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      Urinary N telopeptide levels in predicting the anti-nociceptive responses of zoledronic acid and paclitaxel in a rat model of bone metastases

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          Abstract

          The present study investigated the hypothesis that urinary levels of N telopeptide (NTx) can be used to predict the anti-nociceptive responses of zoledronic acid and paclitaxel on bone metastases in a rat model. Rats were implanted with intra-femur Walker 256 carcinoma cells or control solution, and were treated with either normal saline, zoledronic acid or paclitaxel on the 10th day following surgery. Mechanical allodynia was recorded and the urine collagen-crosslinked NTx values were measured prior to, and 7, 14 and 21 days following the injections. Bone sections and osteoclasts were stained on the 14th day (4 days post-injection). Furthermore, the mRNA and protein expression levels of c-fos in the spinal cord and acid-sensing ion channel 3 (ASIC3) in the dorsal root ganglion (DRG) were analyzed. The mechanical allodynia of rats was attenuated from day 14 in the zoledronic acid group and from day 21 in the paclitaxel group. A positive correlation was observed between the anti-nociceptive responses of zoledronic acid and paclitaxel, and the urinary levels of NTx (r=0.619; P<0.001). The mRNA levels of c-fos in the spinal cord and ASIC3 in the DRG in the zoledronic acid group were reduced 14 and 21 days after inoculation, and this reduction was observed in the paclitaxel group 21 days after inoculation. Low dose paclitaxel was observed to have a weaker anti-nociceptive effect on bone cancer pain, with a later-onset, compared with zoledronic acid. The results suggested that urinary levels of NTx may predict the anti-nociceptive responses of zoledronic acid and paclitaxel in a rat model of bone metastases.

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          Most cited references 26

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          Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

          Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low ( or = 100 nmol/mmol creatinine), and BAP as low ( or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.
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            Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention.

            Peripheral neuropathies induced by chemotherapy (CIPN) are an increasingly frequent problem. Contrary to hematologic adverse effects, which can be treated with hematopoetic growth factors, neither prophylaxis nor specific treatment is available, and only symptomatic treatment can be offered. Neurotoxic drugs are becoming a major dose-limiting factor. The epidemiology is still unclear. Several drug-dependent pathogenetic mechanisms exist. CIPN are predominately sensory, length-dependent neuropathies that develop after a typical cumulative dose. Usually, the appearance of CIPN is dose dependent, although in at least 2 drugs (oxaliplatin and taxanes), immediate toxic effects occur. The most frequent substances causing CIPN are platin compounds, vinka alkaloids, taxanes, and bortezomib and thalidomide. The role of synergistic neurotoxicity caused by previously given chemo-therapies and concomitant chemotherapies and the role pre-existent neuropathy on the development of a CIPN is not clear. As the number of long-term cancer survivors increases and a new focus on long-term effects of chemotherapy-induced neuropathies emerge, concepts of rehabilitation need to be implemented to improve the patients' functions and quality of life.
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              Bone cancer pain.

              In the United States, cancer is the second most common cause of death and it is expected that about 562,340 Americans will have died of cancer in 2009. Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. Once tumors metastasize to bone, they are a major cause of morbidity and mortality as the tumor induces significant skeletal remodeling, fractures, pain, and anemia. Currently, the factors that drive cancer pain are poorly understood. However, several recently introduced models of bone cancer pain, which closely mirror the human condition, are providing insight into the mechanisms that drive bone cancer pain and guide the development of mechanism-based therapies to treat the cancer pain. Several of these mechanism-based therapies have now entered human clinical trials. If successful, these therapies have the potential to significantly enlarge the repertoire of modalities that can be used to treat bone cancer pain and improve the quality of life, functional status, and survival of patients with bone cancer.
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                Author and article information

                Affiliations
                [1 ]Departments of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
                [2 ]Departments of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
                [3 ]Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
                Author notes
                Correspondence to: Professor Shiying Yu, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei 430030, P.R. China, E-mail: syyu@ 123456tjh.tjmu.edu.cn
                [*]

                Contributed equally

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                September 2015
                17 June 2015
                17 June 2015
                : 12
                : 3
                : 4243-4249
                mmr-12-03-4243
                10.3892/mmr.2015.3948
                4526072
                26081451
                Copyright © 2015, Spandidos Publications

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

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