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      Characterization of a rat model of metastatic prostate cancer bone pain

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          Abstract

          Purpose:

          The objectives of this study were to establish and characterize a novel animal model of metastatic prostate cancer-induced bone pain.

          Methods:

          Copenhagen rats were injected with 10 6 MATLyLu (MLL) prostate cancer cells or phosphate-buffered saline by per cutaneous intra femoral injections into the right hind leg distal epiphysis. Over 13 days, rats progressively developed a tumor within the distal femoral epiphysis. On days 3, 7, 10, and 13 post injection, rats were subjected to the incapacitance and Randall–Selitto behavioral tests as they are believed to be indirect reflections of tumor induced pain. Ipsilateral hind limbs were subjected to X-ray and computed tomography (CT) scans and histological sections were stained with hematoxylin and eosin (H&E).

          Results:

          Intra femoral injections of MLL cells resulted in the progressive development of a tumor leading to bone destruction and nociceptive behaviors. Tumor development resulted in the redistribution of weight to the contralateral hind leg and significantly reduced the paw withdrawal threshold of the ipsilateral hind paw as observed via the incapacitance and Randall–Selitto tests, respectively. X-ray and computed tomography scans along with H&E stains indicated tumor-associated structural damage to the distal femur. This model was challenged with administration of meloxicam. Compared with vehicle-injected controls, the meloxicam-treated rats displayed smaller nociceptive responses as observed with the incapacitance and Randall–Selitto tests, suggesting that meloxicam was effective in reducing the pain-related symptoms displayed by model animals and that the model behaved in a predictable way to cyclooxygenase-2 treatment.

          Conclusions:

          This model is unique from other bone cancer models in that it is a comprehensive model utilizing a competent immune system with a syngeneic tumor. The model establishes a tool that will be useful to investigate mechanisms of cancer pain that are induced by cancer cells.

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          Most cited references 14

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          Cancer-induced bone loss and associated pain-related behavior is reduced by risedronate but not its phosphonocarboxylate analog NE-10790.

          Prostate, breast and lung cancers readily develop bone metastases which lead to fractures, hypercalcemia and pain. Malignant growth in the bones depends on osteoclast-mediated bone resorption and in this regard bisphosphonate compounds, which have high-bone affinity and inhibit osteoclast activity, have been found to alleviate bone cancer symptoms. In this study, the bisphosphonate risedronate and its phosphonocarboxylate derivative NE-10790 was tested in a murine bone cancer pain model. Risedronate decreased bone cancer-related bone destruction and pain-related behavior and decreased the spinal expression of glial fibrillary acidic protein, whereas NE-10790 had no effect on these parameters. Furthermore, risedronate but not NE-10790 induced dose-dependent toxicity in NCTC-2472 cells in vitro. Furthermore, the direct toxic effect of risedronate on tumor cells observed in vitro opens the possibility that a direct toxic effect on tumor cells may also be present in vivo and be related to the efficacy of bisphosphonate compounds. In conclusion, these results suggest that risedronate treatment may lead to an increased life quality, in patient suffering from bone cancer, in terms of decreased osteolysis and pain, and merits further study.
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            Meloxicam inhibits the growth of colorectal cancer cells.

            Cyclooxygenase-2 has been reported to play an important role in colorectal carcinogenesis. The effects of meloxicam (a COX-2 inhibitor) on the growth of two colon cancer cell lines that express COX-2 (HCA-7 and Moser-S) and a COX-2 negative cell line (HCT-116) were evaluated. The growth rate of these cells was measured following treatment with meloxicam. HCA-7 and Moser-S colony size were significantly reduced following treatment with meloxicam; however, there was no significant change in HCT-116 colony size with treatment. In vivo studies were performed to evaluate the effect of meloxicam on the growth of HCA-7 cells when xenografted into nude mice. We observed a 51% reduction in tumor size after 4 weeks of treatment. Analysis of COX-1 and COX-2 protein levels in HCA-7 tumor lysates revealed a slight decrease in COX-2 expression levels in tumors taken from mice treated with meloxicam and no detectable COX-1 expression. Here we report that meloxicam significantly inhibited HCA-7 colony and tumor growth but had no effect on the growth of the COX-2 negative HCT-116 cells.
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              Bisphosphonates and breast carcinoma.

              The skeleton is a common site of breast carcinoma metastasis; 75% of patients with breast carcinoma demonstrate bone metastases at autopsy. The lytic destruction of bone in these patients is due to excessive osteoclastic activity. By reducing osteoclastic activity, bisphosphonates inhibit bone resorption. Initial studies of breast carcinoma patients were performed with clodronate, a first-generation bisphosphonate. Studies with small cohorts suggested reduction of pain, analgesic requirement, and development of hypercalcemia. A larger randomized, double-blind, placebo-controlled trial of oral clodronate 1600 mg/day demonstrated a significant reduction of the combined rate of all morbid skeletal events (significant reduction of the incidence of vertebral fractures, rate of vertebral deformity, and hypercalcemic episodes). Trends were observed that favored clodronate for the treatment of nonvertebral fractures and radiotherapy for relief of bone pain. There was no survival difference between the clodronate and placebo groups (Paterson et al., J Clin Oncol 1993;11:59-65). Pamidronate is a second-generation aminobisphosphonate that is a much more potent inhibitor of osteoclastic activity. Phase II studies again suggested an improvement in many of the skeletal complications of breast carcinoma. Two large Phase III studies have recently been completed. Women with Stage IV breast carcinoma who were receiving cytotoxic chemotherapy (380 patients) or endocrine therapy (371 patients) and had at least 1 lytic bone lesion were given either pamidronate 90 mg as a 2-hour infusion monthly for 2 years or a placebo infusion. After the two studies were pooled, 367 patients treated with pamidronate and 384 patients given placebo were available for analysis. The median time to first complication (pathologic fracture, vertebral collapse, spinal cord compression, or treatment of bone with radiation or surgery) was 12.7 months for the pamidronate patients and 7.0 months for placebo patients (P = 0.001). The time to first fracture was 25.2 months for pamidronate patients and 12.8 months for placebo patients (P = 0.003). The proportion of patients with fracture was 40% for pamidronate vs. 52% for placebo (P = 0.002); the proportion with radiation administered to bone was 29% for pamidronate vs. 43% for placebo (P = 0.001); and the proportion with any skeletal event was 51% for pamidronate vs. 64% for placebo (P = 0.001). The skeletal morbidity rate (the number of complications per year) at 24 months was 2.4 for the pamidronate group and 3.7 for placebo (P = 0.001). Pain and analgesic use was decreased among the pamidronate patients. There was no difference in survival between the groups. Not all patients responded to the same dose of bisphosphonate. Recent data suggests that patients who have a normalization of their urinary excretion of N-telopeptide have a reduced risk of progression of disease in bone and fracture. In summary, the addition of pamidronate to standard chemotherapy or endocrine therapy produces a sustained reduction in skeletal complications in breast carcinoma patients with osteolytic bone metastases.
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                Author and article information

                Journal
                J Pain Res
                Journal of Pain Research
                Journal of pain research
                Dove Medical Press
                1178-7090
                2010
                08 November 2010
                : 3
                : 213-221
                Affiliations
                [1 ]Department of Pathology and Molecular Pathology
                [2 ]Pain Research Laboratories
                [3 ]Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada
                Author notes
                Correspondence: Gurmit Singh, Pathology and Molecular Medicine, McMaster University, 699 Concession Street, Hamilton, Ontario L8V5C2, Canada, Tel +1 905 387 9711 ext 67004, Fax +1 905 575 6330, Email gurmit.singh@ 123456jcc.hhsc.ca
                Article
                jpr-3-213
                10.2147/JPR.S14209
                3004636
                21197325
                © 2010 De Ciantis et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

                Anesthesiology & Pain management

                meloxicam, tumor, nociception, behavior

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