A photodynamic therapy combined with topical 5-aminolevulinic acid and systemic hematoporphyrin derivative is more efficient but less phototoxic for cancer.

PURPOSE: Although photodynamic therapy (PDT) has been shown to be effective in cancer treatment, its side effects, such as a long-lasting skin photosensitivity after the application, still cause patient's inconvenience. In this retrospective cohort study, our objective was to explore a more efficient but less phototoxic PDT for skin cancers. METHODS: The PDT combined with a topical photosensitizer 5-aminolevulinic acid (ALA) and an intravenously injected light-sensitive agent hematoporphyrin derivative (HPD) was used to treat 26 patients with 41 skin cancer lesions in head and face. The findings were then compared with the results of the HPD-PDT alone and the ALA-PDT following CO2 laser ablation on 28 and 41 skin cancer patients, respectively. RESULTS: The complete remission rate for the combined PDT was 100 % in 2 months and 97.6 % in a 6 months to 6 years trial after the treatment compared with those of 92.9 and 95.1 % for the HPD-PDT and the ALA-PDT after a single treatment, respectively. Moreover, while the patient treated with the HPD-PDT needs to avoid strong light exposure for 4-5 weeks, the combined PDT significantly reduced the period to 10-14 days. Also, in the combined PDT, the dose of the HPD, a pro-toxic light-sensitive drug, was much lower than that in the HPD-PDT. CONCLUSIONS: The combined PDT not only shows high cure rate for skin cancers but also decreases the dose of the pro-toxic HPD and significantly shortens the photosensitive period, from which the patients are able to benefit.

Safety assessment of oral photodynamic therapy in rats.

Photodynamic therapy (PDT) is based on the synergism of a photosensitive drug (a photosensitizer) and visible light to destroy target cells (e.g., malignant, premalignant, or bacterial cells). The aim of this study was to investigate the response of normal rat tongue mucosa to PDT following the topical application of hematoporphyrin derivative (Photogem®), Photodithazine®, methylene blue (MB), and poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with MB. One hundred and thirty three rats were randomly divided in various groups: the PDT groups were treated with the photosensitizers for 10 min followed by exposure to red light. Those in control groups received neither photosensitizer nor light, and they were subjected to light exposure alone or to photosensitizer alone. Fluorescent signals were obtained from tongue tissue immediately after the topical application of photosensitizers and 24 h following PDT. Histological changes were evaluated at baseline and at 1, 3, 7, and 15 days post-PDT treatment. Fluorescence was detected immediately after the application of the photosensitizers, but not 24 h following PDT. Histology revealed intact mucosa in all experimental groups at all evaluation time points. The results suggest that there is a therapeutic window where PDT with Photogem®, Photodithazine®, MB, and MB-loaded PLGA nanoparticles could safely target oral pathogenic bacteria without damaging normal oral tissue.

[Research progress of the anti-tumor effect of sonodynamic and photodynamic therapy].

Cancer, as a serious threat to human health, is one of the major killers. The treatment of cancer has attracted more and more attention. Currently, the means of treating cancer is also increasing, but there is no emergence of a fully satisfactory treatment. A combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT), named sono-photodynamic therapy (S-PDT), is a new composite cancer therapy. Because the therapy can significantly improve the tumor curing effect, it has good application prospects in cancer prevention and treatment. The present article reviewed the progress of the anti-tumor mechanisms and influencing factors of S-PDT.

Antimicrobial photodynamic action on dentin using a light-emitting diode light source.

OBJECTIVE: The aim of this study was the evaluation of two different photosensitizers activated by red light emitted by light-emitting diodes (LEDs) in the decontamination of carious bovine dentin. MATERIALS AND METHODS: Fifteen bovine incisors were used to obtain dentin samples which were immersed in brain-heart infusion culture medium supplemented with 1% glucose, 2% sucrose, and 1% young primary culture of Lactobacillus acidophilus 10(8) CFU/mL and Streptococcus mutans 10(8) CFU/mL for caries induction. Three different concentrations of the Photogem solution, a hematoporphyrin derivative (1, 2, and 3 mg/mL) and two different concentrations of toluidine blue O (TBO), a basic dye (0.025 and 0.1 mg/mL) were used. To activate the photosensitizers two different light exposure times were used: 60 sec and 120 sec, corresponding respectively to the doses of 24 J/cm(2) and 48 J/cm(2). RESULTS: After counting the numbers of CFU per milligram of carious dentin, we observed that the use of LED energy in association with Photogem or TBO was effective for bacterial reduction in carious dentin, and that the greatest effect on S. mutans and L. acidophilus was obtained with TBO at 0.1 mg/mL and a dose of 48 J/cm(2). It was also observed that the overall toxicity of TBO was higher than that of Photogem, and that the phototoxicity of TBO was higher than that of Photogem. CONCLUSION: Based on our data we propose a mathematical model for the photodynamic effect when different photosensitizer concentrations and light doses are used.

Photodynamic therapy of head and neck basal cell carcinoma according to different clinicopathologic features.

BACKGROUND AND OBJECTIVES: We aimed to treat different pathologic types of basal cell carcinomas (BCCs) using photodynamic therapy (PDT). STUDY DESIGN/MATERIALS AND METHODS: Thirty lesions in six patients underwent PDT. The photosensitizer used was Photoheme, a hematoporphyrin derivative IX. It was injected intravenously at the dose of 2-3.25 mg/kg. After 24 hours, the lesions were illuminated by laser light (lambda = 632 nm, light exposure dose = 100-200 J/cm2). Lesions were evaluated pre and post-operatively and at follow-up sessions (of up to 6 months). RESULTS: After a single session of PDT, the average response rate in different histopathologic kinds of basal cell carcinoma (e.g., ulcerative, superficial, nodular, and pigmented forms) were 100%, 62%, 90%, and 14%, respectively. In patients who responded completely, the cosmetic results were excellent and there were no recurrence at 6th month of follow-up. CONCLUSION: Although PDT seems to be an effective treatment modality for superficial, ulcerative, and nodular BCCs, it is not recommended for pigmented lesions.

Photodynamic therapy of Barrett's esophagus.

Photodynamic therapy seems to be able to control high-grade dysplasia within Barrett's esophagus about 80% of the time. Long-term results are not available, but the treatment is promising. Given the success with surgical intervention, however, use of photodynamic therapy should be reserved for nonsurgical candidates at the current time. The complications that occur with photodynamic therapy are not trivial and must be weighed against the potential benefits.

[Photodynamic therapy of hematoporphyrin derivative on human pancreatic carcinoma cell lines].

OBJECTIVE: To observe the effect of photodynamic therapy (PDT) on human pancreatic carcinoma cell lines in vitro. METHODS: Two lines of human pancreatic carcinoma cell P3 and SW1990 were studied to investigate the killing role of PDT with hematoporphyrin derivative (HPD) as photosensitizer and sodium lamp as light source. The cultured cells were treated with serial concentrations of HPD followed by irradiation of different dosages of visible light, then MTT colorimetric assay was applied to measure the relative inhibitory rate of PDT for the cells. RESULTS: The relative inhibitory rate of PDT for the cells elevated along with the increase in the concentration of sensitizer and dose of light. Under the low photodynamic dose, it increased rapidly, and gradually slowed down to reach the plateau. Under the same photodynamic dose, significant difference in the inhibitory rate between the two lines was observed (P < 0.01), and the LD90 was also different. CONCLUSIONS: PDT has a significant killing effect on human pancreatic carcinoma cell lines in vitro, and its relative inhibitory rate appears to be correlated with the dose of sensitizer and light irradiation. The sensitivity of the two cell lines to PDT is different.

Damage to tumour and brain by interstitial photodynamic therapy in the 9L rat tumour model comparing intravenous and intratumoral administration of the photosensitiser.

In the 9L rat brain tumour model the damage to tumour and normal brain by photodynamic therapy after intratumoural photosensitizer administration (intratumoural PDT) was studied. Twenty four rats received an intratumoural injection of 4 or 40 mm3 haematoporphyrin derivative (HpD, 5 mg ml-1), followed by interstitial irradiation with 20 Joule (J) (630 nm) 5 h later. For comparison, seven rats were treated with 20 Joule 24 h after an intravenous injection of 10 mg kg-1 HpD (intravenous PDT). With the chosen PDT parameters there was no important difference between the damaged areas produced by intratumoural PDT or intravenous PDT. No selective tumour kill was observed. Even though normal brain tissue was heavily damaged, vital tumour parts were still present. Intravenous PDT caused extensive diffuse damage to small blood vessels in tumour and surrounding normal brain. Intratumoural PDT was characterised by an infiltration of polymorphonuclear cells into damaged tissue, dilatation of larger blood vessels and gross haemorrhage. These results suggest an immediate vascular shutdown in the intravenous approach, while in the intratumoural approach the vasculature remained patent initially. Because of the severe side effects observed, the use of HpD seems not advisable for intratumoural PDT of brain tumours.

Mono-L-aspartyl chlorin e6 (NPe6) and hematoporphyrin derivative (HpD) in photodynamic therapy administered to a human cholangiocarcinoma model.

BACKGROUND: Despite their relatively localized nature, the therapy for surgically unresectable cholangiocarcinomas has been largely unsuccessful. Photodynamic therapy is a promising technique for both curative and palliative treatment of this malignancy. The effectiveness of a potential new photosensitizer, mono-l-aspartyl chlorin e6 (NPe6), was compared with that of a traditional drug, hematoporphyrin derivative (HpD), in photodynamic therapy administered to a human cholangiocarcinoma model. METHODS: An established cholangiocarcinoma cell line was inoculated subcutaneously in the left back of male nude mice age 8 weeks. After a predetermined tumor size was reached, the mice were randomly assigned to either a control group or an experimental group. Experimental tumor-bearing mice received either HpD (5 mg/kg or 10 mg/kg) or NPe6 (2 mg/kg, 5 mg/kg, or 8 mg/kg) followed by photoradiation. HpD and NPe6 were administered intraperitoneally at 24 and 2 hours, respectively, prior to light exposure. Photoradiation was conducted using a xenon-mercury arc lamp with a 405-650 nm filter at a light flux of 80 J/cm2. Tumor response was assessed by serial tumor volume measurements. RESULTS: Control mice showed an estimated mean tumor volume doubling rate of 9.0 days. Triaxial tumor measurements correlated well with autopsy measurements (correlation coefficient = 0.9). Overall differences in tumor volume reduction were detected (P < 0.001) among the three groups: HpD, NPe6, and controls (photoradiation only, HpD only, or NPe6 only). The degree of tumor volume reduction was superior for dosages of NPe6 compared with all dosages of HpD (P < 0.05). Although a dose effect was detected (P < 0.05) for HpD and separately for NPe6, a consistent dose-response relationship was not observed for either. Inhibition of tumor regrowth was better for NPe6 compared with HpD. The depth of tissue injury was significantly increased (P < 0.05), by 67%, for 5-8 mg/kg of NPe6 compared with 5-10 mg/kg of HpD. The duration of cutaneous photosensitization was also decreased for NPe6 compared with HpD. CONCLUSION: Photodynamic therapy with HpD or NPe6 was effective inducing tumor regression in the cholangiocarcinoma model in this study. At the dosages studied, NPe6 appeared to induce greater tumor regression than HpD, with decreased tumor regrowth and duration of cutaneous photosensitization.

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.

Photofrin-mediated photodynamic therapy of chemically-induced premalignant lesions and squamous cell carcinoma of the palatal mucosa in rats.

Photodynamic therapy (PDT), an experimental cancer therapy, was studied in an animal model of chemically-induced epithelial dysplasia and squamous cell carcinoma. PDT was performed 24 hours after i.v. injection of 2.5 mg/kg bw Photofrin, and using 100 J/cm2 incident light at two activation wavelengths (514.5 nm or 625 nm). Two days after PDT, the majority of rats macroscopically showed a marked erythema of the entire palatal region. Microscopically all the rats showed oedema, haemorrhage, and necrosis of the epithelium of the intermolar area. The long-term results were not so favourable. No evidence of disease was found in 6 out of 20 rats in the 514.5 nm group and in 2 out of 20 rats in the 625 nm treated group. Epithelial dysplasia was found in 14 out of 20 rats in the 514.5 nm group, and in 18 out of 20 rats of the 625 nm treated group. Squamous cell carcinomas were found in 4 out of 20 rats treated with 514.5 nm and in 7 out of 20 rats in the 625 nm treated groups. Comparing both treatment wavelengths, better results were obtained in the 514.5 nm groups as this wavelength gave less normal tissue damage. Based on the results of this study the application of PDT for the treatment of field cancerization and squamous cell carcinoma of the oral cavity, is discussed.

Photodynamic therapy and hyperthermia as an adjuvant modality in preventing tumor recurrence.

BACKGROUND AND OBJECTIVE: The objective of this study was to determine the relative efficacy in preventing tumor recurrence by photodynamic therapy (PDT), and by ablative CO2 laser surgery followed by PDT, compared to ablative surgery alone (negative control) or ablative surgery followed by a course of hyperthermia (positive control). STUDY DESIGN/MATERIALS AND METHODS: The cheek pouches of 36 hamsters were treated with 0.5% 9,10 dimethyl-1,2-benzanthracene in acetone three times a week. After 12 weeks all animals showed tumors of their cheek pouches and were divided into four groups. In groups number I, II, and III, all visible tumors were removed by aid of a CO2 laser. Animals of group I did not receive any further treatment. After tumor resection, the cheek pouches in group II were treated with hyperthermia by aid of a Nd:YAG laser and a temperature of 43 degrees C for 30 minutes. In group III after resection of the tumors, the cheek pouches were treated with PDT (75mW/cm2 175J/cm2--3mg/kg Photofrin i.p./24h). In group IV, the tumors were not excised, instead they were only treated with PDT (as above). All animals were observed for 50 days for any signs of tumor recurrence. RESULTS: In group I (CO2) all tumors (100%) recurred within 50 days. In group II (CO2 + hyperthermia) 61%, in group III (CO2 + PDT) 27.7%, and in group IV (PDT) 50% of all tumors recurred. The first signs of recurrence could be seen in group I, followed by groups II and IV. Group III was the last one presenting tumor recurrence. CONCLUSIONS: The combination of CO2 surgery and PDT produced significantly better results than CO2 surgery or PDT alone, and better than the combination of CO2 surgery and hyperthermia.

Photodynamic therapy with systemic administration of photosensitizers in dermatology.

We have reviewed the results of clinical investigations into the use of photodynamic therapy (PDT) with intravenous injection of hematoporphyrin derivative (HpD), Photofrin (PF) and Sn-protoporphyrin (Sn-Pp) or oral administration of delta-aminolevulinic acid in the treatment of skin cancers and/or psoriasis. Bowen's disease was highly responsive, provided that adequate light and HpD or PF doses were delivered. In contrast, poor results were shown for squamous cell carcinoma, and the rates of complete response of basal cell carcinoma ranged between 0% and 100%. Treatment failures could be related to the delivery of low drug and/or light doses, but differences in the thickness and pigmentation of the treated lesions may play a relevant role. Good palliation was almost always achieved in patients affected by primary and secondary breast carcinomas, although complete eradication of tumors was very rare. PDT is a very promising treatment modality for both Mediterranean and HIV-related Kaposi's sarcoma, because it appears to be effective, can be repeated and is not associated with immunosuppressive activity or significant systemic toxicity. PDT of psoriasis with low doses of Sn-Pp, HpD or PF plus UVA light and PF plus 630 nm light proved to be effective and was associated with mild, dose-related and reversible photosensitivity.

Haematoporphyrin derivative--photodynamic therapy of colorectal carcinoma, sensitized using verapamil and adriamycin.

The p-glycoprotein export mechanism may have an effect on the cytotoxicity of chemotherapy or photodynamic therapy (PDT) by reducing cytotoxic drug or photosensitizer concentration within cells. In tissues over-expressing this protein, modulation with verapamil (an antagonist of p-glycoprotein) may be useful in reversing this form of treatment resistance. This study examined the bioactivity of the interaction of photodynamic therapy using Haematoporphyrin derivative (HpD), chemotherapy and the response modifier verapamil. Multicellular spheroids derived from the human colorectal cancer line HRT 18 were used in vitro and bioactivity assessed using growth retardation. Bioactivity was observed to be greatest when all three agents and light irradiation were combined. This application may be clinically useful in the treatment of colorectal carcinoma by improving the efficacy of PDT using HpD.

Potentiation of photodynamic therapy-elicited antitumor response by localized treatment with granulocyte-macrophage colony-stimulating factor.

Murine squamous cell carcinoma (SCCVII) cells were genetically engineered to produce marine granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF immunotherapy, based on the peritumoral injection of lethally irradiated GM-CSF-producing SCCVII cells, was examined as adjuvant to photodynamic therapy (PDT) treatment of this tumor. The GM-CSF immunotherapy administered three times in 48-h intervals, starting 2 days before the light treatment, substantially improved the curative effect of Photofrin-mediated PDT. A comparable effect of GM-CSF immunotherapy was observed in the combination with benzoporphyrin derivative-mediated PDT. The tumor-localized GM-CSF immunotherapy alone had no obvious effect on the growth of parental SCCVII tumors. This treatment did not significantly alter the differential peripheral WBC count and appeared not to affect tumor leukocyte infiltration. However, GM-CSF treatment did increase the cytotoxic activity of tumor-associated macrophages against SCCVII tumor cells. It appears, therefore, that tumor-localized immune stimulation by GM-CSF amplifies a PDT-induced antitumor immune reaction, which has a potentiating effect on tumor control.

Gender influences the magnitude of the inflammatory response within embolic cerebral infarcts in young rats.

BACKGROUND AND PURPOSE: The inflammatory response within cerebral infarcts may have an influence on tissue damage. Since old animals with an impaired immune response have decreased inflammation after experimental cerebral infarction, we postulated that female animals with an increased immune response will have an increased inflammatory response after cerebral infarction. METHODS: Embolic cerebral infarcts were produced by photochemical irradiation of the right carotid artery in 12 female Fischer rats. The inflammatory response within 4-day-old infarcts was quantitated by histology with the use of computer-assisted image analysis and compared with that in 12 male rats from a previous series. RESULTS: Severe infarcts had the most pronounced inflammatory response. Female rats had an increased inflammatory response in infarcts of all severity, which was statistically significant in severe cerebral infarcts even after adjustment for infarct size. Severe infarcts in males were significantly larger than those in females. CONCLUSIONS: Gender influences the outcome of embolic cerebral infarcts after photochemical damage to the carotid artery, both in terms of the magnitude of the inflammatory response and infarct size. There are numerous gender-related differences in neurochemicals, cytokine production, and drug metabolism that may influence tissue damage after stroke and responsiveness to therapeutic intervention. The preponderance of male animals in stroke research may produce results not applicable to female stroke patients. The use of female animals will be required to provide adequate models for the study of stroke in women.

The sensitivity of normal brain and intracranially implanted VX2 tumour to interstitial photodynamic therapy.

The applicability and limitations of a photodynamic threshold model, used to describe quantitatively the in vivo response of tissues to photodynamic therapy, are currently being investigated in a variety of normal and malignant tumour tissues. The model states that tissue necrosis occurs when the number of photons absorbed by the photosensitiser per unit tissue volume exceeds a threshold. New Zealand White rabbits were sensitised with porphyrin-based photosensitisers. Normal brain or intracranially implanted VX2 tumours were illuminated via an optical fibre placed into the tissue at craniotomy. The light fluence distribution in the tissue was measured by multiple interstitial optical fibre detectors. The tissue concentration of the photosensitiser was determined post mortem by absorption spectroscopy. The derived photodynamic threshold values for normal brain are significantly lower than for VX2 tumour for all photosensitisers examined. Neuronal damage is evident beyond the zone of frank necrosis. For Photofrin the threshold decreases with time delay between photosensitiser administration and light treatment. No significant difference in threshold is found between Photofrin and haematoporphyrin derivative. The threshold in normal brain (grey matter) is lowest for sensitisation by 5 delta-aminolaevulinic acid. The results confirm the very high sensitivity of normal brain to porphyrin photodynamic therapy and show the importance of in situ light fluence monitoring during photodynamic irradiation.

Preliminary results of photodynamic therapy for recurrent nasopharyngeal carcinoma.

Photodynamic therapy (PDT) is a promising new modality in the treatment of cancer. In Hong Kong where nasopharyngeal carcinoma (NPC) is endemic, radiotherapy has been the primary treatment of choice. For recurrent disease after radiotherapy, there is no effective treatment. This latter report summarizes our initial experience in using PDT for these patients. Twelve patients (three females and nine males) with ages ranging from 33 to 65 years were treated with an infusion of hematoporphyrin derivative (5 mg/kg) 48-72 h before exposure to 200 J/cm2 light (wavelength, 630 nm) delivered from a gold vapor laser. All 12 patients showed a dramatic response as judged by computed tomography or magnetic resonance imaging at 6 months post-PDT. Of the eight patients in whom cure was aimed for, three remained disease-free at 9-12 months after a single treatment. Three of the remaining four patients achieved useful palliation. Skin hypersensitivity occurred in two patients and was the only significant complication encountered. This experience indicates that PDT can be an encouraging palliative or definitive management for recurrent superficial NPC.

Photodynamic therapy of head and neck cancers.

Sixty-five patients with neoplastic diseases of the larynx, oral cavity, pharynx, and skin have been treated with photodynamic therapy (PDT) with follow-up to 56 months. Patients with carcinoma in situ (CIS) and T1 carcinomas obtained a complete response after one PDT treatment. All but two have remained free of disease. Eight patients with T2 and T3 carcinomas treated with PDT obtained a complete response, but they all recurred locally. This is due to the inability to adequately deliver laser light to the depths of the tumor bed. Five patients with massive neck recurrences of squamous cell carcinomas were treated with intraoperative adjuvant PDT following tumor resection. Only one developed recurrence with 24-month follow-up. PDT is highly effective for the curative treatment of early carcinomas (CIS, T1) of the head and neck. Also, intraoperative adjuvant PDT may increase cure rates of large infiltrating carcinomas of the head and neck.