Administration Of Photofrin Research Articles

Photofrin® photodynamic therapy with intratumor photosensitizer injection provides similar tumor response while reducing systemic skin photosensitivity: Pilot murine study.

The goal of this study was to compare tumor response to Photofrin® photodynamic therapy using intravenous and intratumoral injection of photosensitizer. Systemic skin photosensitivity and photosensitizer distribution were also compared between the two delivery methods. SCCVII tumors were initiated in the hind legs of female C3H mice and grown to a volume of ∼1,000 mm3 . Photofrin® was delivered intravenously via the tail vein at a concentration of 2 mg/kg or intratumorally at concentrations ranging from 0.5-2 mg/kg. A 630 nm laser illumination was delivered via interstitial diffuser placement at a fluence rate of 400 mW/cm and fluence of 100 J/cm. Mice were maintained under normal room lighting for 24 hours after treatment, at which point photographs were captured for assessment of skin photosensitivity. Animals were then sacrificed, and their tumors were excised, sectioned, imaged, and stained with hematoxylin and eosin (H&E). H&E slides were imaged to assess necrosis post-PDT, and skin photographs were evaluated by two blinded reviewers for quantification of skin photosensitivity. Whole-body fluorescence imaging was performed before and after photodynamic therapy. Tumor necrosis was not significantly different based on treatment group (P = 0.33), while skin photosensitivity was significantly reduced in animals that received Photofrin® intratumorally (P = 0.0005). Fluorescence imaging revealed similar photosensitizer fluorescence in excised tumors for intratumor and intravenous injection of Photofrin® (P = 0.48), although fluorescence decreased significantly with decreasing intratumor injection concentration (P= 0.01). This pilot study shows that intratumoral administration of Photofrin® has the potential to produce similar tumor outcomes, while reducing systemic skin photosensitivity. Further studies are warranted to characterize and optimize intratumor delivery. Lasers Surg. 50:476-482, 2018. © 2017 Wiley Periodicals, Inc.

Effect of high fluence light emitting diode mediated photodynamic therapy with Photofrin II on high-grade solid tumor model

Backgrounds: Low fluence rates enhance tumor oxygenation sustenance during photodynamic therapy (PDT) but they are not acceptable for surgery due to the prolonged treatment time. This study examinedwhether high fluence rate PDT is efficient in treating solid tumors by reducing the intraoperative time. Methods:Oral squamous cell carcinoma (KB cells) was implanted subcutaneously into nude mice (Balb/c nu/nu). The tumor was irradiated 24 h after the administration of Photofrin II (10mg/kg) and the fluence rate was ranged from 360 J/cm2 to 600 J/cm2 using a prototype light emitting diode (LED) lamp equipped with a cooling system. Results: The emission peak of the prototype LED lamp was located at approximately 630 nm and the temperature of the LED head module was 25 ◦C. At a 600 J/cm2 light dose (500mW/cm2 for 20min), 72% complete tumor remission was observed, whereas 34% and 58% tumor remission at 360 J/cm2 and 410 J/cm2, respectively. Conclusion: High fluence PDT with a high concentration of photosensitizer can be applied to clinical treatments to reduce the intraoperative treatment time dramatically.

Retrospective study of photodynamic therapy vs photodynamic therapy combined with chemotherapy and chemotherapy alone on advanced esophageal cancer

To compare the short-term curative effect of photodynamic therapy (PDT), PDT combined with chemotherapy and chemotherapy alone on the advanced esophageal cancer patients. Retrospective analysis of 90 patients of esophageal cancer underwent PDT, PDT combined with chemotherapy and chemotherapy alone from 2004 to 2007 (stages III-IV), including 27 cases received PDT alone, 33 cases received PDT combined with chemotherapy and 30 cases chemotherapy alone. The enrolled patients were treated with intravenous administration of Photofrin as the photosensitizer at a dose of 2mg/kg. 630 nm laser irradiation was performed through optical fiber that passed through the biopsy channel of a flexible endoscope after 48 h. Two days later, the necrotic tissue was removed, and the primary sites and other newly identified lesions were subjected to a second irradiation and then the residual necrotic tissue was removed according to the patients' condition. Electronic endoscopy was performed to observe the effectiveness on tumor after 1 month. In PDT combined with chemotherapy group, chemotherapy regimen was 5-FU and DDP, administered 4 cycles after PDT and chemotherapy alone group only chemotherapy regimen 5-FU and DDP for four cycles. All the 90 patients were followed up for 2 years. Symptomatic palliation rate of the PDT alone group, the complex treatment group and chemotherapy alone group was 85.2%, 93.9% and 60.0%, respectively, and effective rate under endoscopy was 85.2%, 90.9% and 63.3%, respectively, there is no statistically significant difference; the survival rate of 2 years was 29.6%, 54.5% and 16.7%, respectively, and medium survival time is longer (III stages 13 m, 22 m, 10 m; IV stages 7 m, 5m, 4m), there is statistically significant difference (p=0.046). PDT combined with chemotherapy for the advanced esophageal cancer is superior to PDT alone and chemotherapy alone.

Ultrasound Dose Fractionation in Sonodynamic Therapy

Sonodynamic therapy (SDT) is a new modality in cancer therapy and it is based on preferential uptake and/or retention of a sonosensitizing drug in tumor tissues and subsequent activation of the drug by ultrasound. The dose fractionation effect in radiation therapy has been known for more than a century, but it is not reported in SDT so far. In this study, the in vivo antitumor effect of the simultaneous dual-frequency ultrasound (1 MHz and 150 kHz) at low-level intensity (cumulative I SATA = 2.2W/cm 2; total energy density 3960J/cm 2; for 30 min sonication) in combination with the sonosensitizer of photofrin (PF) (sodium porfimer) was investigated in dose fractionation regime in a spontaneous murine model of breast adenocarcinoma in Balb/c mice. The tumor-bearing mice were divided into six groups (n = 8 to 10): Untreated groups included control and sham; experimental groups were treated with 5 mg/kg intravenous injection of PF alone, with combined PF and ultrasound for 30-min sonication in one fraction at 24 h after PF administration; with combined PF and ultrasound for 30 min sonicatin in three fraction at 18, 24 and 30 h after PF administration; and finally with combined PF and ultrasound for 30 min sonication in five fraction at 12, 18, 24, 30 and 36 h after PF administration. The tumor growth delay (TGD) parameters and the percent of apoptotic index AI (%) were measured in treated and untreated groups. The results show that the TGD parameters in treatment groups with combined drug and ultrasound fractionation mode were significantly different compared with other groups ( p < 0.05). Also the sonodynamic ultrasound dose fractionation in five fractions is more effective than of the three-fraction regime. The AI of the tumor tissues treated by ultrasound dose fractionation was also significantly higher in the other groups ( p < 0.05), in which the AI (%) in the group treated with five fractions was higher with respect to group treated with 3 fractions (11.56 ± 1.2; 8.7 ± 0.87), respectively. In conclusion, the ultrasound dose fractionation can be useful in therapeutic effect in SDT and may have future clinical applications. (E-mail: ah_barati@yahoo.com)

Antitumor effect of photodynamic therapy in mice using direct application of Photofrin dissolved in lidocaine jelly

Photodynamic therapy (PDT) is a non-invasive cancer therapy that has a strong antitumor effect with intravenous administration of Photofrin. However, Photofrin causes light hypersensitivity that impairs the quality of life (QOL) of patients, and thus an improved method of administration is needed. Here, we report the antitumor effect of local administration of Photofrin in combination with a vasodilator, lidocaine hydrochloride. The antitumor effect was investigated in nude mice transplanted with HeLa cells. An incision was made near the tumor and Photofrin dissolved in lidocaine jelly was applied directly to the tumor. The tumor was irradiated at 100 J/cm(2) with a yttrium aluminum garnet (YAG)-dye laser (630 nm) at 2 h after the direct application and the tumor volume was measured for 30 days after PDT to investigate the antitumor effect. In some mice, the tumor was excised 24 h after PDT and the depth of necrosis was measured in the excised specimen. The tumor was mostly necrotized by PDT following direct application of 10 mg/ml Photofrin dissolved in lidocaine jelly and the effect was greater than with direct application of Photofrin alone. The increase in tumor volume observed in control mice was significantly inhibited in mice that received PDT after direct application of Photofrin in lidocaine jelly. PDT using direct application of Photofrin in lidocaine jelly has a strong antitumor effect in mice and this approach may avoid the adverse effects of systemic Photofrin administration.

Clinical study of Photofrin photodynamic therapy for the treatment of relapse nasopharyngeal carcinoma

To evaluate the clinical response and adverse effects of Photofrin photodynamic therapy (PDT) in patients with relapse nasal pharyngeal cancer. Thirty patients with relapse nasal pharyngeal cancer were randomly divided into PDT group and chemotherapy group. In PDT group, patients received intravenous administration of Photofrin (2mg/kg b.w.) and 48h later light (200-300J/cm) was delivered by a 630nm diode laser through a cylinder diffuser under endoscopic assistance. Two days after PDT the necrotic tissues were removed and newly identified sites were subject to another round of light irradiation. In chemotherapy group, the routine cisplatin and 5-fluorouracil (DDP/5-FU) remedy was used. Endoscopic and radiological examinations were performed during 6 months follow-up. The Karnofsy Score was used to evaluate the quality of life. The local response and nasal cavity obstruction remission rate in PDT group were better than that in chemotherapy group. The Karnofsy Score was also improved in PDT group. This pilot study suggests that Photofrin PDT is effective and safe in treatment of advanced nasal pharyngeal cancer and management of nasal obstruction.

Topical use of liposomal copper palmitate formulation blocks porphyrin-induced photosensitivity in rats

Photodynamic therapy (PDT) is a new treatment modality that uses porphyrin derivatives and visible light, especially for the treatment of cancer. However, PDT with certain photosensitisers can cause prolonged skin photosensitization. This is particularly true for Photofrin II (Photofrin)-mediated PDT where patients are required to avoid direct exposure to sunlight for a period of 4–6 weeks. This is the only long-term adverse reaction to the drug. Recent studies have shown that topical copper treatment avoids this type of inflammatory reaction. In this study, we have tested the efficiency of the liposomal formulation of copper palmitate on porphyrin-photosensitized rats. Initially, adult male Sprague–Dawley rats were rendered photosensitive either by administration of Photofrin or aminolevulinic acid (ALA), a precursor of protoporphyrin IX (PpIX). Prior to this, their dorsal skin was shaved and treated topically with a cream consisting of either empty or copper palmitate-encapsulated liposomal formulation. After being kept in a dimmed light environment, the rats were exposed to visible light, and inflammatory responses were inspected. Histological studies revealed that no inflammatory cells were present at the skin sites treated with liposomal cream containing copper palmitate in the Photofrin-sensitized group while no reduction in the number of inflammatory cells was observed at the skin samples treated with the empty liposomes. In conclusion, the data demonstrate the significant protective effect of topically-applied liposome-encapsulated copper palmitate against both Photofrin and ALA-induced PpIX photosensitivity.

Photodynamic therapy for peripheral lung cancer

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

Photodynamic therapy (PDT) in esophageal cancer: a surgical view of its indications based on 14 years experience.

The aim of this paper is to present the updated experience of the Yorkshire Laser Centre in PDT for esophageal cancer and to identify its role in specific subsets of patients. Also, in the light of this experience, to compare and contrast the results of PDT with appropriate subsets of patients treated in my esophageal surgery practice. 102 consecutive patients; 84 with advanced (Group A) and 18 with early (Group E) stage esophageal cancer undergoing endoscopic PDT were entered into a prospective study. Every patient had standard work up including clinical staging. PDT protocol was intravenous administration of Photofrin 2mg/kg body weight followed 24-72 hours later by endoscopic illumination using 630 nm laser light. Assessment of results was made on the basis of mortality, morbidity, patient satisfaction to treatment, symptom relief and survival. For comparison of PDT role with non PDT treated patients, reference is made to 3 previous publications comprising over 1100 patients [Moghissi, K., Br. J. Surg. 79, 935-937 (1992) (ref. 1); Sawant, D., Moghissi, K. Eur. J. Cardio-Thorac. Surg. 8, 113-117 (1994) (ref. 2); Sharpe, D. A. C., Moghissi, K. Eur. J. Cardiothorac. Surg. 10, 359-364 (1996) (ref. 3)]. There was no mortality associated with PDT. All patients expressed satisfaction to treatment. Post PDT complications consisted of photosensitivity skin reaction (sunburn) in 5 patients (5%) and esophageal stricture in 8 (8%) patients. Group A: There was significant symptom and dysphagia grade improvement. Mean survival was 9.5 months. Group E: There were no significant symptoms pre or post PDT and mean survival was 60.5 months. Comparison of PDT results in Group A with results of other palliative treatment methods, indicates that palliation can be achieved in all intraluminal cancer using PDT which is at least as good as other treatments. There is, in addition, advantage over other methods in patients with cervical esophageal cancer and in cases with re-growth of tumor obstructing previously placed stents. In early cases PDT appears capable of replicating surgical results in selected cases. PDT is an effective and safe treatment method in esophageal cancer. In advance disease it improves swallowing. In early stage disease it offers long survival and the prospect of cure in some patients. At present the role of PDT in early stage cancer should be limited to patients who are unsuitable for surgical resection. Therefore, PDT should be considered as a valid oncological option to be applied in selected cases.

Liposomal photofrin enhances therapeutic efficacy of photodynamic therapy against the human gastric cancer

Photodynamic therapy (PDT) has been established as a potent and less invasive treatment for gastrointestinal tumors. The aim of the present study was to investigate whether or not liposomalization of the photosensitizer enhanced the therapeutic efficacy of PDT. Photofrin (PF) was entrapped in multilammelar liposomes. Mice implanted with a human gastric cancer xenograft, were divided into a PF group and a liposomal photofrin (LPF) group and intravenously administered 10 mg/kg of PF or LPF (as a dose of PF), respectively. At 8 h after injection PF level in tumor tissue in the LPF group was significantly higher level by 2.4-fold of that in the PF group, whereas the PF levels in the skin were almost equal. Irradiation was performed with the excimer dye laser at 150 mW/cm 2, total dose 40 J, at 8 h after PF or LPF administration. The results revealed that the volume of necrotic tumor tissue was significantly higher in the LPF group than in the PF group. The apoptotic index of the tumor was also significantly higher in the LPF group. In conclusion, the liposomalization of the photosensitizer increased its tumor accumulation, with a resulting enhancement of the therapeutic effect of PDT.

Safe Use of Pulse Oximetry During Verteporphin Therapy

Photodynamic therapy (PDT) is a relatively uncommon treatment modality, which is occasionally used intraoperatively at extraocular sites. Verteporphin is a photosensitizing chemotherapeutic drug used in PDT that is activated by exposure to red light in the presence of oxygen (1). The resulting free-radical damage can selectively destroy tissues that preferentially take up verteporphin and are exposed to appropriate wavelengths and intensities of light. PDT is most commonly used to treat neovascularization associated with macular degeneration. Laser diodes at 690 nm are often used as a light source for PDT, which is near the absorption peak of verteporphin (689 mn). Verteporphin is also finding new uses in the treatment of intracranial malignancies. PDT may present significant difficulties for patient care because patients remain photosensitive for 5 days after the administration of verteporphin. Photofrin (porfimer sodium), a similar, but longer lasting drug, results in 30 to 90 days of photosensitivity after administration (2). Standard 2-wavelength pulse oximeters emit light at 660 nm, which is within the range that can activate photofrin, and is close to the absorption maximum of verteporphin. Farber et al. (3) reported that prolonged exposure to pulse oximetry caused second-degree nonthermal skin “burns” after photofrin administration, although healing occurred without skin grafting. In a similar report, a second-degree “burn” resulted in loss of a fingernail (4). During a clinical trial, cutaneous injury developed in several volunteers (5), prompting several letters as well as a newspaper article, which produced serious financial repercussions for the manufacturer of a similar photosensitizing drug (6–11). Some of these reports highlighted the need to give close attention to the injection technique and drug preparation, because some compounds are highly insoluble in water and may precipitate upon injection with local injury (12). During the photosensitive period, patients are normally kept in dark environments, and extravasation of the drugs on injection may require shielding from sunlight for much longer than the usual photosensitive period. Of major concern for anesthesiologists is that perioperative lighting requirements for avoidance of cutaneous damage result in conditions in which lighting is insufficient to observe for cyanosis. The avoidance of pulse oximetry because of the risk of skin damage may pose additional hazards because of the inability to adequately monitor oxygenation. We adopted the following use of pulse oximetry for a patient with satisfactory results. Case Report A 53-year-old man with a recurrent left parietal malignant meningioma was scheduled for intracranial resection and intraoperative photochemotherapy with verteporphin. After the induction of general anesthesia, positioning of the patient, and exposure of the tumor, 32 mg of verteporphin was administered IV over 10 min. The room lighting was kept on for the first 30 min after the administration because of surgical requirements. Because room lighting enabled our assessment of the patient’s skin color visually during this time, we attempted to minimize patient exposure to pulse oximetry by performing intermittent checks for periods of a few seconds at intervals of 5–10 min. Although we recognize that pulse oximetry is superior to visual inspection of skin color, intermittent pulse oximetry still allowed us to identify small, long-term changes in oxygen saturation that would not be otherwise apparent. After this time, the operating room lights were turned off to avoid cutaneous damage. Continuous pulse oximetry was then used at rotating sites for the remainder of the 6-h surgical procedure, allowing only 7–15 min intervals at each site. We chose to use each phalanx as one site, allowing a potential for 14 different sites on each hand and foot. Each site was marked to avoid reuse on a subsequent occasion. Daily patient observation for 5 inpatient days, and telephone contact 2 weeks postoperatively, confirmed no cutaneous injury. Although no specific protocols have been promoted by the manufacturers of the photosensitizing drugs or pulse oximeters for use in the above situation, we found that limited use of pulse oximetry during the most critical aspects of anesthesia care can be performed without pulse oximeter-induced cutaneous damage. One should always be aware that published experience on the safe use is limited, and unstudied factors may increase the potential for skin damage in this situation. Although photofrin may require administration long in advance of PDT, verteporphin can be administered immediately before intraoperative PDT, and therefore is likely to be administered by anesthesiologists. Because anesthesiologists may not have experience or training in the administration of chemotherapy, attention to existing protocols and specific knowledge of each drug is essential to avoid injury to either patient or physician.

Photoirradiation therapy of experimental malignant glioma with 5-aminolevulinic acid

Accumulation of protoporphyrin IX (PPIX) in malignant gliomas is induced by 5-aminolevulinic acid (5-ALA). Because PPIX is a potent photosensitizer, the authors sought to discover whether its accumulation might be exploited for use in photoirradiation therapy of experimental brain tumors, without injuring normal or edematous brain. Thirty rats underwent craniotomy and were randomized to the following groups: 1) photoirradiation of cortex (200 J/cm2, 635-nm argon-dye laser); 2) photoirradiation of cortex (200 J/cm2) 6 hours after intravenous administration of 5-ALA (100 mg/kg body weight); 3) cortical cold injury for edema induction; 4) cortical cold injury with simultaneous administration of 5-ALA (100 mg/kg body weight) and photoirradiation of cortex (200 J/cm2) 6 hours later; or 5) irradiation of cortex (200 J/cm2) 6 hours after intravenous administration of Photofrin II (5 mg/kg body weight). Tumors were induced by cortical inoculation of C6 cells and 9 days later, magnetic resonance (MR) images were obtained. On Day 10, animals were given 5-ALA (100 mg/kg body weight) and their brains were irradiated (100 J/cm2) 3 or 6 hours later. Seventy-two hours after irradiation, the brains were removed for histological examination. Irradiation of brains after administration of 5-ALA resulted in superficial cortical damage, the effects of which were not different from those of the irradiation alone. Induction of cold injury in combination with 5-ALA and irradiation slightly increased the depth of damage. In the group that received irradiation after intravenous administration of Photofrin II the depth of damage inflicted was significantly greater. The extent of damage in response to 5-ALA and irradiation in brains harboring C6 tumors corresponded to the extent of tumor determined from pretreatment MR images. Photoirradiation therapy in combination with 5-ALA appears to damage experimental brain tumors selectively, with negligible damage to normal or perifocal edematous tissue.

Detection of Photofrin Fluorescence From Malignant and Premalignant Lesions in the Bronchus using a Full‐color Endoscopic Fluorescence Imaging System

Study objectives: To detect invisible lung cancer and to determine field of laser radiation during PDT we developed a full-color fluorescence fiberscopic system. We tested the efficacy of this system in patients with various bronchial malignancies. System design: A fiber-optic endoscope was attached to a camera box containing a color ICCD camera which can detect from 400 to 700nm fluorescence in full-color. Light of average wavelength 405 nm was selected and radiated through the light channel of the fiberscope from a 300W Xenon lamp. Patients and methods: We examined nine consecutive patients with bronchial malignancy admitted in our hospital to receive PDT. Sixteen lesions in these nine patients were observed with white light and excitation light and the results were compared. Histological examinations were done by taking biopsy specimens and samples for pathological and cytological examination. After the diagnosis was confirmed, 2.0 mg/kg Photofrin was injected. Forty eight hours after the administration of Photofrin, observation of the bronchial wall was made using a full-color endoscopic fluorescence imaging system just before PDT. Results: Bright red fluorescence from Photofrin was Observed in 14/14 bronchial malignancies: 3 squamous cell carcinoma, 9 squamous cell carcinoma in situ, 1 metastatic breast cancer and 1 metastatic islet cell tumor. Bright red fluorescence was also detected in 2/2 squamous dysplasia. Green autofluorescence was observed in the normal part of the bronchus. Conclusions: Results of the present study suggest that the full-color endoscopic fluorescence imaging system can be used to detect malignant and premalignant lesions as red fluorescence against green autofluorescence with Photofrin administration, and this system has the potential to detect absence of autofluorescence in cancerous lesions.

Potentiation of the anti-tumour effects of Photofrin-based photodynamic therapy by localized treatment with G-CSF.

Photofrin®-based photodynamic therapy (PDT) has recently been approved for palliative and curative purposes in cancer patients. It has been demonstrated that neutrophils are indispensable for its anti-tumour effectiveness. We decided to evaluate the extent of the anti-tumour effectiveness of PDT combined with administration of granulocyte colony-stimulating factor (G-CSF) as well as the influence of Photofrin®and G-CSF on the myelopoiesis and functional activity of neutrophils in mice. An intensive treatment with G-CSF significantly potentiated anti-tumour effectiveness of Photofrin®-based PDT resulting in a reduction of tumour growth and prolongation of the survival time of mice bearing two different tumours: colon-26 and Lewis lung carcinoma. Moreover, 33% of C-26-bearing mice were completely cured of their tumours after combined therapy and developed a specific and long-lasting immunity. The tumours treated with both agents contained more infiltrating neutrophils and apoptotic cells then tumours treated with either G-CSF or PDT only. Importantly, simultaneous administration of Photofrin®and G-CSF stimulated bone marrow and spleen myelopoiesis that resulted in an increased number of neutrophils demonstrating functional characteristics of activation. Potentiated anti-tumour effects of Photofrin®-based PDT combined with G-CSF observed in two murine tumour models suggest that clinical trials using this tumour therapy protocol would be worth pursuing. © 2000 Cancer Research Campaign

Tumor blood-flow changes following protoporphyrin IX-based photodynamic therapy in mice and humans

The effects of aminolevulinic acid (ALA)-based photodynamic therapy (PDT) on tumor blood flow are controversial. This study examines the effects of ALA and Photofrin-based PDT on blood flow of Colon-26 tumors implanted in mice as well as the effects of ALA-based PDT on blood flow of human colorectal carcinomas and a carcinoid tumor in situ. Tumors are implanted in both flanks of mice. One tumor of each animal serves as a control. Blood flow is measured using a laser Doppler method. Tumor blood flow in mice not receiving a photosensitizer but treated with three different light fluences (50, 100 and 150 J/cm 2) does not differ significantly from blood flow in the untreated tumor in the opposite flank. PDT after ALA administration using the three different light fluences does not significantly affect blood flow. In contrast, PDT after Photofrin administration causes a significant decrease in tumor blood flow with each light fluence, but this change is not as dramatic as reported in other studies. In contrast to mice, six patients who receive ALA prior to surgery all show a decrease in blood flow (mean=51.8%, p<0.001) after PDT using 100 J/cm 2. Comparison with other published results suggests that it is likely that flow measurement by the laser Doppler method underestimates the effects of PDT on tumor blood flow due to the depth of laser penetration. Nevertheless, the present observations on blood flow suggest that the effects of ALA-based PDT on adenocarcinomas of the colon and rectum as well as an intra-abdominal carcinoid tumor in humans are more pronounced than would be predicated by some animal studies.

Distribution and pharmacokinetics of Photofrin in human bile duct cancer.

Prognosis of patients with bile duct tumors is mostly poor due to late diagnosis and a lack of adequate curative and palliative treatment modalities. To evaluate the potential of photodynamic therapy (PDT) as a novel and alternative treatment approach, we have investigated the uptake and tumor-specific localization of the photosensitizer Photofrin in human biliary tract neoplasms. We have quantified the distribution and the pharmacokinetics of Photofrin in normal and tumor tissue biopsies of the human bile duct by quantitative fluorescence microscopy and digital image analysis of cryosections. Fluorescence intensities (expressed as a percentage of a standard) are 19.0 +/- 11.4% and 25.2 +/- 12.7% for tumors and 10.9 +/- 2.9% and 13.2 +/- 9.1% (mean +/- SD) for normal bile duct tissue at 24 h (n = 5) and 48 h (n = 8) after Photofrin administration (2 mg kg-1 i.v.), respectively, and decrease afterwards in normal bile duct tissue over the period of investigation (4-35 days). The ratios of fluorescence in tumor versus normal tissue are found to be 1.7 +/- 0.7 and 2.3 +/- 1.2 (mean +/- SD) at days one and two after Photofrin administration, respectively. Thus, Photofrin preferentially accumulates in bile duct neoplasms, reaching peak values during the first two days. These data suggest that laser irradiation should be performed within this period after Photofrin injection to achieve tumor selectivity of PDT for effective treatment of bile duct carcinoma.

Phase I trial of photo dynamic therapy in the treatment of recurrent superficial transitional cell carcinoma of the bladder

Objectives A Phase I trial of photodynamic therapy (PDT) in the treatment of superficial transitional cell carcinoma (TCC) of the bladder was performed. Methods Twenty patients with recurrent superficial TCC of the bladder after receiving a mean of 2.6 (range 1 to 6) courses of intravesical therapy were treated with PDT. The photosensitizer Photofrin II dose was 1.5 or 2.0 mg/kg. A 630-nm intravesical red laser was used to activate the photosensitizer 2 days after administration of Photofrin II. A 0.01 % intralipid solution was used as a bladder-filling medium to scatter light and achieve more homogeneous light distribution. Light doses from 5.1 to 25.6 J/cm 2 (total dosage 1500 to 5032 J) were used to illuminate the bladder. Results Twenty patients underwent 21 treatments with PDT. Complications included asymptomatic reflux in 4 patients. One other patient, treated at the highest total light dose, experienced bladder contraction and fibrosis. Nine patients (45%) had no tumor evident at cystoscopy, on random biopsies, or in urinary cytology at the 3-month evaluation after treatment. Four patients remained without recurrent disease for 23 to 56 months. Sixteen of 20 (80%) patients experienced recurrence, and 8 of the 16 underwent cystectomy. Conclusions An intravenous photosensitizer dose of 1.5 mg/kg Photofrin II followed by light energy in the range of 13 J/cm 2 (total light dose 2500 to 3250 J) was defined as a safe treatment parameter and resulted in tumor responses. With present technologies, administration of PDT requires careful dosimetry.

Photodynamic therapy of 9L gliosarcoma with liposome-delivered photofrin.

The effect of Photofrin encapsulated in a liposome delivery vehicle for photodynamic therapy (PDT) of the 9L gliosarcoma and normal rat brain was tested. We hypothesized that the liposome vehicle enhances therapeutic efficacy, possibly by increasing tumor tissue concentration of Photofrin. Male Fisher rats bearing a 9L gliosarcoma were treated 16 days after intracerebral tumor implantation with either Photofrin in dextrose (n = 5) or Photofrin in liposome (n = 6). Nontumor-bearing animals were treated with Photofrin delivered either in dextrose (n = 4) or liposome (n = 4) vehicle. Tissue concentrations of Photofrin delivered either in dextrose (n = 4) or liposome (n = 4) vehicle were measured in tumor, brain adjacent to tumor and in normal brain tissue. Photofrin was administered (intraperitoneally) at a dose of 12.5 mg/kg and PDT (17 J/cm2 of 632 nm light at 100 mW/cm2) was performed 24 h after Photofrin administration. Brains were removed 24 h after PDT and stained with hematoxylin and eosin for analysis of cellular damage. The PDT using Photofrin in the liposome vehicle caused significantly more damage to the tumor (P < 0.001) than did PDT with Photofrin in dextrose. The PDT of tumor with Photofrin delivered in liposomes caused a 22% volume of cellular necrosis, while PDT of tumor with Photofrin delivered in dextrose caused only scattered cellular damage. Photofrin concentration in tumors was significantly higher (P = 0.021) using liposome (33.8 +/- 18.9 micrograms/g) compared to dextrose delivery (5.5 +/- 1.5 micrograms/g). Normal brain was affected similarly in both groups, with only scattered cellular necrosis. Our data suggest that the liposome vehicle enhances the therapeutic efficacy of PDT treatment of 9L tumors.

1996 Hoffman–LaRoche Award Lecture Photochemistry and photobiology of perylenequinones

Photodynamic therapy relies on the selective accumulation of photosensitizers within neoplastic tissue, followed by light activation to generate cytotoxic singlet oxygen. At present, PhotofrinTM, a preparation of hematoporphyrin derivatives (HPD) with the bulk of the porphyrin monomers removed, is the only clinically approved photosensitizer. Intravesical administration of Photofrin or HPD has failed to photosensitize bladder tumors. Bladder cancer is the second most common genitourinary malignancy. In 1994 there were an estimated 51 200 cases of bladder cancer with 10 600 deaths in the United States. The predominant histopathology is transitional cell carcinoma, occurring in 90–95% of these cases. Most patients (85%) have superficial disease at the time of initial diagnosis. Superficial bladder cancer is defined as disease involving the mucosa with carcinoma in situ or papillary lesions and invasion limited to submucosa. To address these limitations we have been conducting preclinical studies with perylenequinones (PQs). The majority of our effort has focused on developing and characterizing derivatives of PQs. Following site-directed modifications, we have identified certain congeners that warrant further preclinical development. These compounds are monomeric and do not effect cutaneous photosensitization beyond 24 h. With clinically relevant drug and light doses we have cured &gt;90% of experimental subcutaneous murine tumors. Keywords: photodynamic therapy, perylenequinones, photobiology, photochemistry.

Influence of Photofrin® on the Hematopoietic Accessory Function of Murine Peritoneal Cells

The porphyrin photochemotherapeutic agent Photofrin® stimulates hematopoietic activity within the bone marrow (BM) and spleens of normal mice. We found that the intraperitoneal (i.p.) administration of Photofrin® also caused a 3–4 fold increase in peritoneal cell (PC) numbers, particularly cells bearing granulocyte surface antigens. Little granulocyte-macrophage progenitor activity was detectable within the PC population of control and Photofrin®-injected mice suggesting that Photofrin® had elicited an influx of inflammatory cells into the region. In contrast to cells from control animals, PC obtained 6 h to 168 h after the i.p. injection of Photofrin® exhibited a consistently inferior capacity to support the growth of BM colony forming units granulocyte-macrophage (CFU-GM). When PC from control or Photofrin®-treated mice were added to the BM culture system in the presence of defined growth factors there was no effect on the number of colonies formed. This finding indicated that negative regulatory elements were not responsible for the reduced hematopoietic accessory activity exhibited by PC from Photofrin®-treated mice. Supernatants conditioned by PC from Photofrin®-injected mice poorly supported BM CFU-GM growth in vitro and in contrast to PC supernatants prepared from control mice did not contain detectable amounts of granulocyte-macrophage colony stimulating factor (GM-CSF). The cellular changes which occur within the peritoneal cavity represent bystander events not directly related to the hematostimulatory action of Photofrin®.