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Trang 9Photodynamic Therapy to Eradicate Tumor Cells
Ana Cláudia Pavarina1, Ana Paula Dias Ribeiro1, Lívia Nordi Dovigo1, Cleverton Roberto de Andrade2, Carlos Alberto de Souza Costa2 and Carlos Eduardo Vergani1
1Araraquara Dental School, UNESP- Univ Estadual Paulista,
Department of Dental Materials and Prosthodontics
2Araraquara Dental School, UNESP- Univ Estadual Paulista,
Department of Phisiology and Pathology
Brazil
1 Introduction
The cell cycle is a collection of highly ordered processes involving numerous regulatory proteins that guide the cell through a specific sequence of events culminating in the duplication of the cell (Elledge, 1996) In general, the cell cycle can be altered to the advantage of many factors Three basic cell cycle defects are mediated by misregulations of cyclin-dependent kinases (CDKs), unscheduled proliferation, genomic instability (GIN) and chromosomal instability (CIN) In the first case, mutations result in constitutive mitogenic signaling and defective responses to anti-mitogenic signals The second, GIN, leads to additional mutations (Kastan & Bartek, 2004), and CIN is responsible for numerical changes
in chromosomes (Lee et al., 1999) Moreover, data suggest that the mutations leading to tumorigenesis are even more numerous and heterogeneous than previously thought (Hudson et al., 2010) This accumulation of genetic mutations can arise by nucleotide substitutions, small insertions and deletions, chromosomal rearrangements and copy number changes that can affect protein-coding or regulatory components of genes Cancer genomes usually acquire somatic epigenetic “marks” compared to non-neoplastic tissues
from same organ (Hudson et al., 2010) In this context, a neoplasm (Greek, neo = new + plasis
= growth) can be defined as an abnormal mass of tissue whose growth exceeds and is uncoordinated with that of the normal tissue, and persists in the same excessive manner after cessation of the stimuli that initiated the change
Head and neck cancer is considered a worldwide problem due to its raising in developing countries (Lim et al., 2011) Approximately 90% of this type of cancer consists of oral squamous cell carcinoma (OSCC), which arises from the oral mucosal lining (Neville & Day, 2002) The risk factors related to OSCC includes tobacco and alcohol abuse, solar exposure, human papillomavirus, immunosuppression conditions, iron deficiency anemia in combination with dysphagia and esophageal webs, and tumor genesis that can occur as a result of genetic predisposition or epigenetic pathway involving DNA and/or histone modification (Neville & Day, 2002; Schweitzer & Somers, 2010) Although there have been
Trang 10many advances in the conventional treatment, the survival rate for patients with late stage
of OSCC is the lowest of the major cancers, remaining at 50% over the last two decades (Neville & Day, 2002; Funk et al., 2002) The standard treatment for early OSCC includes surgery, radiation, chemotherapy or a combination of these procedures However, the side effects of these treatments are severe and can result in structural defects leading to dysphagia, and also hyperpigmentation, scars and xerostomia (Hooper et al., 2004; Schweitzer & Somers, 2010) Therefore, alternative treatments have been proposed in order
to reduce the toxicity and side effects from the conventional therapies
Less invasive surgical modalities including the Photodynamic Therapy (PDT) are examples
of new treatments that comprise the era of conservative surgery (Karakullukcu et al., 2011)
In this context, the purposes of this chapter are: 1 discuss about PDT as a relatively new therapy for treating head and neck neoplasms including its advantages and disadvantages when compared to conventional treatments; 2 describe the pathophysiology of cancer cells that allows the photosensitizer to accumulate on these cells rather than normal tissue and
mechanisms of cell/tumor death; 3 review the in vivo findings avaiable in the literature; and
4 present the anti-tumor effect observed in vitro when Hela cells were exposed to
Curcumin, a natural photosensitizer
2 Photodynamic therapy
PDT is a relative recent therapy, and excellent results have been reported after its application for the treatment of oral cancer and premalignant lesions (Allison et al., 2005; Yu
et al., 2008), as well as bacterial and fungal infections (Teichert et al., 2002; Williams et al., 2006; Donnelly et al., 2008) The simplicity of PDT mechanism stimulated the interest for this therapy, which is characterized by the association of a photosensitizing agent (PS) and visible light with a wavelength compatible with the photosensitizer’s absorption spectrum (Konopka & Goslinski, 2007; Buytaert et al., 2007) Photon absorption by the PS leads it to a triple state of excitation that may interact with the available oxygen, in two different ways The reaction type 1 involves electron/hydrogen transfer directly from the PS or electron/hydrogen removal from a substrate molecule to form free radicals such as superoxide, hydroxyl radicals, and hydrogen peroxide The reaction type 2 involves the production of the electronically excited and highly reactive state of oxygen known as singlet oxygen (Konopka & Goslinski, 2007) Both reactions can occur at the same time and the PS’ characteristics and the substrate molecules are important components to define the ratio of each reaction All these products originated from PDT may result in a cascade of oxidative events that cause direct cell death, destruction of tumor vascularization and activation of the host’s immune response (Buytaert et al., 2007)
The success of PDT depends on several parameters such as the type and concentration of the
PS, its localization during the irradiation, the pre-incubation period with the drug, type of light sources, light fluence and density, type of tumor and its level of oxygenation (Dolmas
et al., 2003) Regarding the PS, the most commonly used in PDT for cancer treatment includes porphyrins, phthalocyanines, the 5-aminolevulinic acid and chlorine These PSs have been preferentially selected due to their approval for clinical use In the present, PDT has been approved for use in clinical treatment in the USA, EU, Canada, Russia and Japan (Bredell et al., 2010) The Food and Drug Administration (FDA) has approved the treatment
of Barret’s esophagus, obstructing esophageal and tracheobronchial carcinomas with