A micro-imaging study linking bone cancer pain with tumor growth and bone resorption in a rat model

Doré-Savard, Louis; Beaudet, Nicolas; Tremblay, Luc; Xiao, Yongjun; Lepage, Martin; Sarret, Philippe

doi:10.1007/s10585-012-9530-0

Cited by 13 publications

(14 citation statements)

References 66 publications

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“…Cancer-bearing rats inoculated with 30,000 MRMT-1 cells directly into the femur displayed a decreased PWT in the dynamic von Frey test compared with sham-operated animals ( Figure 7C). As previously observed (44,45), tactile allodynia progressively developed until day 18, reaching a 60% decrease of the mechanical threshold (17.2 ± 1.2 g vs. 42.6 ± 1.0 g; P < 0.001). After pain detection on day 18, we evaluated the effects of i.v.…”

Section: Discussionsupporting

confidence: 81%

“…Finally, we validated the effect of ANG2002 on bone cancer pain. This model of mixed pain involving neuropathic and inflammatory components is one of the most severe and intractable types of chronic pain reported (44,45). Cancer-bearing rats inoculated with 30,000 MRMT-1 cells directly into the femur displayed a decreased PWT in the dynamic von Frey test compared with sham-operated animals ( Figure 7C).…”

Section: Discussionmentioning

confidence: 97%

“…Surgical implantation of mammary carcinoma cells in the femur was performed according to Doré-Savard et al (44,45). Briefly, the rat right hind paw was shaved and disinfected, and a minimal skin incision (8-10 mm) was made to expose the quadriceps femoris.…”

Section: Ang2002 Binding and Signalingmentioning

confidence: 99%

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Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Demeule¹,

Beaudet²,

Régina³

et al. 2014

J. Clin. Invest.

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101

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Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor-related protein-1 (LRP1). Using in situ brain perfusion in mice, we found that the compound ANG2002, a conjugate of An2 and NT, was transported at least 10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1 and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v. ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain. At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by the development of neuropathic and bone cancer pain in animal models. The analgesic properties of ANG2002 demonstrated in this study suggest that this compound is effective for clinical management of persistent and chronic pain and establish the benefits of this technology for the development of neurotherapeutics.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Demeule¹,

Beaudet²,

Régina³

et al. 2014

J. Clin. Invest.

Self Cite

101

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“…PET/MR image registration allowed us to perform region-specific analyses of the bone environment. On day 15, our previous results demonstrated the consistent presence of a tumor, ranging in size from 25 to 60 mm 3 (20). At that stage, PET images showed elevated accumulation at the border of the metaphysis or diaphysis region, compared with the contralateral side.…”

Section: Resultsmentioning

confidence: 57%

Mammary Cancer Bone Metastasis Follow-up Using Multimodal Small-Animal MR and PET Imaging

et al. 2013

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Despite tremendous progress in the management of breast cancer, the survival rate of this disease is still correlated with the development of metastases-most notably, those of the bone. Diagnosis of bone metastasis requires a combination of multiple imaging modalities. MR imaging remains the best modality for soft-tissue visualization, allowing for the distinction between benign and malignant lesions in many cases. On the other hand, PET imaging is frequently more specific at detecting bone metastasis by measuring the accumulation of radiotracers, such as 18 F-sodium fluoride ( 18 F-NaF) and 18 F-FDG. Thus, the main purpose of this study was to longitudinally monitor bone tumor progression using PET/MR image coregistration to improve noninvasive imaging-assisted diagnoses. Methods: After surgical implantation of mammary MRMT-1 cells in a rat femur, we performed minimally invasive imaging procedures at different time points throughout tumor development. The procedure consisted of sequential coregistered MR and PET image acquisition, using gadolinium-diethylenetriaminepentaacetic acid (DTPA) as a contrast agent for MR imaging and 18 F-FDG, 11 C-methionine, and 18 F-NaF as molecular tracers for PET imaging. The animals were then euthanized, and complementary radiologic (micro-CT scans) and histologic analyses were performed. Results: In this preclinical study, we demonstrated that coregistered MR and PET images provide helpful information in a rat mammary-derived bone cancer model. First, MR imaging provided a high-definition anatomic resolution that made the localization of bone resorption and tumor extension detectable between days 9 and 18 after the injection of cancer cells in the medullary channel of the femur. Indeed, the calculation of mean standardized uptake value (SUV mean ) and maximal SUV (SUV max ) in bone and softtissue regions, as defined from the gadolinium-DTPA contrastenhanced MR images, showed 18 F-NaF uptake modifications and increased 18 F-FDG or 11 C-methionine uptake in the bone and surrounding soft tissues. 18 F-FDG and 11 C-methionine were compared in terms of the magnitude of change in their uptake and variability. We observed that 11 C-methionine SUV mean variations in the tumor were more important than those of 18 F-FDG. We also found fewer interindividual variations using SUV mean as a quantitative parameter than SUV max . Conclusion: This preclinical evaluation demonstrated that a PET/MR image coregistration protocol provided a powerful tool to evaluate bone tumor progression in a rat model of bone metastasis and that this protocol could be translated to improve the clinical outcome for metastatic breast cancer management.

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“…Data are shown as means ± SEM (6-8 rats/group for reference compounds, 10-15 rats/group for CCI and sham treatment). ***P< 0.001. measure proxies of the quality-of-life in freely moving rats (47,56). Here, we used a DWB device to monitor the effects of NTS2 agonists and reference drtigs on different qualit}'-of-life proxies, including time-of-use of the injured limb, weight load deficits, and compensatory shifts in weight distribution.…”

Section: Nts2 Agonists Reduce Neuropathy-induced Weightbearing Deficimentioning

confidence: 99%

Spinal NTS2 receptor activation reverses signs of neuropathic pain

Tétreault¹,

Beaudet²,

Perron

et al. 2013

FASEB j.

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Management of painful peripheral neuropathies remains challenging, since patients with chronic pain respond poorly to the available pharmacopeia. In recent years, the G-protein-coupled receptor neurotensin (NT) type 2 (NTS2) emerged as an attractive target for treating transitory pain states. To date, however, there is no evidence for its role in the regulation of chronic peripheral neuropathies. Here, we found that NTS2 receptors were largely localized to primary afferent fibers and superficial dorsal horns. Changes in the time course of the gene expression profile of NT, NTS1, and NTS2 were observed over a 28-d period following the sciatic nerve constriction [chronic constriction injury (CCI) model]. We next determined the effects of central delivery of selective-NTS2 agonists to CCI-treated rats on both mechanical allodynia (evoked withdrawal responses) and weight-bearing deficits (discomfort and quality-of-life proxies). The NTS2 analogs JMV431, levocabastine, and β-lactotensin were all effective in reducing ongoing tactile allodynia in CCI-treated rats. Likewise, amitriptyline, pregabalin, and morphine significantly attenuated CCI-induced mechanical hypersensitivity. NTS2 agonists were also efficient in reversing weight-bearing and postural deficits caused by nerve damage, unlike reference analgesics currently used in the clinic. Thus, NTS2 agonists may offer new treatment avenues for limiting pain associated with peripheral neuropathies and improve functional rehabilitation and well-being.

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A micro-imaging study linking bone cancer pain with tumor growth and bone resorption in a rat model

Cited by 13 publications

References 66 publications

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Mammary Cancer Bone Metastasis Follow-up Using Multimodal Small-Animal MR and PET Imaging

Spinal NTS2 receptor activation reverses signs of neuropathic pain

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