New proposal for the treatment of nodular basal cell carcinoma with intralesional 5-aminolevulinic acid

Photodynamic therapy (PDT) is a treatment modality using a photosensitizer, light and oxygen to cause photochemically-induced selective cell death. Topical PDT is most suitable for thin lesions such as superficial basal cell carcinoma and actinic keratoses in dermatology. Results with PDT as treatment of thicker lesions such as nodular basal cell carcinoma appear to have a limited role because the photosensitizer or the light cannot penetrate deeply enough into the thicker tumor volume. In this preliminary study we use intralesional administration of 5-aminolevulinic acid to enhance the efficacy of the photosensitivity of nodular basal cell carcinomas, thus improving clinical cure.     

Efficacy of Photodynamic Therapy as a Treatment for Gorlin Syndrome-related Basal Cell Carcinomas

AimsThe management of the multiple basal cell carcinomas (BCCs) that develop throughout life of patients with Gorlin syndrome can be challenging. Surgical excision can result in significant disfigurement from scarring and tissue defects. Radiotherapy is contraindicated because of enhanced radiation tumourigenesis in these patients. Photodynamic therapy (PDT) is a simple, repeatable out-patient procedure, which is associated with minimal skin deterioration. It is now routinely used to treat superficial sporadic BCCs, using a topically-applied photosensitiser and external light, but its role in the management of Gorlin syndrome-related BCCs has yet to be established. In particular, Gorlin syndrome is often associated thick, nodular lesions which can be resistant to treatment with topical PDT.Materials and methodsWe report our outcome data for 33 Gorlin patients (138 lesions) treated with PDT. Lesion thicknesses were assessed using ultrasound, both prior to treatment and during follow-up, to quantify treatment response and to guide the choice of treatment methods. Topical PDT was used to treat superficial lesions (<2 mm thick) and a systemic photosensitiser +/? light delivered by interstitially-placed optical fibres was employed for thicker lesions (>2 mm).Results and conclusionsLocal control rates of 56.3% at 12 months were achieved overall. The use of a systemic photosensitiser +/? interstitial light delivery extended the remit of PDT, allowing thicker lesions (>2 mm) to be treated, resulting in local control rates of 59.3% in this group. PDT can be considered as a treatment option for patients with multiple BCCs as a result of Gorlin syndrome. The use of ultrasound to accurately assess lesion thickness helps to select the optimum treatment method. Systemic photosensitisers and interstitial optical fibres can be used to treat thicker lesions, offering a treatment option for patients with thick nodular tumours who wish to avoid surgery.     

Photodynamic therapy for non-melanoma skin cancer

Photodynamic therapy (PDT) involves the administration of a photosensitizing drug and its subsequent activation by light at wavelengths matching the absorption spectrum of the photosensitizer. Because the skin is readily accessible to light-based therapies, PDT with systemic and particularly with topical agents has become important in treating cutaneous disorders. Topical PDT is indicated for treating actinic keratosis, superficial or thin non-melanoma skin cancer, including some cases of nodular basal cell carcinoma, and some cutaneous lymphomas. Advantages of aminolevulinic acid/methyl aminolevulinate PDT include the possibility of simultaneous treatment of multiple tumors and large surface areas, good cosmesis, and minimal morbidity, such as bleeding, scarring, or infection.     

Induction of apoptosis and manganese superoxide dismutase gene by photodynamic therapy in cervical carcinoma cell lines

Background. Photodynamic therapy (PDT) is a cancer treatment modality in which systemic administration of a tumor-localizing photosensitizer is followed by irradiation of the tumor with visible light. Although PDT is undergoing clinical trials for various cancers, the mechanisms of its action are not fully understood. To investigate the mechanism of cell death by PDT, we performed in-vitro PDT, using Photofrin II as a photosensitizer, in two human cervical carcinoma cell lines, HeLa and CaSki. Methods. Cells were incubated with Photofrin II for 24 h, followed by illumination, using a YAG-OPO laser. Cell survivability after PDT was evaluated by an MTT assay. Cytotoxicity was assayed by measuring the release of lactate dehydrogenase (LDH) into the supernatant. DNA of the PDT-treated cells was electrophoresed in an agarose gel to determine fragmentation. In situ detection of apoptosis in the PDT-treated cells was performed by identification of the 3′-OH ends of DNA. In addition, induction of manganese superoxide dismutase mRNA (MnSOD) was analyzed in the PDT-treated cells. Results. The CaSki cells were more sensitive to this PDT treatment than were the HeLa cells. DNA fragmentation was observed with less than 5 μg/ml of Photofrin II in both cell lines, whereas PDT-induced cell membrane destruction, determined by LDH release, was observed only at 10 μg/ml. The MnSOD mRNA was induced in the HeLa cells in the early hours after PDT with a non-lethal dose of Photofrin II, but was reduced with a high dose, whereas the CaSki cells did not show any induction of the MnSOD gene by PDT. Conclusion. The present results suggest that PDT induces cell death by a mechanism involving membrane destruction and apoptosis. Differences in cell susceptibilities to PDT may depend upon a protective mechanism, such as MnSOD gene induction. Received: August 5, 1999 / Accepted: December 10, 1999     

Recent advances in the prevention and treatment of skin cancer using photodynamic therapy

Photodynamic therapy (PDT) is a noninvasive procedure that involves a photosensitizing drug and its subsequent activation by light to produce reactive oxygen species that specifically destroy target cells. Recently, PDT has been widely used in treating non-melanoma skin malignancies, the most common cancer in the USA, with superior cosmetic outcomes compared with conventional therapies. The topical 'photosensitizers' commonly used are 5-aminolevulinic acid (ALA) and its esterified derivative methyl 5-aminolevulinate, which are precursors of the endogenous photosensitizer protoporphyrin IX. After treatment with ALA or methyl 5-aminolevulinate, protoporphyrin IX preferentially accumulates in the lesion area of various skin diseases, which allows not only PDT treatment but also fluorescence diagnosis with ALA-induced porphyrins. Susceptible lesions include various forms of non-melanoma skin cancer such as actinic keratosis, basal cell carcinoma and squamous cell carcinoma. The most recent and promising developments in PDT include the discovery of new photosensitizers, the exploitation of new drug delivery systems and the combination of other modalities, which will all contribute to increasing PDT therapeutic efficacy and improving outcome. This article summarizes the main principles of PDT and its current clinical use in the management of non-melanoma skin cancers, as well as recent developments and possible future research directions.     

Photodynamic therapy--a new treatment option for epithelial malignancies of the skin

Photodynamic therapy (PDT) is based on the activation of a photosensitizer by illumination with visible light, leading to photochemical tissue destruction or immunomodulation. The greatest disadvantage of systemic administration of photosensitizers is cutaneous photosensitization of the patients, which lasts for some months. An alternative approach for epithelial precancerous lesions, such as actinic keratoses and Bowen's disease, as well as for superficial skin tumors, such as basal cell carcinomas, is the topical application of sensitizers, especially 5-aminolevulinic acid. Topical PDT causes selective tissue necrosis and tumor destruction and produces excellent cosmetic results. The following article summarizes the main principles of PDT and provides a synopsis of the present status of the use of PDT for epithelial skin malignancies.     

Photodynamic therapy and urothelial carcinoma

PurposePhotodynamic therapy (PDT) is an innovative therapeutic modality in urologic oncology.Material and methodsWe reviewed the current literature on principles and modalities of PDT in urothelial and penile oncology.ResultsPDT has been tested for the treatment recurrent superficial bladder tumors and in situ carcinoma. Carcinologic efficacy has been observed with first generation photosensitizer. The lack of selectivity for tumoral cells was responsible of serious adverse events. Development of selective photosensitizers has reduced the importance of side effects. Data concerning PDT for upper urinary tract urethra and carcinoma are still limited.ConclusionFirst PDT clinical applications in urothelial oncology have shown some effectiveness at the cost of significant morbidity. The development of selective photosensitizers should help to reduce side effects.     

Antitumor effect of photodynamic therapy with chlorin-based photosensitizer DH-II-24 in colorectal carcinoma

While photodynamic therapy (PDT) has been recognized as a promising therapeutic modality for the treatment of various cancers and diseases, developments of effective photosensitizers are highly desired to improve the prospect for the use of PDT. In this study, we evaluated DH-II-24, a new photosensitizer, for antitumor PDT in vitro and in vivo . Loaded into human colorectal carcinoma cells (HCT116), DH-II-24 was primarily accumulated in mitochondria, lysosomes, and endoplasmic reticula. Administration of DH-II-24 followed by light exposure induced necrotic cell death in a dose-dependent manner, whereas DH-II-24 in the absence of light induced minimal cell death. In order to investigate the distribution and phamacokinetics of the photosensitizer in vivo , DH-II-24 was intravenously injected to female BALB/c nude mice. Fluorescence imaging in vivo showed that DH-II-24 was rapidly distributed across the entire body and then mostly eliminated at 24 h. Next, effectiveness of DH-II-24-mediated PDT was examined on colorectal carcinoma xenografts established subcutaneously in BALB/c nude mice. DH-II-24 (1 mg/kg, i.v. administration) followed by light exposure significantly suppressed growth of xenograft tumors, compared to light exposure or DH-II-24 alone. Histological examination revealed necrotic damage in PDT-treated tumors, concomitantly with severe damage of tumor vasculature. These results suggest that DH-II-24 is a potential photosensitizer of photodynamic therapy for cancer. ( Cancer Sci 2009; 100: 2431–2436)     

Topical 5-Aminolevulinic Acid and Photodynamic Therapy in Dermatology: a Minireview

Abstract

Photodynamic therapy (PDT) is a treatment modality using a photosensitiz-er, light and oxygen to cause photochemically induced selective cell death. When exposed to light with the proper wavelength, the topically applied photo-sensitizer or photosensitizer precursor can activate a biomolecule through electron transfer to yield free radicals or produce singlet oxygen from energy transferred from the excited sensitizer to molecular oxygen. The tissue damage is the result of the activation of reactive singlet oxygen or free radical production. Photodynamic therapy with topical application of 5-aminolevulinic acid (ALA) is a new technique and although it remains largely experimental, it has potential application for treatment of malignant skin tumors, various precancerous and selected benign skin diseases. This technique yields not only a high percentage of good therapeutic results but also excellent cosmetic outcome. This paper reviews the recently published data on clinical ALA-based PDT in dermatology.     

Photodynamic therapy of cancer. Basic principles and applications

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality approved for clinical treatment of several types of cancer and non-oncological disorders. In PDT, a compound with photosensitising properties (photosensitiser, PS) is selectively accumulated in malignant tissues. The subsequent activation of the PS by visible light, preferentially in the red region of the visible spectrum (λ≥600 nm), where tissues are more permeable to light, generates reactive oxygen species, mainly singlet oxygen (¹O₂), responsible for cytotoxicity of neoplastic cells and tumour regression. There are three main mechanisms described by which ¹O₂ contributes to the destruction of tumours by PDT: direct cellular damage, vascular shutdown and activation of immune response against tumour cells. The advantages of PDT over other conventional cancer treatments are its low systemic toxicity and its ability to selectively destroy tumours accessible to light. Therefore, PDT is being used for the treatment of endoscopically accessible tumours such as lung, bladder, gastrointestinal and gynaecological neoplasms, and also in dermatology for the treatment of non-melanoma skin cancers (basal cell carcinoma) and precancerous diseases (actinic keratosis). Photofrin®, ALA and its ester derivatives are the main compounds used in clinical trials, though newer and more efficient PSs are being evaluated nowadays.     

Recombinant human tumor necrosis factor alpha does not potentiate cell killing after photodynamic therapy with a silicon phthalocyanine in A431 human epidermoid carcinoma cells

Photodynamic therapy (PDT) is a novel cancer treatment utilizing a photosensitizer, visible light and oxygen. PDT with the silicon phthalocyanine Pc 4, a new photosensitizer, is highly effective in cancer cell destruction and tumor ablation. The mechanisms underlying cancer cell killing by PDT are not fully understood. Tumor necrosis factor alpha (TNF) is a multifunctional cytokine that has been implicated in photocytotoxicity. We asked whether recombinant human TNF (rhTNF) affects Pc 4-PDT cytotoxicity in A431 human epidermoid carcinoma cells. Co-treatment of A431 cells with various doses of Pc 4-PDT and a sub-lethal rhTNF dose led to a sub-additive reduction in cell survival. In addition, in the presence of Pc 4-PDT or rhTNF, caspase-3 activity and apoptosis were induced. The combined treatment, however, did not potentiate either caspase-3 activity or apoptosis. Similar to previous findings we observed that Pc 4-PDT initiated a time-dependent extracellular TNF accumulation. The data suggest that: a) PDT and rhTNF induce cancer cell killing through different mechanisms; and b) Pc 4-PDT-induced TNF production is a stress response that may not directly affect photocytotoxicity.     

The Use Of Porphyrins And Non-Ionizing Radiation For Treatment Of Cancer

Photodynamic therapy (PDT) is the treatment of malignant lesions with visible light following systemic or local administration of a photosensitizer or its precursor. Initially, hematoporphyrin derivative and a purified component called Photofrin II was used for clinical PDT. Later on interest has focused on new sensitizers with more favourable absorption as regards light transmission in tissues. Twenty years of clinical experience has revealed that PDT is best applied to early stage cancers. The present review discusses the basic components of PDT and its clinical use in treatment of cancer.     

The kinetics of protoporphyrin fluorescence during ALA-PDT in human malignant skin tumors

Fluorescence monitoring during photodynamic therapy (PDT) with the use of topical 5-aminolevulinic acid (ALA) was carried out in patients bearing superficial and nodular basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and Kaposi's sarcomas. A new diagnostic-therapeutic system based on an incoherent CW light source was used for fluorescence spectral measurements and imaging. The results showed that photoirradiation reduced ALA-induced protoporphyrin IX (PP) fluorescence in all tumors. The rate of PP photobleaching in superficial BCC and SCC tumors was significantly higher than in large nodular BCC tumors. The results showed that the differences in kinetics of fluorescence reduction could be attributed to the tumor thickness. One hour after photoirradiation with a light dose of 170 J/cm² a phenomenon of re-appearance and recovery of PP fluorescence was observed in the large deeply penetrating BCC tumors and Kaposi's sarcoma lesions. In such cases an additional light treatment was performed. The results of the study demonstrated that fluorescence monitoring is very appropriate for the definition of an optimal ALA-PDT clinical protocol.     

Defining the therapeutic window of vertebral photodynamic therapy in a murine pre-clinical model of breast cancer metastasis using the photosensitizer BPD-MA (Verteporfin)

Breast cancer is known to cause metastatic lesions in the bone, which can lead to skeletal-related events. Currently, radiation therapy and surgery are the treatment of choice, but the success rate varies and additional adjuncts are desirable. Photodynamic therapy (PDT) has been applied successfully as a non-radiative treatment for numerous cancers. Earlier work has shown that the athymic rat model is suitable to investigate the effect of PDT on bone metastasis and benzoporphyrin-derivative monoacid ring A (BPD-MA; verteporfin) has been shown to be a selective photosensitizer. The aim of this study was to define the therapeutic window of photosensitizer with regard to drug and light dose. Human breast carcinoma cells (MT-1)—stable transfected with the luciferase gene—were injected intra-cardiacally into athymic rats. At 14 days, the largest vertebral lesion by bioluminescence imaging was targeted for single treatment PDT. A drug escalating-de-escalating scheme was used (starting drug dose and light energy of 0.2 mg/kg and 50 J, respectively). Outcomes included 48 h post-treatment bioluminescence of remaining viable tumour, histomorphometric assessment of tumour burden, and neurologic evaluation. The region of effect by bioluminescence and histology increased with increasing drug dose and light energy. A safe and effective drug-light dose combination in this model appears to be 0.5 mg/kg BPD-MA and applied light energy of less than 50 J for the thoracic spine and 1.0 mg/kg and 75 J for the lumbar spine. For translation to clinical use, it is an advantage that BPD-MA (verteporfin), a second-generation photosensitizer, is already approved to treat age-related macular degeneration. Overall, PDT represents an exciting potential new minimally-invasive local, safe and effective therapy in the management of patients with spinal metastases.     

Hypericin-mediated photodynamic therapy of pituitary tumors: preclinical study in a GH4C1 rat tumor model

Objective Hypericin-mediated photodynamic therapy (PDT) is receiving greater interest as a potential treatment for a variety of tumors and nonmalignant disorders. PDT involves systemic administration of a photosensitizer that selectively accumulates within tumor tissue followed by focal light activation. In the presence of molecular oxygen, a photochemical reaction generates a reactive oxygen species that induces apoptosis in target cells. The purpose of this preclinical study was to evaluate the efficacy of hypericin-mediated PDT for treatment of pituitary adenoma in a rodent model. Methods Wistar-Furth rats were implanted with a pituitary adenoma rat cell line, GH4C1. Tumor masses were allowed to develop over 28 days; rats with tumors of comparable sizes were then assigned to three treatment groups: control (neither hypericin nor light); light only; and hypericin and light. Hypericin was administered in four doses (1 mg/kg) at 28-h intervals prior to light exposure, wherein those rats treated with light were exposed to a light source four hours after the last hypericin dose. Tumor size was measured up to 12 days after treatment. Results Over the short interval examined, hypericin-mediated PDT was not effective against large tumors greater than 1 cm³, but this treatment significantly slowed tumor growth for tumors less than 1 cm³. Histological evaluation and TUNEL assay of the treated tumor identified apoptotic clusters on the periphery of the PDT-treated specimens. Conclusions Hypericin-mediated PDT shows promise in its effectiveness in the treatment of residual small tumor rests.     

Effects of chlorin-mediated photodynamic therapy combined with fluoropyrimidines in vitro and in a patient

Although photodynamic therapy (PDT) is becoming an additional cancer therapy, only little is known about its interactions with other drugs and treatment modalities in vitro and in vivo. We investigated the combination of 5-fluoro-2'-deoxyuridine (5FdUr), a chemotherapeutic drug, with 5,10,15,20-tetra( m-hydroxyphenyl)chlorin (mTHPC), a potent photosensitizer. Two cell lines, MCF-7 and LNCaP, were either simultaneously or consecutively incubated with both drugs and irradiated with laser light to activate mTHPC, and cell survival was determined. The combination of the two treatments was additive or antagonistic in LNCaP cells but additive or synergistic in MCF-7 cells depending on the protocol and concentration of 5FdUr. In one patient with multiple basal cell carcinoma, the effect of the combination of 5-fluorouracil administration followed by PDT resulted in significantly stronger effects than expected, leading to severe oedema, redness and ulceration. The healing process was delayed by 2 months compared to PDT alone. It is therefore important to find optimal conditions under which PDT and chemotherapy combinations do not fall outside the therapeutic window.     

Nimotuzumab increases the anti-tumor effect of photodynamic therapy in an oral tumor model

Oral squamous cell carcinoma (OSCC) represents 90% of all oral cancers and is characterized with poor prognosis and low survival rate. Epidermal growth factor receptor (EGFR) is highly expressed in oral cancer and is a target for cancer therapy and prevention. In this present work, we evaluate the efficacy of photodynamic therapy (PDT) in combination with an EGFR inhibitor, nimotuzumab in oral cancer cell lines and OSCC xenograft tumor model. PDT is a promising and minimally invasive treatment modality that involves the interaction of a photosensitizer, molecular oxygen and light to destroy tumors. We demonstrated that EGFR inhibitors nimotuzumab and cetuximab exhibits anti-angiogenic properties by inhibiting the migration and invasion of oral cancer cell lines and human endothelial cells. The EGFR inhibitors also significantly reduced tube formation of endothelial cells. Chlorin e6-PDT in combination with nimotuzumab and cetuximab reduced cell proliferation in different oral cancer and endothelial cells. Furthermore, our in vivo studies showed that the combination therapy of PDT and nimotuzumab synergistically delayed tumor growth when compared with control and PDT treated tumors. Downregulation of EGFR, Ki-67 and CD31 was observed in the tumors treated with combination therapy. Analysis of the liver and kidney function markers showed no treatment related toxicity. In conclusion, PDT outcome of oral cancer can be improved when combined with EGFR inhibitor nimotuzumab.     

Cell kinetics of mouse tumour subjected to photodynamic therapy--evaluation by proliferating cell nuclear antigen immunohistochemistry

Tumour reaction and tumour cell kinetics in mouse NR-S1 carcinoma subjected to photodynamic therapy (PDT) were evaluated by percentage of necrotic area as well as by proliferating cell nuclear antigen (PCNA) immunohistochemistry, and an effective PDT fractionation interval was proposed. PDT was carried out in mouse NR-S1 carcinomas using a photosensitizer (haematoporphyrin oligomers: 20 mg kg body weight) and pulsed Nd:YAG dye laser. The percentages of tumour necrotic area and PCNA labelling indices (LIs) in the tumours were assessed at intervals of 0, 0.5, 5, 2.5, 6, 24, 48, and 72 h after PDT. It was demonstrated that maximum damage and repopulation of the tumour cells emerge at 24 and 48 h, respectively, following PDT, suggesting that subsequent light treatment should be performed within 24 h to enhance the therapeutic effect of PDT.     

Ｐｈｏｔｏｆｒｉｎ光动力治疗舌癌的临床观察

目的　观察Ｐｈｏｔｏｆｒｉｎ光动力治疗舌癌的临床疗效和安全性。方法　２００３年７月至２００９年８月收治舌癌患者１４例,Ⅰ ～Ⅱ期４例,Ⅲ ～Ⅳ期１０例,所有舌癌患者均放弃或拒绝手术和放射治疗,并经病理确诊为高分化鳞癌。按２ｍｇ／ｋｇ静脉滴注光敏剂Ｐｈｏｔｏｆｒｉｎ,４８ｈ后经内镜导入光导纤维予波长６３０ｎｍ激光照射,照射方式分两种,即表面照射和组织间照射,治疗２４ｈ后清除坏死组织,并对深部肿瘤进行重复照射,治疗后１、３和６个月随访观察患者病灶的局部反应,并随访１４例患者的生存情况。结果　治疗后２４ｈ,病灶局部明显变暗、发紫,肿瘤组织坏死。舌癌患者光动力治疗总有效率为８５.７％,完全缓解率为２８.６％。获ＣＲ４例中Ⅰ期２例,Ⅱ、Ⅲ期各１例。１４例患者中位生存期为１３.５个月。结论　光动力治疗舌癌总有效率高,且耐受性好,早期舌癌患者可以保留语言功能并达到临床根治的目的,晚期患者可以明显改善生活质量,是一种较好的姑息治疗手段。     

Photodynamic therapy by topical meso-tetraphenylporphinesulfonate tetrasodium salt administration in superficial basal cell carcinomas

The efficacy of an originally developed photodynamic approach, using topical administration of tetraphenylporphinesulfonate as the photosensitizer, was evaluated in a series of 292 basal cell carcinoma lesions (less than 2-mm thick) in 50 treated patients. The lack of indication for conventional therapies was the main selection criterion. The photosensitizing agent (2% solution) was topically applied at 0.1 ml/cm2, followed by light irradiation with a dye laser emitting at 645 nm (120 or 150 J/cm2). After initial treatment, all lesions responded, with 273 (93.5%) complete responses. Recurrences were observed in 29 (10.6%). A second application of photoradiation was performed in 15 persistent lesions and 11 relapsed lesions, producing 19/26 complete responses. Our results suggest that this technique can be considered a promising alternative treatment modality in selected cases of superficial basal cell carcinomas.