光敏剂m-THPC在原位移植性肝癌大鼠体内的组织分布和药代动力学研究

目的 探讨光敏剂m-THPC在原位移植性肝癌大鼠体内的分布和消除情况,为m-THPC光动力治疗肝癌提供参考和依据.方法 大鼠尾静脉注射m-THPC 0.3 mg/kg后,采用荧光分光光度计法测定组织和血浆中的原形药物浓度,用PK-GRAPH程序拟合并计算药代动力学参数.结果 m-THPC血药浓度-时间曲线符合二室模型,血浆分布半衰期(T1/2α)为1.18 h,血浆消除半衰期(T1/2β)为22.57 h.药物在大鼠体内分布广泛,各组织药物浓度均在40 ng/g以上;其中肝脏组织浓度最高,肝癌次之,肌肉、皮肤组织相对较低,给药6 h后多数组织药物浓度达到最高,24 h后多数组织药物浓度有所下降,而肝癌药物浓度在24 h达到最高,肝癌和正常组织药物分配比也达到最高.结论 m-THPC在大鼠组织中分布广泛,血浆药物清除相对较快;给药后24 h是肝癌光动力治疗的最佳时间窗.

Abstract：

Objective To study the pharmacokinetics, distribution and excretion of m-THPC in rat models of liver cancer via orthotropic implantation using Walker-256. Methods After an intravenous injection of m-THPC with 0.3 mg/kg, the concentrations of m-THPC in biological specimens were determined by a fluorescence method. The data obtained were processed with PK-GRAPH pharmacokinetic procedure. Results The disposion of m-THPC in rat models of liver cancer Walker-256 was conformed to a two compartment model with T1/2α = 1.18 h, T1/2β =22. 57 h at the dose of 0. 3 mg/kg. m-THPC was shown to be widely distributed to the various tissues. There was a highest drug accumulation in liver and liver cancer, and lowest in skin and muscle. Ratio of m-THPC concentration in the Walker-256 tumor compared to normal tissue reach the peak 24 h after m-THPC administration. Conclusions m-THPC is distributed widely and eliminated at a rapid rate in Walker-256 rats. Twentyfour hours after m-THPC administration may be the best time for photodynamic therapy of liver cancer.     

Photodynamic treatment as a novel approach in the therapy of arthritic joints

BACKGROUND AND OBJECTIVE: Minimal invasive local treatment of joints is a desirable option in the therapy of rheumatoid arthritis (RA). Aim of this study was to evaluate the effects of photodynamic treatment (PDT) with different doses of the photosensitizer meta-tetra(hydroxyphenyl)chlorin (m-THPC; or temoporfin) in a murine model of RA (antigen-induced arthritis, AIA). METHODS IN VIVO DISTRIBUTION: The distribution of native and liposomal m-THPC (including a formulation with polyethylene glycol [PEG] coating) was assessed by fluorescence spectrometry in arthritic joints, normal joints, and skin. TREATMENT: AIA mice received different concentrations of pegylated liposomal m-THPC (0.1, 0.05, 0.01, or 0.005 mg/kg body weight; n = 5 per group) and subjected to PDT with a laser system 12 hours post-injection of the photosensitizer. Treatment effects were evaluated histologically in comparison to untreated AIA (n = 5). RESULTS: Pegylated liposomal m-THPC showed the most favorable accumulation in arthritic joints compared to native m-THPC and to non-peg-liposomal m-THPC, therefore it was selected as photosensitizer for PDT treatment. In comparison to untreated AIA, PDT reduced the arthritic score with all doses of pegylated liposomal m-THPC; statistical significant effects were obtained with doses of 0.05 and 0.01 mg/kg. CONCLUSION: Our study demonstrated that local PDT of arthritic joints is feasible. Application of pegylated liposomal m-THPC for PDT resulted in significant reduction of arthritis scores.     

Photodynamic therapy for head and neck cancer xenografts in athymic mice

This study examines efficacy and optimal treatment variables of photodynamic therapy (PDT) for human head and neck squamous cancer (HNSC) xenografts in athymic mice. Two and four days after injection of hematoporphyrin derivative (HPD), tumors were illuminated with red light from an argon-dye laser. Sixty-three tumors were treated. With HPD dose and light intensity constant at 7.5 mg/kg and 100 mW/cm2, respectively, the extent of tumor necrosis was strongly dependent on duration of light exposure. There was no substantial difference in results for 30- and 60-minute treatment durations between animals injected with HPD 2 and 4 days before treatment. After 30 minutes treatment time, responses were seen in 8 of 10 mice (2 days post-HPD) and 11 of 12 mice (4 days post-HPD). After 60 minutes treatment time, toxicity was high. We conclude that, in this model, PDT is effective in selective killing of HNSC. For future comparison studies in this model, if the indicated HPD dose and light intensity are used we recommend a 2-day delay after HPD injection and a light exposure duration of 30 minutes.     

Photodynamic therapy of malignant brain tumors: clinical results of, difficulties with, questions about, and future prospects for the neurosurgical applications

Photodynamic therapy (PDT) has been applied in a variety of oncological fields with good results. In neurosurgery, the clinical series are limited and the number of treated patients is not statistically significant. This work examines the results of PDT performed in our clinic and discusses some difficulties and causes of failure of this method in neurosurgical patients. Eight patients with malignant brain tumors underwent PDT. All had been treated previously by operation and radiation therapy and one patient had also received chemotherapy. At 24 hours after the i.v. injection of hematoporphyrin (5 mg/kg body weight), the tumor was removed as radically as possible and the residual tumor bed was exposed to either 630-nm light from an argon-dye laser or 600- to 680-nm light isolated from the emission of a quartz-halogen lamp. The type of sensitizer, the irradiation methods, and the peculiarities of glial tumors are examined as possible causes of failure. The longer survivals of some patients with glial tumors treated by PDT may make this treatment suitable when traditional therapies fail.     

Effect of hematoporphyrin derivative photoradiation therapy on survival in the rat 9L gliosarcoma brain-tumor model

Intracerebral tumors were produced in 99 rats by stereotaxic implantation of 9L gliosarcoma brain-tumor cells. Hematoporphyrin derivative (HPD), 10 or 20 mg/kg, was administered as an intravenous bolus 24 or 48 hours before irradiation of the tumor region with light from an argon pumped-dye laser (632 nm). Laser light, at a dose of 30, 60, or 200 joules/sq cm, was delivered through a craniectomy 10 or 13 days after tumor implantation. Survival times were significantly prolonged in rats exposed to laser light at a dose of 200 joules/sq cm 24 hours after administration of HPD, 20 mg/kg.     

Effect of hematoporphyrin derivative 2 on estrogen receptors in experimental mammary tumors

This study reports the effect of hematoporphyrin derivative 2 (HPD2) on estrogen receptors (ER) in the animal model used to develop the clinical ER assay. Fifty 200-g female Sprague-Dawley rats were given 20 mg of dimethylbenzanthracene by gastric intubation. Spontaneous mammary tumors occurred in 35 animals. Animals were anesthetized and 50% of each tumor was removed when the tumors were 2 cm in diameter. Animals were then randomized to receive 5 mg/kg (group A), 10 mg/kg (group B), or 0 mg/kg (group C) HPD2 intravenously 48 hours after biopsy. The remaining tumor was excised 48 hours post HPD2 injection. All samples were weighed, placed on ice, and frozen to -70 degrees C. ER assay was performed by batch run. Results (fmol/mg cytosol) were as follows: All animals (n = 35) pre HPD2 34.2 +/- 5.4, post HPD2 34.2 +/- 5.8; group A: (n = 11) pre HPD2 33.9 +/- 7.9, post HPD2 37.1 +/- 7.8; group B: (n = 13) pre HPD2 29.2 +/- 3.8, post HPD2 25.5 +/- 3.6; group C: (n = 11) pre HPD2 40.3 +/- 5.2, post HPD2 41.5 +/- 7.9. HPD2 does not affect ER in this animal model. Confirmatory studies with human tumor material must be completed.     

Photodynamic therapy of superficial bladder tumors

Photodynamic therapy (PDT), using hematoporphyrin derivative (HPD) and the red light (wavelength 630 nm) of an argon-dye laser as the source of excitation energy was performed on 46 patients with superficial bladder tumors. Two methods of laser irradiation, (1) focal PDT using a 400 micron quartz fiber through a cystourethroscope in 22 patients with superficial bladder tumors and (2) whole bladder wall total PDT using a motor-driven laser light scattering device in 24 patients with multifocal carcinoma in situ and/or dysplasia of bladder mucosa associated with multicentric concurrent superficial tumors, were used. The patients in (2) had been referred for total cystectomy, and 19 of these 24 patients had a history of several transurethral resections, hyperthermia and/or instillation therapy. HPD 2-4 mg/kg was i.v. injected 48 to 72 hours before PDT. Judging from the results of 60 protrusions treated by focal PDT, the light power should be 200 mW/cm2 for 5-10 minutes or more and the total light energy should be 100 J/cm2 or more in tumors up to 2 cm in size. With focal PDT, 4 of the 22 patients had no recurrence with the mean tumor free time of 20.8 months. In 6 of the 24 patients treated with total PDT using 10, 20 or 30 J/cm2 of light energy, there was no recurrence with a mean tumor-free time of 7.5 months and there was no significant relationship between the recurrence rate and total light energy used.     

Palliative treatment by photochemotherapy of 54 digestive cancers: phase I clinical trial

Photochemotherapy (PDT) is based on the interaction of a phototoxic drug (HPD) retained by cancer tissues and excited with a specific laser light. We present here a phase I clinical trial including 54 patients selected on the grounds of non-operability and T1 NO MO staging (UICC) and divided into 3 groups: I) 24 squamous cell carcinoma (SCC), II) 14 adenocarcinomas (ADN) of the upper GI tract, III) 16 ADN of the rectosigmoid colon. All received an HPD infusion of 2.5 to 5 mg/kg I.V. 72 hours before being laser irradiated endoscopically (632 nm, 150 to 220 j/cm2). Results documented on histology obtained after grip biopsies and on resected specimens (6 cases), were classified as complete response (ST), partial response (PR) or no change (NC). Eleven patients of group I, 5 of group II, and 8 of group III (24/54 patients) were classified ST with a mean follow-up of 15.2 months. Analysis of resected specimens showed a complete disappearance of tumor tissue and prominent fibrosis all around the treated area. Adverse effects were noted in 22% of patients, PDT of rectosigmoid ADN gave a survival (life table analysis) at least equal to SCC. These results should allow clinical indications for PDT to be broadened in combined protocols.     

Photodynamic therapy: response of normal canine urethra using a cylindrical fiber

Normal urethral response to photodynamic therapy (PDT) utilizing a cylindrical fiber was assessed in ten study and two control NIH fox-hounds. The canine urethras were treated 48 hours after intravenous injection of 3 mg/kg dihematoporphyrin ether (Photofrin II). A 1-mm fused silica optical fiber, with the distal 2-3 cm modified for cylindrical light distribution (660-microns diameter), was placed in the pendulous urethra. An argon-pumped dye laser delivered 100 mW of 630-nm light for 7 minutes (42 J) to the treatment area. Urethroscopy using either a 2.5-mm or a 2.8-mm flexible pediatric bronchoscope with video recording capability was performed immediately after PDT (12 animals) and 6 weeks later (nine animals); intravenous urography was performed 3 days and 6 weeks after PDT. There was no evidence of either urethral damage or stricture formation in any animal. Histopathology of the first three study specimens, obtained at 6 weeks, confirmed the absence of any pathology. Flexible instrumentation facilitates post-treatment assessment. This study demonstrates for the first time that, when a cylindrical fiber is used, photodynamic therapy may be applied to the urethra without damage to the normal urethral mucosa. This result has implications for potential treatment of initial or recurrent carcinoma in situ of the urethra using PDT.     

Fluorescence localization of early colonic cancer in the rat by hematoporphyrin derivative.

Laser excitation of hematoporphyrin derivatives (HPD) localizing in tumors of the tracheobronchial tree and bladder is useful in the identification and treatment of those tumors. A comparable utility for HPD in the endoscopic localization of colonic tumors may be possible. In this study the ability of HPD to identify 1,2 dimethylhydrazine (DMH) induced colon cancer in rats is evaluated. A total of 111 rats were studied with HPD. Sixty-nine rats received weekly injections of DMH (20 mg/kg) and 42 received injections of the vehicle alone. Twenty-four hours after the intravenous injection of 5 mg/kg of HPD, 18 DMH-induced tumors were identified by visual fluorescence using excitation by either a blue light (390-436 nm) or an argon laser (488 and 514 nm). This represented 100% of the visually or microscopically detected tumors. Seventy-five fluorescent areas were noted that did not contain evidence of cancer. The majority (63) of false positive areas contained lymphoid follicles. All but 2 false positive areas (73/75, 97%, p less than .001) were seen in DMH-treated animals, suggesting that they were an artifact of DMH treatment. HPD fluorescence did not identify microscopic dysplasia. We conclude that HPD fluorescence is an effective method of identifying early colonic cancer and may have a potential clinical role in patients at high risk for colorectal cancer.     

氨基胍对大鼠急性脊髓损伤后脊髓水肿的作用机制研究

目的氨基胍(aminoguanidine,AG)能显著减轻脑外伤及中风动物模型脑水肿,提高神经功能恢复程度。探讨AG对大鼠急性脊髓损伤(spinal cord injury,SCI)后脊髓水肿的作用及相关机制。方法取成年雄性SD大鼠150只(体重230～255 g),分为对照组(A组,25只)、假损伤组(B组,25只)、SCI后未治疗组(C组,25只)和SCI后AG治疗组(75只);AG治疗组按给药剂量分为AG 75 mg/kg组(D组,25只)、AG 150 mg/kg组(E组,25只)和AG300 mg/kg组(F组,25只)。A组未行任何处理,B组仅行椎板切除术但不治疗;C、D、E、F组制备静压型大鼠SCI模型后,C组腹腔注射5%DMSO,D、E、F组腹腔注射相应剂量AG。于造模后0、12、24、48 h用干湿重法检测受损脊髓组织含水量以筛选最佳剂量,进一步用伊文思兰(Evans blue,EB)法评测血-脊髓屏障功能,用RT-PCR检测水通道蛋白4(aquaporins 4,AQP4)mRNA表达,Western blot和免疫组织化学染色检测AQP4蛋白表达。结果脊髓组织含水量检测示,E组在造膜后12、24、48 h对SCI后脊髓组织水肿有明显抑制作用(P<0.05),选择该剂量组用于后续实验。造模后12、24、48 h,E组EB含量明显低于C组(P<0.05),降低血-脊髓屏障通透性。RT-PCR检测结果示造模后12、24、48 h,B、E组AQP4 mRNA表达明显低于C组;Western blot检测示造模后24、48 h,B、E组AQP4蛋白表达明显低于C组;免疫组织化学染色示造模后48 h,B、E组AQP4蛋白表达明显低于C组,差异均有统计学意义(P<0.05);但各指标各时间点B、E组间比较,差异均无统计学意义(P>0.05)。结论急性SCI后大鼠经150 mg/kg AG治疗后,能降低AQP4表达,改善脊髓水肿,减轻损伤。     

Photodynamic modulation of wound healing with BPD-MA and CASP.

BACKGROUND AND OBJECTIVE: Wound healing is an intricate process requiring the orchestration of cells, growth factors, cytokines, and the extracellular matrix. Cytokines, specifically TGF-beta, are believed to be instrumental in sustaining the fibrotic process, which leads to scarring. Photodynamic therapy (PDT) uses potent photosensitizers, which induce a wide range of effects on cells and the extracellular matrix. The influences of PDT on wound healing are not well known. STUDY DESIGN/MATERIALS AND METHODS: Seven full-thickness incisional wounds were placed on each of 24 hairless Sprague Dawly rats, three wounds on one flank serving as dark controls and four on the contralateral side treated with PDT. Wounds were created two days before, one hour before, or one hour after red light exposure with an argon ion pumped dye laser. Twelve rats were injected with 0.25 mg/kg or 0.5 mg/kg of the PDT drug, BPD-MA, and the other 12 with 5 mg/kg or 10 mg/kg of the PDT drug, CASP, 3 and 24 hours prior to irradiation of light, respectively. At low doses of both photosensitizers, animals were irradiated with 1, 5, 10, and 20 J/cm2. At higher doses of BPD-MA and CASP animals were treated with 10, 20, 50, and 100 J/cm2 of light. Wounds were examined each day for 14 days and noted for edema, erythema, inflammation, necrosis, and quality of scarring. Wounds were also photographed at day 0, 2, 5, 8, and 14 post-irradiation. All animals were sacrificed 14 days after irradiation and the wounds were evaluated by light microscopy. RESULTS: Grossly, animals treated with 0.25 mg/kg BPD-MA showed no effect with PDT. Animals treated with 0.5 mg/kg BPD, and 5 and 10 mg/kg CASP showed responses that varied with both light and drug dose. Erythema, edema, inflammation, and necrosis attributed to PDT were all observed, but there was no apparent influence of PDT on either the rate or final appearance of wound healing. Histologically, there were no apparent differences between treated and untreated sites, regardless of the drug, dose of light, or time of irradiation. CONCLUSION: A single PDT treatment given before or after skin wounds does not apparently alter wound healing even when PDT caused brisk inflammatory reactions. PDT may have effects that were not detected. We conclude that PDT does not greatly influence incisional skin wound healing in the rat model.     

Fluorospectral study of the rat brain and glioma in vivo

An animal model of cerebral glioma was utilized by implanting C6 glioma cells into the brains of adult Wistar rats. Once tumors developed to 7–12 mm in diameter, we conducted continuous fluorimetry monitoring of glioma up to 24 hours using a fibre-optic system connected to an intensified multichannel photodetector after an intravenous injection of hematoporphyrin derivative (HPD) into the rats. The intensity of the fluorescence in normal brain reached a plateau 6 hours after intravenous injection of HPD while that in glioma reached a plateau 80 minutes after injection. These fluorescence intensities of glioma, brain adjacent to tumor (BAT), and surrounding normal brain were measured in vivo 24 hours after intravenous administration of 5 mg/kg of HPD. The ratio of fluorescence intensities between glioma and brain was 6.1 while the ratio between BAT and brain was 3.9. There were no obvious differences in shapes between the spectra of the natural fluorescence (autofluorescence) of rat glioma and brain but the intensity of autofluorescence was much weaker in glioma. There are many problems in spectroscopic studies of biological tissues in vivo. It cannot be overemphasized that very strict criteria must be applied in order to get accurate data. Fluorescence from HPD administration may be used to discriminate tumor tissue from surrounding normal brain tissue during operation if the measuring conditions could be kept constant. It is important to understand the photospectral properties of glioma and brain tissue in order to get the most benefits in clinical application of light-induced fluorescence or photoradiation therapy. © 1993 Wiley-Liss, Inc.     

High-field magnetic resonance imaging of the response of human prostate cancer to Pc 4-based photodynamic therapy in an animal model

INTRODUCTION: High-field magnetic resonance imaging (MRI) is an emerging technique that provides a powerful, non-invasive tool for in vivo studies of cancer therapy in animal models. Photodynamic therapy (PDT) is a relatively new treatment modality for prostate cancer, the second leading cause of cancer mortality in American males. The goal of this study was to evaluate the response of human prostate tumor cells growing as xenografts in athymic nude mice to Pc 4-sensitized PDT. MATERIALS AND METHODS: PC-3, a cell line derived from a human prostate malignant tumor, was injected intradermally on the back flanks of athymic nude mice. Two tumors were initiated on each mouse. One was treated and the other served as the control. A second-generation photosensitizing drug Pc 4 (0.6 mg/kg body weight) was delivered to each animal by tail vein injection 48 hours before laser illumination (672 nm, 100 mW/cm(2), 150 J/cm(2)). A dedicated high-field (9.4 T) small-animal MR scanner was used for image acquisitions. A multi-slice multi-echo (MSME) technique, permitting noninvasive in vivo assessment of potential therapeutic effects, was used to measure the T2 values and tumor volumes. Animals were scanned immediately before and after PDT and 24 hours after PDT. T2 values were computed and analyzed for the tumor regions. RESULTS: For the treated tumors, the T2 values significantly increased (P<0.002) 24 hours after PDT (68.2+/- 8.5 milliseconds), compared to the pre-PDT values (55.8+/-6.6 milliseconds). For the control tumors, there was no significant difference (P = 0.53) between the pre-PDT (52.5+/-6.1 milliseconds) and 24-hour post-PDT (54.3+/-6.4 milliseconds) values. Histologic analysis showed that PDT-treated tumors demonstrated necrosis and inflammation that was not seen in the control. DISCUSSION: Changes in tumor T2 values measured by multi-slice multi-echo MR imaging provide an assay that could be useful for clinical monitoring of photodynamic therapy of prostate tumors.     

Cell biology of hematoporphyrin derivative (HPD)

Tissue culture cells were treated with hematoporphyrin derivative (HPD) and analyzed for (1) HPD uptake, (2) HPD washout, and (3) fluorescence changes. The absorption peaks were the same for HPD in solution and HPD bound to cells. HPD was taken up by all cell types rapidly within the first 10 hours of exposure, and leveled off by 20 hours of exposure. HPD came out of all cell types to control levels by 72 hours after removal of the HPD bathing solution. The HPD appeared to come out of the malignant 3-T-12 cells more slowly than from the parental (non-malignant) 3-T-3 cells. The fluorescence spectrum of HPD-treated cells changed markedly from the time that the bathing HPD solution was removed from the cells. As time progressed the weakly fluorescent 590-nm peak increased greatly and the 615-nm and 630-nm peaks decreased significantly.     

The effect of photodynamic therapy on rat urinary bladder with orthotopic urothelial carcinoma

OBJECTIVE: To assess the effect of whole-bladder photodynamic therapy (PDT) on a rat model with orthotopic superficial bladder cancer, as PDT is an alternative intravesical therapy for treating superficial bladder cancer, based on an interaction between a photosensitizer and light energy to induce oxygen radicals that destroy tissue by lipid peroxidation. MATERIALS AND METHODS: In all, 76 female Fischer F344 rats were inoculated intravesically with AY-27 tumour cells. After establishing superficial tumour, 24 rats were treated with PDT using aminolaevulinic acid (ALA)-induced protoporphyrin IX as a photosensitizer, and a continuous-wave argon pumped-dye laser (638 nm). At 4 h after intravenous (300 mg/kg) or intravesical (100 mg/mL) administration of ALA the bladders were intravesically exposed to a 40 J/cm(2) light dose; 12 rats received no ALA but were exposed to the same light dose. Before administering ALA, urine cytology samples were taken for analysis. At 3 or 21 days the treated rats were killed and morphological changes in the bladder walls analysed by light microscopy. Forty rats served as controls to examine the presence of tumour. RESULTS: The tumour established in 33 of 40 rats (83%) in the controls, but after PDT with intravesical ALA there was carcinoma in only in one of 12 (P < 0.001, Pearson's chi(2) test). After PDT with intravenous ALA there was carcinoma in five of 11 rats (P = 0.063, Pearson's chi2 test). In the control group of 12 rats receiving only light energy there was carcinoma in three (P = 0.001, Pearson's chi(2) test). Histologically, at 3 days after PDT there was only mild superficial damage in all six rats treated intravesically. Bladder wall destruction reached the muscular layer, with an abscess in one of six rats treated intravenously. After 3 weeks of PDT there was muscular necrosis with perforation and abscess from catheterization two of six rats treated intravesically and in three the bladder wall totally recovered. In the intravenous group the bladder walls were normal or had only mild superficial damage. Cytology of the urine sediment failed to detect half the tumours in the treatment groups. CONCLUSION: These results support the use of PDT with intravesical ALA-induced protoporphyrin X for treating superficial bladder carcinoma. Intravesical was better than intravenous ALA in eradicating bladder carcinoma with PDT.     

Basic studies of photodynamic therapy in experimentally induced canine gastric cancer

Photodynamic therapy (PDT) was used in two cases of experimental canine gastric cancer produced by the oral administration ofN-ethyl-N′-nitro-N-nitrosoguanidine (ENNG). Endoscopic examination and biospy showed the development of cancer in the gastric antrum. The cancerous lesions, a polypoid lesion and the normal epithelium were photoradiated superficially by an argon dye laser with a power of 300 to 400 mW for five to ten 30-s periods, 48 h after the intravenous injection of 3.0 mg/kg body weight of haematoporphyrin derivative (HPD). Dog 1 was killed three days after PDT, and was examined histologically. The tumour cells showed vacuolar degenerative changes in the mucosa, and the irradiated normal epithelium was less damaged. Dog 2 was followed up periodically by means of gastrofibrescope and biopsy. A wider and deeper ulcerative lesion was observed three days after PDT and it was healed by day 40. But the recurrence of a cancerous lesion was shown on day 80. The remnant of a small cancer nest was revealed histologically by means of biopsy and autopsy. The results show that PDT is suitable for superficial gastric cancer and that long-term follow-up observation is necessary for the evaluation of PDT.     

Photodynamic therapy of C3H tumours in mice: Effect of drug/light dose fractionation and misonidazole

C3H mammary carcinomas transplanted to the feet of mice were treated with haematoporphyrin derivative (HPD) or Photofrin II(PII) and laser light at 630 nm. While fluence rates lower than 100 mW cm⁻² gave minimal hyperthermic effects, a slight but significant growth delay was observed in unsensitized tumours exposed to a fluence rate of 150 mW cm⁻² which induced tumour temperatures in the range 40–50°C. Different modes of fractionation of the light fluence and of the HPD dose were tested but were found to give poorer rather than better results than the application of a single light exposure 24 h after intraperitoneal injection of HPD. Different PII doses were applied together with different light fluences, keeping the product of the drug dose and light fluence constant. In the dose range 6.25–50 mg/kg body weight the resulting effect on tumours was constant, allowing for a slight effect of hyperthermia at the highest light fluences, and possibly a photodegradation of PII. Misonidazole given before photodynamic treatment (PDT) slightly reduced the effect of PDT on the tumour growth. When given after PDT, however, misonidazole improved the therapeutic results significantly.     

Toxicity of photodynamic therapy after combined external beam radiotherapy and intraluminal brachytherapy for carcinoma of the upper aerodigestive tract

BACKGROUND AND OBJECTIVE: To describe the toxicity of photodynamic therapy (PDT) in patients with carcinoma of the upper aerodigestive tract who received prior treatment with external beam irradiation and intraluminal brachytherapy (IB). STUDY DESIGN/MATERIALS AND METHODS: Hospital records of PDT patients were reviewed. Three patients who received prior treatment with external beam irradiation and IB were identified. Two patients had esophageal carcinoma treated with combined chemotherapy and external beam irradiation (55.8 and 50.4 Gy) followed by IB (12 Gy and 35 Gy at 1 cm). These patients then received PDT for treatment of recurrence (2 mg/kg Photofrin injection and 2 light applications: 630 nm, 150--200 J/cm, 200--400 mW/cm). One patient had non-small cell lung cancer treated with external beam irradiation (60 Gy) followed by IB (36.1 Gy at 1 cm) and then received PDT for recurrence (1 mg/kg Photofrin injection and one light application: 630 nm, 150 J/cm, 200 mW/cm). RESULTS: One patient with esophagus cancer had formation of a tracheoesophageal fistula, which required stent placement. The other esophageal cancer patient developed quadriplegia due to an epidural abscess arising from a fistula with the diseased portion of the esophagus. The lung cancer patient had massive hemoptysis after the procedure and died 2 days later. Autopsy showed necrotizing arteritis of the right pulmonary artery. CONCLUSION: Patients with upper aerodigestive tract carcinoma who have received treatment with both external beam irradiation and IB seem to be at higher risk for complications when treated with PDT.     

Synergistic enhancement of the efficacy of the bioreductively activated alkylating agent RSU-1164 in the treatment of prostatic cancer by photodynamic therapy

Bioreductively activated alkylating agents (BAA) require metabolic reduction to become cytotoxic. Hypoxia induces a massive increase in reductive metabolism activating BAA to their cytotoxic form. One of these BAA agents is cis-2,3-dimethyl 1-(2-nitro-1-imidazolyl)-3-(1-aziridinyl)-2-propanol referred to as RSU-1164. In a hypoxic environment, RSU-1164 is activated to a highly reactive bifunctional alkylating agent capable of crosslinking macromolecules which results in cell death. Photodynamic therapy (PDT) is a treatment modality which consists of the initial accumulation of hematoporphyrin derivative (HPD) within a tumor followed by the activation of the HPD by 630 nm. light to induce a cytotoxic response. The precise mechanism of PDT is not known, however, two actions of the activated HPD have been documented. The first is a direct cytotoxic effect, secondary to singlet oxygen production. The second is through vascular collapse and subsequent hypoxia. The combination of a chemotherapeutic agent like RSU-1164, which is activated by hypoxia, with PDT to produce such hypoxia, therefore, should greatly increase the efficiency and utility of RSU-1164. To test this hypothesis, Copenhagen rats bearing established Dunning R-3327 AT-2 prostate cancers were treated with PDT treatment alone (HPD 20 mg./kg. injected IP and then 24 hr. later, the tumor exposed to 630 nm. light at 400 mW/cm.2 for 30 min. [total dose 720 J/cm.2]), RSU-1164 alone (injected IP at a dose of 200 mg./kg.) or with the combination of this PDT treatment plus RSU-1164 given 30 min. before light exposure. These results demonstrated that this combinational treatment synergistically produces a greater retardation in the growth of the AT-2 tumor than either of the monotherapies of RSU-1164 or PDT alone.