Chemotherapy-induced peripheral neuropathy (CIN) is a common toxicity of anticancer treatment and its incidence is growing. It significantly affects quality of life and is a dose-limiting factor that interferes with treatment. Its diagnosis can be established in clinical terms but some complementary tests can help when the diagnosis is difficult. There is still no proven method to prevent it that has become a standard of care in spite of the huge amount of investigation carried out in recent years. There are promising strategies that could help reduce the burden of this complication. This review will suggest an approach to the diagnosis of these disorders and provide an update on new therapies.

Reactive Oxygen Species (ROS) result from cell metabolism as well as from extracellular processes. ROS exert some functions necessary for cell homeostasis maintenance. When produced in excess they play a role in the causation of cancer. ROS mediated lipid peroxides are of critical importance because they participate in chain reactions that amplify damage to biomolecules including DNA. DNA attack gives rise to mutations that may involve tumor suppressor genes or oncogenes, and this is an oncogenic mechanism. On the other hand, ROS production is a mechanism shared by many chemotherapeutic drugs due to their implication in apoptosis control. The ROS mediated cell responses depend on the duration and intensity of the cells exposing to the increased ROS environment. Thus the status redox is of great importance for oncogenetic process activation and it is also implicated in tumor susceptibility to specific chemotherapeutic drugs. Phospholipid Hydroperoxide Glutathione Peroxidase (PH-GPx) is an antioxidant enzyme that is able to directly reduce lipid peroxides even when they are bound to cellular membranes. This article will review the relevance of oxidative stress, particularly of lipid peroxidation, in cell response with special focus in carcinogenesis and cancer therapy that suggests PH-GPx as a potentially important enzyme involved in the control of this processes.

No abstract

No abstract

Purpose: Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a wholeexome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy.Experimental Design: Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes.Results: WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4 Ã 20 allele) and a novel missense variant (CYP3A4 Ã 25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4 Ã 20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4 Ã 8 and the novel CYP3A4 Ã 27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2-and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P ¼ 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7-and 3-fold higher risk for loss-of-function and missense variants, respectively, P ¼ 5.9 Â 10 À5 ).Conclusion: This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization.

No abstract

Radiation has a limited but relevant role in the adjuvant therapy of gastric cancer (GC) patients. Since Chk1 plays a critical function in cellular response to genotoxic agents, we aimed to analyze the role of Chk1 in GC as a biomarker for radiotherapy resistance. We analyzed Chk1 expression in AGS and MKN45 human GC cell lines by RT-QPCR and WB and in a small cohort of human patient’s samples. We demonstrated that Chk1 overexpression specifically increases resistance to radiation in GC cells. Accordingly, abrogation of Chk1 activity with UCN-01 and its expression with shChk1 increased sensitivity to bleomycin and radiation. Furthermore, when we assessed Chk1 expression in human samples, we found a correlation between nuclear Chk1 accumulation and a decrease in progression free survival. Moreover, using a luciferase assay we found that Chk1’s expression is controlled by p53 and RB/E2F1 at the transcriptional level. Additionally, we present preliminary data suggesting a posttranscriptional regulation mechanism, involving miR-195 and miR-503, which are inversely correlated with expression of Chk1 in radioresistant cells. In conclusion, Chk1/microRNA axis is involved in resistance to radiation in GC, and suggests Chk1 as a potential tool for optimal stratification of patients susceptible to receive adjuvant radiotherapy after surgery.

Although rare, cardiotoxicity is a significant complication of cancer treatment. The incidence and severity of cardiovascular side effects are dependent on the type of drugs used, dose and schedule employed, and age of patients, as well as the presence of coexisting cardiac diseases and previous mediastinal irradiation. Classically, anthracyclines are among one of the most active agents in oncology, but their use is often hampered by their cumulative dose-limiting cardiotoxicity. In the past decade, combination therapy with new drugs such as taxanes or anti- EGFR, and Her-2 therapy as a single agent have also resulted in unexpected cardiotoxicity. Cardiac damage can be secondary to an alteration of cardiac rhythm, changes in blood pressure and ischaemia, and can also alter the ability of the heart to contract and/or relax. The clinical spectrum of these toxicities can range from subclinical abnormalities to being catastrophic, life-threatening and sometimes fatal. Knowledge of this toxicity can aid clinicians to choose the optimal and least toxic regimen suitable for an individual patient. In this work we present an exhaustive review of the cardiovascular side effects associated to new anticancer drugs, from new formulations of anthracyclines to tyrosine kinase inhibitors and monoclonal antibodies.