Effects of High‐Dose Cisplatin Chemotherapy and Conventional Radiotherapy on Urinary Oxidative and Nitrosative Stress Biomarkers in Patients with Head and Neck Cancer

Abstract

Cisplatin is a chemotherapeutic agent widely used in the treatment of several solid tumours. For patients with advanced head and neck squamous cell carcinoma in whom surgery is contraindicated, treatment with high-dose cisplatin administered every 21 days for 3 cycles concomitantly with conventional radiotherapy is recommended [1][2][3].Its anticancer mechanism is mediated by DNA binding, which leads to the formation of inter-and intrastrand crosslinks and results in defective DNA templates, arrest of DNA synthesis and replication, DNA damage and, finally, cell death [4]. In addition, cisplatin accumulates in human cells (normal and tumour cells) resulting in enhanced production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which leads to mitochondrial damage and dysfunction [5,6]. In addition, there is a decrease in the antioxidant defence system mediated primarily by links formed between cisplatin and glutathione, which culminates in the depletion of glutathione [7]. The excessive generation of ROS and RNS damages biomolecules, resulting in lipid, protein and DNA/RNA oxidation and causing toxicities including nephrotoxicity, neurotoxicity, ototoxicity and hepatotoxicity [8][9][10][11]. The intensity of biomolecular damage can be determined by oxidative/nitrosative stress biomarkers. In this study, we used malondialdehyde (MDA) and lipid hydroperoxides, which are indicators of lipid peroxidation/ oxidative stress biomarkers and nitrite, a nitrosative stress biomarker.Therefore, the aim of this study was to determine the effects of high-dose cisplatin chemotherapy and conventional radiotherapy on urinary levels of MDA, lipid hydroperoxides and nitrite biomarkers in patients with head and neck cancer. Material and MethodsThis was a prospective study conducted from January 2013 to November 2013 at the oncology clinic of a public teaching hospital in the state of São Paulo, Brazil. The research ethics committee of the institution approved the study, and all patients signed a consent form authorizing the use of their data.Patients and treatment characteristics. All patients were diagnosed with primary squamous cell carcinoma of the head and neck by a biopsy and were administered antineoplastic treatment with high-dose cisplatin (80 or 100 mg/m 2 ) with concomitant conventional radiotherapy as a therapeutic regimen. Patients who had undergone previous treatments for their tumours (surgery, chemotherapy and radiotherapy), or who refused to participate in the study, were excluded. Patients were dropped from the study if their treatment regimen changed before the study commenced, if they died or abandoned the treatment, or if complete oxidative stress data were not available (biomarkers or measurement times).The treatment regimen consisted of 3 cycles of chemotherapy with high-dose cisplatin (80 or 100 mg/m 2 ) on days 1, 22 and 43. Concomitantly with the chemotherapy, patients received a total dose of 70 Gy of radiation therapy divided into 35 daily applications of 2 Gy administered 5 days per w...

Can acetylcysteine ameliorate cisplatin‐induced toxicities and oxidative stress without decreasing antitumor efficacy? A randomized, double‐blind, placebo‐controlled trial involving patients with head and neck cancer

“…5 Consequently, after cisplatin treatment, oxidative stress biomarkers increase in the plasma and urine and antioxidants decrease. [6][7][8][9][10] Based on this, several antioxidant compounds have been studied as possible protective agents against toxicities caused by cisplatin. 6,7 Acetylcysteine (NAC) is a drug used in clinical practices as a mucolytic agent, as an antidote for paracetamol poisoning, and as a protector of contrast-induced nephropathy.…”

“…In addition, cisplatin binds to glutathione by glutathione‐S‐transferase to be eliminated from the cell, thus depleting cellular glutathione content . Consequently, after cisplatin treatment, oxidative stress biomarkers increase in the plasma and urine and antioxidants decrease . Based on this, several antioxidant compounds have been studied as possible protective agents against toxicities caused by cisplatin …”

MicroRNAs e biomoléculas oxidadas como possíveis biomarcadores de nefrotoxicidade induzida pela cisplatina em pacientes com câncer de cabeça e pescoço

“…As características clínicas e demográficas dos pacientes inseridos no estudo estão de acordo com a literatura e com trabalhos prévios realizados por nosso grupo de pesquisa 43,60,61,84 , uma vez que a idade média foi de 58,12 anos, com prevalência de pacientes do sexo masculino, brancos, tabagistas e etilistas acentuados e com tumores em estágios avançados. Nós observamos a prevalência de tumores localizados na cavidade oral, o que distoa de nossos trabalhos prévios onde observamos tumores de faringe como os mais prevalentes 43,60,61,84 . No entanto, outros autores também já observaram a maior prevalência de tumores na cavidade oral 182,183 .…”

“…O envolvimento do estresse oxidativo nas etiologias das toxicidades induzidas pela cisplatina já está bem estabelecido na literatura. O aumento da produção de EROs e a depleção das defesas antioxidantes pela administração de cisplatina aumenta o dano tecidual causado pela reação das EROs com biomoléculas, incluindo lipídeos e proteínas, liberando substâncias oxidadas no sangue 98 e na urina 60,193 .…”

“…Como citado anteriormente, a cisplatina é capaz de interagir com o DNA mitocondrial, interferindo na bioenergética da mitocôndia e aumentando a produção de EROs, o que culmina com a liberação de fatores pró-apoptóticos, induzindo a morte das células tubulares 46,59 . Nosso grupo de pesquisa já mostrou em dois diferentes estudos biomarcadores de estresse oxidativo associados com alterações em parâmetros renais 60,61 , e ainda que o peróxido de hidrogênio (H2O2) pode ser a principal ERO associada a nefrotoxicidade induzida pela cisplatina, uma vez que uma maior variação de H2O2 foi diretamente correlacionada com maiores graus de toxicidade para aumento de creatinina sérica e redução do clearance de creatinina 61 . Nosso grupo também publicou uma revisão na qual discutimos o papel da CYP450 na formação de EROs associada a nefrotoxicidade e hepatotoxicidade induzida pela cisplatina, uma vez que estudos in vitro e in vivo mostram que a CYP450, principalmente a CYP2E1, é uma importante fonte de ferro catalítico para geração de EROs após a administração da cisplatina [62][63][64] .…”