.
In order to examine the optimal condition of irradiation of 810nm AlGaAs diode laser for the acceleration wound healing, the experimental wound was irradiated on five conditions. The experimental animals (Wister strain male rat) were divided into fivr groups noticing the energy density and the power density of 810nm laser. One of two circular wounds with 1.0cm diameter on the rat dorsal was irradiated. The condition of irradiation was as follows; A 1J/cm2-17mW/cm2 B 1J/cm2-50mW/cm2 C 10J/cm2-17mW/cm D 10J/cm2-50mW/cm2 E 50J/cm2-200mW/cm2. As a result, the most effective condition of irradiation on accelerating of wound healing was C group. Both irradiated side and non irradiated side irradiated with the condition C was healed faster than the other 4 groups and control. It is necessary for the resolution of the mechanism of the biostimulation effect to examine the optimal condition of irradiation (wavelength, mode, energy density, power polalizing characteristics, etc.) and the transmittance charcteristics of the irradiating object.

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To analyse the mechanisms of wound healing by low power He-Ne laser, it was investigated whether laser irradiation affects the human platelet aggregability.
Platelet rich plasma (PRP) was prepared from 45 subjects, and was divided into two, one of which was irradiated by laser with 10mW of radiation energy for 15 minutes and the other was not(control).
Platelet aggregability induced by ADP or Epinephrine was significantly augmented after PRP was radiated by laser compared to control. After irradiation, a dose-dependent courve of ADP induced aggregation showed a biphasic pattern of low response to low concentrations of ADP and marked response to high ADP concentrations.
These results suggest that under pathogenic conditions laser could augument the platelet functions and several chemical mediators secreted during the process of platelet aggregation could play an important role to accelerate wound healing.

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Recently, sulphonated aluminum chloro phthalocyanine (AIPC) has attracted a great deal of attention as a new photosensitizer in photodynamic therapy (PDT). Tissue concentrations and photodynamic effects of AIPC and hematoporphyrin derivative (HpD), that has been using clinically in PDT, were determined in nude mice transplanted bladder tumors. Photodynamic effect with AIPC and light (light emission at 675nm from the titanium-sapphire laser) were compared with that of HpD and laser light at 630nm. According to the tissue distribution of AIPC and HpD at various times after administration, the ratios of tumoral concentration to muscular concentration of AIPC were higher than those of HpD, and skin concentration of AIPC at 24 to 168 hr after administration was lower than that of HpD, These results suggest that more selectively AIPC localizes in malignant tumor than HpD, and there is a possibility of reducing skin photosensitivity with AIPC as compared with HpD. The regression of tumor volume after PDT was higher with AIPC than with HpD.
These results suggest that AIPC may be promising photosensitizer for PDT in respect of the selective tumor destruction and the reducing skin photosensitivity.

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Porphyrin and pheophorbide derivatives have been synthesized and investigated the optical properties as photosensitizer for photodynamic therapy (PDT). In the result, PH-1126 which is a pheophorbide derivative, is selected because of the excellent properties which are absorption characteristics, tumor selectivity and ability of generating active oxygen.

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We synthesized and purified the basic porphyrins, azaporphyrins and their metal complex as the sensitizers for POT and examined their physicochemical properties. The substrate of photooxygenation was evaluated, and limonene and cholesterol was used. The oxidized limonene was analyzed by GC after the reduction. The oxidized cholesterol was analyzed by TLC and the oxidized cholesterol derivative (3,5-dinitrobenzoate) by HPLC.
Chlorin-e₆ in porphyrins, Ga complex in metalloporphyrins and Zn complex in phthalocyanines seem to be more useful for PDT. In porphyrins typefl mechanism predominated, and in phthalocyanines type I mechanism did.

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Pulse laser beams from an excimer dye laser can be used for cancer diagnosis and treatment. 48 hours prior to diagnosis or treatment photosensitizers such as HpD or DHE are administered intravenously, and diagnosis is performed by examination of fluorescence from the lesion with 405 nm laser beam exposure. This is effective for localization of cancer. For treatment the lesion is exposed to a 630 nm laser beam and the PTD result in the deep sites in the tissue is expected due to the high light intensity of the excimer dye laser.
An optical parametric oscillator is another type of the pulse laser which is expected to be used for medical applications. It can tune wavelength in wide range in real time, and is also applicable for PDT use.

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At the beginning of 1980s, Nd: YAG laser endoscopy had been carried out for the treatment of the gastrointestinal (GI) tumors instead of the other hemostatic therapy to GI bleedings. Since 1983, we have been studing and developing the Nd: YAG laser contact irradiation method with several kinds of new ceramic contact probes.
Moreover, as a new modality of the hyperthermia, endoscopic Nd: YAG laser local hyperthermia (named Laserthermia) using the newly developed computer controlled Laserthermia system and the interstitial frosted contact probe has been studying experimentally and clinically.
Accordance of basic studies, effects of endoscopic Laserthermia in the normal canine gastric wall limited in the depth from the epitherial layer to the middle part of the submucosal layer,and affected about 10-12mm in width at the surrounded area. Although the tumor reduction effect was detected to the experimentally produced gastric tumor in the beagle dog with ENNG administration. A stable low-power Nd: YAG laser irradiation under 2-3 watts could not be possible with the first Laserthermia system using a conventional high power Nd: YAG laser delivery system, an attenuater and personal computer. So sophisticated computerized low-power Nd; YAG laser system (GL-50) should be desirable.
On the other hands, clinical radical effects of Laserthermia to the treatment of the upper GI tumors (especially gastric cancer) limited to the superficial mucosal cancer (early gastric cancer). Then the combination therapy of Laserthermia with the other therapeutics should be required to the treatment of the GI advanced cancers.
According to the experimental studies, reported by our coworker H. Narumi in the 7th annual meeting of the Japanese Society for Hyperthermia, Laserthermia and combination of Laserthermia with chemotherapy could suggest tumor reduction effects compared with the conventional chemotherapy and Laserthermia alone. Now, new Laserthermia probe (Hybrid probe) will be developing as another basic thechnological study for the endoscopic treatment to the GI tumors. Further studies of Laserthermia for the treatment of the GI tumors should be carried out methodologically, histologically and histochemistolically.

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A compaprtive study of laser hyperthermia and microwave hyperthermia was carried out in vivo and in vitro in an attempt to clarify the therapeutic effect and the mechanism. Both therapies, after seven days, caused marked amounts of coagulated necrosesin the transplanted tumors of human pancreatic carcinoma. Immediately after those therapies, electron microscopic examination of the tumor tissues showed membranous, cytoplasmic, nuclear and mitochondrial damage; however, this damage was much more extensive in laser hyperthermia compared to microwave hyperthermia. The cytocidal effects of heating alone, laser hyperthermia and microwave hyperthermia were also studied in vitro. Of the three, laser hyperthermia demonstrated the most notable decrease in viability. Thus, in the mechanism of laser hyperthermia, it seems that the immediate effect is cellular damage caused by both heat energy and Nd: YAG laser light followed by subsequent damage of tumor vessels. On the other hand, laser hyperthermia was conducted for pancreatic carcinoma of Syrian golden hamsters induced by N-nitrosobis- (2-oxypropyl) -amine (BOP). Disappearance of tumor tissues and coagulated necroses were histologically found after seven days. Though the findings of secondary pancreatitis followed by pancreatic carcinoma were recognized in surrounding pancreatic tissues, the effect of laser hyperthermia itself was minimal.

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Experimental and clinical studies showed that laser hyperthermia using Nd: YAG laser was easy, safe to use and effective to treat deep seated brain tumors.

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Following the penetration of the ceramics probe of the ND: YAG laser into the tumor, the laserthermia was applied in combination with the conventional therapy in patients with head and neck cancer. The combination of laserthermia and CDDP chemotherapy was found to give a much better cytocidal effect on the tumor tissue in nude mice inplanted with human thyroid cancer cells. In a clinical study on 6 cases showed complete remission after combined treatments of laserthermia. and radiochemotherapy.
Both exmental and clinical results were indicated that laserthermia would be expected one of the multidisciplinary procedures treating head and neck cancer.

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Temperature rise of KK-47 bladder tumors transplanted into nude mice, 200 to 300mm was determined at an average output of 150mW/cm² (9J/cm²/min) or 300mW/cm² (18J/cm²/min) with a gold vaporlaser (GVL). Approximately 43°C hyperthermia of the entire tumor was attained with the 300mW/cm² output.
After 10mg/kg HpD injection, GVL-photoradiation and concomitant GVL-induced hyperthermia achieved CR (complete remission) in 6 of 6 tumor-bearing nude mice at 3, 7.5, 15 and 30 minute-irradiation times.
With decreasing HpD dosage ranging from 10 to 5mg/kg, CR rate was decreased at all the irradiation times. However, analysis of the tumor growth curves of two groups received HpD 1 or 2.5mg/kg and control groups without HpD demonstrated that HpD resulted in a significant reduction of the GVL-induced hyperthermia antitumor effects.

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To investigate the effect of laserthermia in CIN, we performed fundamental study and clinical trial, using Nd-YAG laser. As the result of fundamental study using OMC-i which was established from a uterine cervical squamous cell carcinoma, the antitumor effect of laserthermia was confirmed. We devised aluminium reflector, in which Intralipid dilution injected, as a novel method of laserthermia in the uterine cervix.
Laserthermia was performed in 15 patients included 8 cases of mild dysplasia, 6 cases of severe dysplasia and 1 case of intraepithelial cancer. Seven cases (46.7%) showed disease free after three months of laserthermia. Therefore, although irradiation method needs to be improved further, laserthermia is considered that it should become a useful therapeutic method in the future for the CIN.

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ヌードマウス可移植ヒト腎癌 (以下GCA)を用いて, パルス波発振装置である金蒸気レーザーの光線力学的治療 (以下PDT) における効果を検討した。また同時に腫瘍内の温度変化もあわせ検討した。対照としてアルゴンダイレーザーを使用した。
GVL280mW/cm2, 3分間50.4J照射, HPD投与群では, 照射翌日より腫瘍の縮小がみられ, 照射14日後には, 4匹で腫瘍の完全消失がみられ, 残る1匹でも腫瘍の著明な縮小がみられた。ADLでは同一条件の照射時には, 腫瘍の縮小はみられず, 腫瘍の増大がみられた。
腫瘍内の温度変化は, GVL照射時には腫瘍中心部で照射10分後には55度以との著明な温度上昇がみられたが, ADL照射では, 41度までの温度上昇がみられなかった。
GVLはADLに比較し, 組織深達性や励起効率が良いことに加え, ハイパーサーミア効果が加わり, 良好なPDT効果がえられる新しいレーザーであると考えられた。

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This is the first report on the use of photodynamic treatment (PDT) for pituitary tumor in vivo. For this study, rat pituitary tumor (GH3) was subcutaneously implanted in nude mice, and pheophorbide-a (Ph-a) and white light were prepared. Despite the delay in the disappearance of Ph-a from the tumor, Ph-a in the pituitary gland rapidly decreased after intravenous administration. Through PDT, the tumor grossly disappeared, the plasma levels of rat growth hormone secreted from the tumor also remarkably decreased, and the development of giantism was inhibited.
These results indicate that PDT is effective against rat pituitary tumor in vivo, and suggest that if the interval between the time of injection of Ph-a and irradiation is selected, PDT for human pituitary adenoma may be applied without adversely affecting the pituitary gland.

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The photodynamic therapy, using Nd: YAG laser, Qswitch and Pheophorbide-a, has tumor-cidal effect against the murine bladder tumor. Pheophorbide-a itself was proved to have little toxicity to the tumor cells. The damage produced with the PDT seems to cause gradual cell death even after the treatment of PDT. It is warranted to investigate further course of this treatment, to clarify how long this effect lasts.

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We evaluated the effect of photodynamic therapy (PDT) with pheophorbide-a (PpA) as a photosensitizing agent and pulsed Nd-YAG Laser (1064nm) on human gastric cancer cells (Hs 746T) by MTT (methyl-thiazolylte-trazolium ) assay.
Optical density (O. D.) of MTT assay decreased slightly immediately after irradiation, but remarkably decreased successively 1 and 3 days after irradiation in the group treated with PpA more than 34.6 μg/ml, which represented that the number of living cells decreased,

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Experimental studies in vitro and vivo were performed to evaluate the effect of PDT using pulsed Nd-YAG LASER with Pheophorbide-A (Ph-A) for human gastric cancer. In vitro study we used three cell lines; KATO III, KKLS, NKPS. The cytocidal effect was evaluated in the MTT assay three days after treatment. In vivo study a human gastric cancer transplanted subcutaneously into the backs of nude mice (BALB/c-nu) was used. We evaluated the pharmacodynamics in two ways of ph-A administration; I. P and I.T injection. We also evaluated the photodynamic effect in I. T. injection of Ph-A. The PDT using Ph-A exerted a synergistic anti-tumor effect against the gastric cancer cells both in vitro and in vivo, But Ph-A was not accumulated to the tumor in the way of I. P. injection, so that suggested the necessity of local administration for the sake of effective PDT.

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Balb/C mice weighing 15 to 17g. and mKS·A cell line were used in this study. 1×10⁶mKS·A cells were injected into the posterior part of the cerebral hemisphere of mice. Three days after transplantation, the photosensitive drug (PH-1126) was administered orally at the doses of 0, 10, 20, 30 and 40mg/kg using gastric tubing. At 48 hours after dosing, the transplanted tumor was examined under an operating fluorescence microscope (Topcon OMS-600). Fluorescence spectra of PH-1126 was clearly observed at the site of tumor, but not in the brain parenchyma. For the quantitative comparison of PH-1126 accumulated at normal areas and at the site of tumor, an Exicimer dye laser endoscope fluorescence spectrometer was used to detect the fluorescence spectrum of 655nm. Fluorescence spectra of PH-1126 detected at the site of transplanted tumor were from 6 to 13 times that in the normal brain. These facts demonstrate that PH-1126 accumulates at high concentrations at brain tumors.

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The new photosensitizer, PH-1126 (Hamari Chemical Co. Ltd. Osaka) has amine in the d-ring of pheophorbide. The agent is considered to be more useful for PDT due to its greater absorption band in longer wavelength region. In order to investigate its efficacy, tumor-bearing rats were sacrified at intervals from 2 to 96hours after PH-1126 administration of 10mg/kg intravenously. Samples of each organ were frozened, sectioned to 30μm thickness, and the fluorescence value was measured with excimer dye laser endoscopical fluorescence spectrophotometer using 405nm excitation beam. Also, the tissue concentration was analyzed by means of the high performance liquid chromatography.
The tissue concentration among organs such as lung, heart liver, spleen, kidney and skin kept high level till 24hours after administration, and then quickly decreased after 48hours.
Maximal PH-1126 level in brain tumor was 3.2μg/g at 24hours after administration. The other normal brain tissue such as cortex and white matter showed no presence of fluorescence, morover PH-1126 level in normal brain tissue were scant, 0.05μg/g. The ratio of tumor and normal brain tissue concentrations of PH-1126 was 64 to 1.
The PH-1126 uptake or retention into brain tumor was greater than that into normal brain tissue.

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The effect of photodynamic therapy (PDT) using argon-pumped dye laser on new photosensitizer, PH-1126 (amine in the d-ring of pheophorbide, Hamari Chemical Co. Ltd. Osaka) on T9 glioma, was investigated.
T9 cells, in vitro, were incubated independently with HpD and PH-1126, and irradiated. Using 1μg/ml of PH-1126, 100% cell death needed for 34J/cm2. PDT with PH-1126 was more favorable than that with HpD in tumorcidal effect.
Rat brain tumor, in vivo, was established by implanting T9 cells in Fischer 344 male rat. PDT was carried out 24hours after administration of 10mg/kg PH-1126 with craniotomy, in which the tip of an optical fiber was contact with the tumor surface. Histologically, the depth of tumor necrosis was 3.7mm at 30joules, 5.3mm at 60joules, and 6.4mm at 120joules.
It is suggested that PH-1126 is one of useful photosensitizers for treatment of brain tumors.

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The new photosensitizer (PH-1126) is a pheophorubaide derivative which have amine in the D-ring of pheophorubaide structure. This photosensitizer have the longest absorbance peak of Q band at 652.4nm. Comparing PH-1126 and HpD in terms of the longest absorbance peak of Q band, the wavelength of PH-1126 is 35nm longer. Its longest absorbance peak of Q band showed the 7.5 times than the HpD's at same concentration. Since blood (hemogrobin) and tissues absorbs light in the 500-600nm wavelength range, light transmittance is low in this range. Longer wavelength, especially those greater than 600nm, are not affection by the blood and tissues. The effect of the PH-1126 and red light at 647.1nm wavelength of Kr'-laser on Meth-A tumors transplanted in mice was examind. The animals were given a oral administration of PH-1126 in doses range of 0-40mg/kg b. w.. At 48hrs after administration, Kr⁺-laser were irradiated with laser power of 50mw/cm2 and power density of 0-60J/cm2. In the experimental animals, tumor mass with PH-1126 in doses of 40mg/kg b. w. and laser Power density of 60J/cm2 were 11.4% to non-treatment tumor mass at 7days after PDT.

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The new photosensitizer, PH-1126, has amine in the D-ring of pheophorbide with ester ring was studied. PH-1126 has its longest Q-band at 655nm, which is expected for longer tissue penetration. The studies of the relative localization and specified uptake of PH-1126 in tumor and other tissue after oral administration was performed spectroscopically, using mice baring Meth-A fibrosarcoma. At 48 hours after administration, PH-1126 had significant selectivity for Meth-A tumor, however, all drug was discharged from the liver at this time. It is concluded that PH-1126 has a possibility to be a promising photosensitizer because of its superior tumor selectivity at 48 hours after injection.

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Zinc-sulfo-phthalocyanine mixture (ZnSPc Iigroup) was compared with zinc-tetra-sulfo-phthalocyanine (ZnTSPc: Igroup) in their ability to sensitize cells to red light. Both groups were prepared in order to obtain the required concentration (4.0×10^-5M-4.0×10^-8M), and incubated with HeLa cells for 30 min before laser-irradiation. Cells were damaged strongly by IIgroup even if the concentration and the irradiation energy was lower (4.0×10^-7M, 1J/cm2). Moreover, a large difference between cellular morphological changes of two groups was recognized.

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The absorption and fluorescence spectra, and fluorescence lifetime of hematoporphrin oligomers (HpOs )(mean molecular weights 2000, 3000, 5000 and 12000), Photofrin I′ and Photofrin II′ have been measured in distilled water and cetyl trimethyl ammonium bromide (CTAB) aqueous solution. Two different lifetimes were observed from the fluorescence decay curve of the several photosensitizers dissolved in distilled water and CTAB aqueous solution. In distilled water, the fraction rate of the long lifetime increased with increasing of the concentration. Using 0.1mM and 10mM CTAB aqueous solutions, the fraction rates were less than 20% and more than approx. 50%, respectively. From these results, it was thought that the long lifetime component may be resulted from several photosensitizers aggregated in distilled water and the short lifetime component from several photosensitizers aggregated in 0.1mM CTAB aqueous solution.

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Relative yield of the activated oxygen produced by the photosensitization of various sensitizers was determined by a spin trapping method of singlet oxygen (¹O₂) or OH radical (OH:) with ESR and by a detection of the emission at 1270 nm of ¹O₂ with a laser flash photolysis. (1) The relative intensities of the ESR signal of 2, 2, 6, 6-tetramethy1-4-pyperidone hydrochloride (TMPD) with ¹O₂ in 50% dimethyl sulfoxide (DMSO) aqueous solution were 1.0 (Photofrin II^®), 0.28 (Hp oligomer=HpO) and 1.31 (Pheophorbide derivative=PH-1126), respectively. (2) The relative intensities of ESR signal of 5, 5′ -dimethyl-1-pyroline-N-oxide (DMPO) with OH: in 95% DMSO aqueous solution were 1.0 (Photofrin II), 0.93 (HpO) and 0.08 (PH-1126), respectively. (3) The relative intensities of the emission of ¹O₂ at 1270 nm in 98% deutrium methanol (CH₃OD) solution were 1.0 (Photofrin II), 0.2 (HpO) and 8.8 (PH-1126), respectively. The each intensities were enhanced by 2.3 times (Photofrin II), 23 times (HpO) and 3.2 times (PH-1126), respectively, when the oxygen was bubbled in each samples. It was found that PH-1126 was more excellent in ¹O₂ production than Photofrin II.

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Aluminium-chloro-tetrasulphonated phthalocyanine (PC) showing an absorption peak at 678 nm was compared to hematoporphyrin derivative (HpD), a photosensitizer commonly used in the photodynamic therapy (PDT) of human cancers. In vitro studies: KK-47 cells were exposed to UVA or red lights (>600 nm, >640 nm and >660 nm) after drug sensitization. With UVA irradiation, a higher photodynamic cell killing effect was shown in the cells treated with HpD than with PC. However, with two kinds of red light irradiation (>640 nm and >660 nm) PC demonstrated greater cell damage. PC was less toxic to KK-47 cells in the dark. In vivo studies: Using a gold vapor laser (GVL: 627.8 nm, 200 mW/sqcm, 200 J/sqcm), the photodynamic tumor response was determined in C3H/He mice bearing transplantable squamous cell carcinoma. No significant difference was observed in the tumor volume between the PC and HpD groups, except that the PC group (10.0 mg/kg body weight) showed a significantly higher remission rate (3/6) than the control group (0/10, p<0.05). Skin photosensitivity test:Skin photosensitivity was estimated by measuring changes in back skin thickness due to photosensitization. With UVA irradiation, a stronger skin reaction was observed in the HpD group, while with visible light irradiation there was no significant difference between the HpD and PC groups. Based on the superior cell killing effect with red light, less toxicity to the cells in the dark and mild skin reaction with UVA, PC may be a more promising photosensitizer for PDT

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The photosensitizing efficiency per an absorbed photon was compared among three photosensitlzers by the parameters of cytotoxic effect of the tusor cells in vitro. The efficiency of HpO is stronger than that of Photofrin II, and PH-1126 showed a little photosensitizing efficiency. And HpO also showed the highest nuclear DNA dasage In the study using fluorescence cytophotouetory.
However, PH-1125 cost inhibited the Increase of cell numbers as a total dose at least for 2-3 days after photoirradiatlon, because the concentration of PH-1126 Incorporated into the cells was very high.

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