Photodynamic Therapy for Gynecological Diseases and Breast Cancer
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CancCancerer Biol Med 2012;2012 /9: Vol. 9-17 9 /doi: No. 10.3969/j.issn.2095-3941.2012.1 01.002 9 Review Photodynamic Therapy for Gynecological Diseases and Breast Cancer Natashis Shishkova, Olga Kuznetsova, Temirbolat Berezov Department of Biochemistry, School of Medicine, People’s Friendship University of Russia, Moscow 117198, Russia ABSTRACT Photodynamic therapy (PDT) is a minimally invasive and promising new method in cancer treatment. Cytotoxic reactive oxygen species (ROS) are generated by the tissue-localized non-toxic sensitizer upon illumination and in the presence of oxygen. Thus, selective destruction of a targeted tumor may be achieved. Compared with traditional cancer treatment, PDI has advantages including higher selectivity and lower rate of toxicity. The high degree of selectivity of the proposed method was applied to cancer diagnosis using fluorescence. This article reviews previous studies done on PDT treatment and photodetection of cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, ovarian and breast cancer, and PDT application in treating non-cancer lesions. The article also highlights the clinical responses to PDT, and discusses the possibility of enhancing treatment efficacy by combination with immunotherapy and targeted therapy. KEY WORDS: photodynamic therapy, photosensitizers, cervical/vulvar intraepithelial neoplasia, ovarian neoplasms, breast neoplasms Introduction frequently used drug in PDT is 5-aminolaevulinic acid (ALA). However, 5-ALA is not a photosensitizer, but a precursor of Photodynamic therapy (PDT) is a mode of therapy used in the endogenous photosensitizer protoporphyrin IX, which is cancer treatment where drug activity is locally controlled by a member of the heme synthesis pathway that occurs in the light (Figure 1). The ground state non-toxic photosensitizer mitochondria [5]. PDT affects the tumor vasculature, where achieves a higher unstable energy state (singlet state) upon illumination and ROS production cause vessel shutdown illumination with an appropriate light wavelength and in and lead to tumor hypoxia [6]. PDT also affects the immune the presence of oxygen. In this unstable state, the activated system [7, 8]. The tissue selectivity of different photosensitizers photosensitizer releases energy either by emitting heat is currently under investigation. Moreover, the laser and light or by the conversion of the unstable state into an irradiation restricted within the lesion area combined with intermediate energy state (triplet state) before returning to the short lifespan of the emerging cytotoxic species ensures the stable ground state. In the triplet state, the photosensitizer that phototoxic damage is mainly localized in the lesion with generates reactive oxygen species (ROS), such as superoxide minimal inclusion of the surrounding tissues. The application and hydroxyl radicals or singlet oxygen. ROS rapidly reacts mode of photosensitizers may be topical or systemic (oral with biological substrates, which initiates an apoptotic or or intravenous). Indications for PDT include cancers where necrotic response. This process eventually leads to oxidative the entire lesion is visible through an endoscope to enable damage and cell death. The intracellular localization of laser irradiation. PDT has been applied for the treatment the photosensitizer activity is of great importance because of skin cancer, surperficial esophageal cancer, lung cancer, mitochondrial damage generally leads to apoptosis, whereas and gastric cancer [9, 10]. In addition, bladder and prostate plasma membrane damage induces necrosis [1-3]. Photofrin, cancers have been treated with PDT [11–13]. In this review, one of the most widely used photosensitizers, is localized in PDT effectiveness in treating gynecological cancers, such the mitochondria due to its hydrophobicity and its affinity as ovarian cancer, cervical intraepithelial neoplasia (CIN), to the binding site on the mitochondrial membrane [4]. A and vulvar intraepithelial neoplasia (VIN) is discussed. The available data on targeted and non-targeted treatment modes Correspondence to: Natashis Shishkova for breast cancer is also summarized. Tel: 972-545264823 Fax: 972-8-9407889 Cervical Intraepithelial Neoplasia (CIN) E-mail: [email protected] Received October 26, 2011; accepted January 12, 2012. Copyright © 2012 by Cancer Biology & Medicine Cervical cancer is the second most common malignancy 10 Shishkova et al. PDT for Gynecological Diseases and Breast Cancer hv Heat Photosensitizer Photosensitizer Ground state Singlet state Fluorescence Photosensitizer Triplet state ROS Tumor cell necrosis/apoptosis Vascular damage Immune response Tumor destruction Figure 1. Photodynamic therapy mechanism, as explained in detail in the text. in women worldwide, with about 500,000 new patients without anesthesia because the patient experiences no pain diagnosed every year. CIN is a precancerous condition during the procedure. Furthermore, bleeding does not occur localized in the squamo-columnar junction of the cervix during PDT, and fertility can be preserved while leaving the uteri. The classification ranges from CIN 1 (mild dysplasia) cervix relatively intact because no adverse effects of PDT to CIN 3 (severe dysplasia). Human papillomavirus (HPV) have been noted on pregnancy and delivery. In a previous infection, mainly high-risk types 16 and 18, is directly related study, 22 patients became pregnant after receiving PDT to the development of CIN and cancer [14]. CIN prevalence with Photofrin and 12 of them went on to have normal has increased during the last few decades particularly among transvaginal deliveries [20]. The same study also reported younger women. Results of recently established screening on PDT with Photofrin on 131 cases (95 CIN, 31 dysplasia, programs showed that the incidence of cervical cancer has 1 VIN, 3 squamous cell carcinoma, and 1 endocervical decreased by about 50% to 60%. The recent standard of adenocarcinoma) [21]. Of these cases, 127 responded favorably care consists of excision, e.g., loop electrosurgical excision to the treatment (96.9%). However, the main side effect of procedure (LEEP), cold knife excision of the transformation PDT with Photofrin was skin photosensitivity [22]. Thus, PDT zone or local destruction by laser or cryotherapy [15]. These with topically applied photosensitizers, mainly 5-ALA and procedures are commonly painful during treatment and may its esterified derivate hexylaminolevulinate (HAL), was cause post-operative bleeding. Thus, anesthesia is usually used[23–29]. A cylindrical light applicator with a backscattering used as a necessary prerogative. The recurrence rates of surface for light homogenization was used to illuminate the CIN lesions for more than six months after the treatment are endocervical canal. A tip, which reached the endocervical between 5% and 16% for LEEP, 4% and 24% for cryotherapy, canal, fixed the light applicator to the cervix and provided and 3% and 30% for laser therapy [16]. The major drawback endocervical illumination. From a clinical point of view, of these excision methods is the destruction of the cervical the application of liquid solutions to the cervix could be stroma, which may cause cervical insufficiency and/or problematic. Three studies have shown that the application cervical scar structure that may lead to premature delivery of 5 mL to 10 mL of 10% solution of 5-ALA to the portio and increase the risk of infertility and the need for caesarean uteri using an appropriately sized cervical cap for 4 h to 8 h operation [17–19]. followed by illumination using a laser (wavelength 635 nm) through a specially developed cervical applicator induces PDT in CIN Treatment regression of the CIN lesion, but does not entirely eradicate the lesion [23-25]. However, PDT with the application of 12% of PDT has been used as an alternative therapy to meet the ALA was very effective in eradicating 80% of cervical HPV demands of the increasing number of younger patients infection [26, 27]. The application of a special thermogel was waiting to preserve fertility and to accommodate high-risk performed to improve the adhesion of the 5-ALA solution [28]. patients and those who refuse surgery. PDT can be performed The application of 5-ALA gel followed by laser illumination Cancer Biol Med 2012 / Vol. 9 / No. 1 11 using a special light catheter led to a complete response in 4 investigational procedure. Most published studies have used out of 5 patients suffering from CIN 2 for 9 months [29]. local application of 5-ALA. Martin-Hirsch et al. [40] reported Promising results have been demonstrated with HAL, that 16 out of 18 patients who received PDT had symptom which is an esterified derivate of 5-ALA, in PDT [30]. relief (89%), and 9 out of 10 patients developed local Topically applied HAL had a high epithelial fluorescence recurrence at the treatment site detected during the follow as a result of significant selectivity of epithelium over the up procedure 2 years after the treatment. In a subsequent lamina propria [31, 32]. PDT with HAL thermogel applied to study of PDT treatment, 5 out of 6 women suffered from a the cervix followed by laser illumination (wavelength 633 persistent disease at the follow-up visit 6 months after the nm) resulted in a complete response and remission of HPV treatment [41]. In yet another study, 25 women with 111 lesions infection for 6 months in 15 out of 24 patients with CIN [33]. of VIN 2 and VIN 3 were topically sensitized with 10 mL of The remission