Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0279530 (bone cancer)
 1,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over half of all chronic cancer pain arises from metastases to bone and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Currently, bone pain is treated primarily by opioid-based therapies, which are frequently accompanied by significant unwanted side effects. In an effort to develop nonopioid-based therapies that could rapidly attenuate tumor-induced bone pain, we examined the effect of intravenous administration of the bisphosphonate, ibandronate, in a mouse model of bone cancer pain. Following injection and confinement of green fluorescent protein-transfected murine osteolytic 2472 sarcoma cells into the marrow space of the femur of male C3H/HeJ mice, ibandronate was administered either as a single dose (300 microg/kg), at Day 7 post-tumor injection, when tumor-induced bone destruction and pain were first evident, or in three consecutive doses (100 microg/kg/day) at Days 7, 8, and 9 post-tumor injection. Intravenous ibandronate administered once or in three consecutive doses reduced ongoing and movement-evoked bone cancer pain-related behaviors, neurochemical markers of central sensitization, tumor burden, and tumor-induced bone destruction. These results support limited clinical trials that suggest the potential of ibandronate to rapidly attenuate bone pain and illuminate the mechanisms that may be responsible for limiting pain and disease progression.
J Pain Symptom Manage 2008 Sep
PMID:Intravenous ibandronate rapidly reduces pain, neurochemical indices of central sensitization, tumor burden, and skeletal destruction in a mouse model of bone cancer. 1841 Oct 18

It has been shown that interleukin-1beta (IL-1beta) facilitates nociception during neuropathic and inflammatory pain, but its involvement in bone cancer pain and its mechanisms have not previously been established. This study is an investigation of IL-1beta spinal expression and the N-methyl-D-aspartate (NMDA) receptor (NMDAR) NR1 subunit phosphorylation during cancer pain, co-localization of IL-1 receptor type I (IL-1RI) and NMDAR in the spinal cord, and the effects of IL-1 receptor antagonist (IL-1ra) on NMDAR1 (NR1) phosphorylation and hyperalgesia in a rat model of bone cancer pain. Cancer was induced by injecting AT-3.1 prostate cancer cells into the tibia of the male Copenhagen rat. Phosphorylation of NR1, an essential subunit of the NMDAR, is known to modulate NMDAR activity and facilitate pain. Mechanical hyperalgesia, established by a decrease in paw withdrawal pressure threshold (PWPT), was measured at baseline and 2 h after IL-1ra treatment. IL-1ra was given (i.t.) daily for 7 days between days 13 and 19 after the cancer cell inoculation. Spinal cords were removed for Western blot to measure IL-1beta and NR1 phosphorylation and for double immunostaining of IL-1RI and NR1. The data showed that 1) spinal IL-1beta was up-regulated and NR1 phosphorylation was increased, 2) IL-1ra at 0.1 mg/rat significantly (P<0.05) inhibited mechanical hyperalgesia, increasing PWPT on day 14 from 71.1+/-3.1-85.3+/-4.6 g and on day 19 from 73.5.0+/-3.5-87.1+/-3.7 g, and inhibited NR1 phosphorylation compared with saline control, and 3) IL-1RI is localized in NR1-immunoreactive neurons within the spinal cord. The results suggest that spinal IL-1beta enhances NR1 phosphorylation to facilitate bone cancer pain.
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PMID:Interleukin 1beta facilitates bone cancer pain in rats by enhancing NMDA receptor NR-1 subunit phosphorylation. 1855 6

The focus of this work was to examine the potential role of p38 mitogen activated protein kinase (p38) in a mouse model of bone cancer (osteosarcoma) pain. To generate osteosarcoma and sham animals, osteosarcoma cells or medium were injected into the medullary canal of the femur. Initially, ipsilateral tactile allodynia was observed in both groups, but by 12 days post-surgery, thresholds in the sham group returned towards baseline while hypersensitivity in the osteosarcoma group lasted throughout the study. An increase in phosphorylated p38 was detected by western blotting in dorsal root ganglia (DRG) and spinal cord day 14 after surgery. Immunohistochemistry showed that p38 was phosphorylated in DRG and spinal dorsal horn neurons at this time point. Two doses of a selective p38 inhibitor, SCIO-469, were administered in the chow starting 5 days post-surgery and continued throughout the study. Treatment with SCIO-469 led to a decrease in osteosarcoma-induced clinical score but had no effect on the allodynia. Bone erosion and tumor growth were also examined but no significant reduction of bone erosion or tumor growth was observed in the SCIO-469 treated mice. These data suggest that the p38 signaling pathway does not play a major role in bone cancer-mediated pain.
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PMID:Role of p38 mitogen activated protein kinase in a model of osteosarcoma-induced pain. 1858 57

Modern cancer therapies have significantly increased patient survival rates in both human and veterinary medicine. Since cancer patients live longer they now face new challenges resulting from severe, chronic tumor-induced pain. Unrelieved cancer pain significantly decreases the quality of life of such patients; thus the goal of pain management is to not only to alleviate pain, but also to maintain the patient's physiological and psychological well-being. The major impediment for developing new treatments for cancer pain has been our limited knowledge of the basic mechanisms that drive cancer pain and the lack of adequate animal cancer pain models to study the molecular, biochemical and neurobiological pathways that generate and maintain cancer pain. However this situation has recently changed with the recent development of several novel animal models of cancer pain. This review will focus on describing these animal models, many of them in rodents, and reviewing some of the recent information gained from the use of these models to investigate the basic mechanims that underlie the development and maintenance of cancer pain. Animal models of cancer pain can be divided into the following five categories: bone cancer pain models, non-bone cancer pain models, cancer invasion pain models, cancer chemotherapeutic-induced peripheral neuropathy models, and spontaneous occurring cancer pain models. These models will be important not only for enhancing our knowledge of how cancer pain is generated, but more importantly for the development of novel therapeutic regimes to treat cancer pain in both domestic animals and humans.
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PMID:Animal models of cancer pain. 1858 64

Pain due to bone malignancies is one of the most difficult types of cancer pain to fully control and may further decrease the patients' quality of life. Animal models of chronic pain conditions resulting from peripheral inflammatory reactions or nerve injuries are responsive to treatment with cannabinoid agonists. However, the use of cannabinoid agonists in humans may be hampered by CNS related side effects and development of tolerance. In the present study, we investigated the effect of repeated low dose administration of the synthetic cannabinoid agonist WIN 55,212-2 on bone cancer pain and neuropathic pain in mice. In addition, we investigated the development of CNS related side effects and tolerance. We found that 0.5 mg/kg/day for 18 days reduced pain related behavior and expression of spinal glial fibrillary acidic protein in the bone cancer pain model but not in the neuropathic pain model. Furthermore, this treatment strategy was not found to induce measurable CNS related side effects or tolerance. Cancer cell viability assays and bone volume fraction assessed by micro computed tomography (microCT) demonstrated that these effects were not due to changes in cancer progression. The difference in WIN 55,212-2 efficacy between the bone cancer and neuropathic pain models may reflect the different pain generating mechanisms, which may be utilized in designing new therapeutic drugs.
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PMID:Differential effects of repeated low dose treatment with the cannabinoid agonist WIN 55,212-2 in experimental models of bone cancer pain and neuropathic pain. 1861 8

The femur bone cancer pain model was developed by implanting mouse osteolytic tumor cells (NCTC 2472) into the intramedulla of the femur in C3H/HeN mice. In vivo imaging analysis revealed that the implanted tumor cells grew progressively over 14 days. Associated with the tumor growth, guarding behavior, which was an indication of ongoing pain, time-dependently increased. Limb use abnormality and allodynia, which were indications of ambulatory and neuropathic pain, respectively, also appeared. The analgesic effects of oxycodone and other opioids, such as morphine and fentanyl, were evaluated at 14 days when all pain-related behaviors clearly appeared. Oxycodone (2-20 mg/kg, s.c.), morphine (10-50 mg/kg, s.c.) and fentanyl (0.05-0.2 mg/kg, s.c.) significantly reduced guarding behavior. Oxycodone (5-20 mg/kg, s.c.) and fentanyl (0.1 and 0.2 mg/kg, s.c.) significantly reversed limb use abnormality, but morphine (5-50 mg/kg, s.c.) did not. Moreover, oxycodone (5-20 mg/kg, s.c.) dose-dependently reversed allodynia without affecting the sham-treated mice. Morphine (50 mg/kg, s.c.) and fentanyl (0.075-0.2 mg/kg, s.c.) also reversed allodynia, but morphine (50 mg/kg, s.c.) tended to affect and fentanyl (0.1 and 0.2 mg/kg, s.c.) affected the withdrawal threshold in sham-treated mice. These results suggested that oxycodone relieved not only ongoing pain, but also ambulatory and neuropathic pain, and that the analgesic profile of oxycodone could be different from that of either morphine or fentanyl.
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PMID:Oxycodone-induced analgesic effects in a bone cancer pain model in mice. 1875 99

Recently, it has been demonstrated that intrathecal delivery of resiniferatoxin (RTX) produces strong analgesia, even in models of bone cancer pain. RTX has been investigated to treat bladder dysfunction of spinal origin, applied by intravesical instillation. However, RTX delivered by this route was not completely satisfactory in controlling urinary incontinence and high intravesical pressure. Thus, the present study assessed the effects of intrathecal injections of RTX in bladder dysfunction in rats with spinal cord transection (SCT). Bladder function was evaluated in SCT rats 24 h following intrathecal administration of RTX. Detrusor overactivity and intravesical pressure were reduced in a dose-dependent manner. This was accompanied by a decrease in spinal cord TRPV1 and CGRP, but not in IB4 binding sensory fibres. Also, intrathecal RTX induced a dose-dependent reduction in spinal cord activation of the ERK pathway. Overall, our results show that intrathecal administration of RTX effectively reduces detrusor overactivity and reduces intravesical pressure in models of complete chronic spinal cord transection by suppressing the activity of TRPV1 expressing afferent fibres. Also, intrathecal RTX decreases sensory input, as shown by reduced spinal ERK activation. These findings might be relevant for the management of patients with spinal cord injuries.
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PMID:Intrathecal delivery of resiniferatoxin (RTX) reduces detrusor overactivity and spinal expression of TRPV1 in spinal cord injured animals. 1882 69

Tumors in bone are associated with pain in humans. Data generated in a murine model of bone cancer pain suggest that a disturbance of local endocannabinoid signaling contributes to the pain. When tumors formed after injection of osteolytic fibrosarcoma cells into the calcaneus bone of mice, cutaneous mechanical hyperalgesia was associated with a decrease in the level of anandamide (AEA) in plantar paw skin ipsilateral to tumors. The decrease in AEA occurred in conjunction with increased degradation of AEA by fatty acid amide hydrolase (FAAH). Intraplantar injection of AEA reduced the hyperalgesia, and intraplantar injection of URB597, an inhibitor of FAAH, increased the local level of AEA and also reduced hyperalgesia. An increase in FAAH mRNA and enzyme activity in dorsal root ganglia (DRG) L3-L5 ipsilateral to the affected paw suggests DRG neurons contribute to the increased FAAH activity in skin in tumor-bearing mice. Importantly, the anti-hyperalgesic effects of AEA and URB597 were blocked by a CB1 receptor antagonist. Increased expression of CB1 receptors by DRG neurons ipsilateral to tumor-bearing limbs may contribute to the anti-hyperalgesic effect of elevated AEA levels. Furthermore, CB1 receptor protein-immunoreactivity as well as inhibitory effects of AEA and URB597 on the depolarization-evoked Ca(2+) transient were increased in small DRG neurons cocultured with fibrosarcoma cells indicating that fibrosarcoma cells are sufficient to evoke phenotypic changes in AEA signaling in DRG neurons. Together, the data provide evidence that manipulation of peripheral endocannabinoid signaling is a promising strategy for the management of bone cancer pain.
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PMID:A decrease in anandamide signaling contributes to the maintenance of cutaneous mechanical hyperalgesia in a model of bone cancer pain. 1897 57

Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel that functions as an integrator of multiple pain stimuli including heat, acid, capsaicin and a variety of putative endogenous lipid ligands. TRPV1 antagonists have been shown to decrease inflammatory pain in animal models and to produce limited hyperthermia at analgesic doses. Here, we report that ABT-102, which is a potent and selective TRPV1 antagonist, is effective in blocking nociception in rodent models of inflammatory, post-operative, osteoarthritic, and bone cancer pain. ABT-102 decreased both spontaneous pain behaviors and those evoked by thermal and mechanical stimuli in these models. Moreover, we have found that repeated administration of ABT-102 for 5-12 days increased its analgesic activity in models of post-operative, osteoarthritic, and bone cancer pain without an associated accumulation of ABT-102 concentration in plasma or brain. Similar effects were also observed with a structurally distinct TRPV1 antagonist, A-993610. Although a single dose of ABT-102 produced a self-limiting increase in core body temperature that remained in the normal range, the hyperthermic effects of ABT-102 effectively tolerated following twice-daily dosing for 2 days. Therefore, the present data demonstrate that, following repeated administration, the analgesic activity of TRPV1 receptor antagonists is enhanced, while the associated hyperthermic effects are attenuated. The analgesic efficacy of ABT-102 supports its advancement into clinical studies.
Pain 2009 Mar
PMID:Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia. 1916 16

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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PMID:Cancer-induced bone loss and associated pain-related behavior is reduced by risedronate but not its phosphonocarboxylate analog NE-10790. 1944 17


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