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In Reply

Ottawa Hospital Regional Cancer Center/University of Ottawa Hospital, Ottawa, Ontario, Canada

S. Gail Eckhardt

University of Colorado Cancer Center, Aurora, CO

In response to Dr Di Lorenzo's intriguing question regarding sunitinib malate and multiple receptor tyrosine kinase inhibitors as novel drugs for the treatment of chronic and neuropathic pain, there are no planned trials or intended evaluation of these drugs for this indication.¹ Chronic pain is a complex phenomena not well-characterized by physiologic pathogenic mechanisms or mediators, and is heavily influenced by psychosocial factors. Neuropathic pain may be due to damaged connective tissue nerve sheaths unable to guide growing axons, leading to directionless axons and tangled neuromas with disrupted excitatory glutamate and inhibitory gamma-aminobutyric acid neurotransmitters generating hyperexcitability of membrane sodium channels, changes in voltage dependent calcium changes, and initiation of rapid etopic firing from afferents.² Although poorly understood, angiogenesis does not appear to play a major role in the pathogenesis of this condition. Furthermore, there are no reports in the preclinical or clinical literature exploring sunitinib or any multitargeted antiangiogenic agents in the treatment of these conditions. The pain relief that cancer patients experience with sunitinib and other multitargeted antiangiogenic agents is likely due to its anticancer effect and reduction of tumor bulk rather than any effects on specific pain mediators or pathways.

In addition to the antiangiogenic and platelet-derived growth factor receptor inhibition mediated by thalidomide, it also selectively blocks tumor necrosis factor-alpha (TNF) production in activated macrophages, thereby decreasing the TNF-mediated regulation of receptor sensitivity in afferent nerve fibers and effects on endothelial cells.^3-5 In an animal model of neuropathic pain with chronic constriction of the rat sciatic nerve, thalidomide started preoperatively was able to decrease mechanical allodynia and thermal hyperalgesia, and immunohistochemistry revealed reduced endoneurial immunoreaction and pathologic vascular changes postsurgery compared with sham-treated animals.^6,7 As thalidomide has a broad spectrum of activities, it is not known whether its neuropathic pain analgesic effects are related to its antiangiogenic properties. Agents used to treat chronic pain such as nonsteroidal anti-inflammatory drugs, through prostaglandin-mediated mechanisms, and capsaicin, although excitation of nociceptive terminals in pain perception also have prominent antiangiogenic properties.^8-10 However, it is not known if inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs or capsaicin would contribute mechanistically to analgesia.

Multitargeted antiangiogenic agents like sunitinib may be effective in treating nonmalignant disease. As vascular endothelial growth factor (VEGF) is involved in the pathogenesis of diabetic renal disease, retinopathy, and neuropathy,¹¹ multitargeted antiangiogenic agents with VEGF-receptor inhibition may be helpful in these diabetic complications; however, VEGF agonists would be more appropriate for the treatment of diabetes-related cardiovascular disease.¹² Antiangiogenic and anti-VEGF therapy are also being explored for age-related macular degeneration due to choroidal neovascularization. Inhibition of VEGF with anti-VEGF antibodies such as ranibizumab appears to slow down disease progression with some improvement of visual acuity.^13,14 Furthermore, antiangiogenic agents preclinically demonstrate some activity in the treatment of rheumatoid arthritis (RA). Inflammatory cytokines, interleukins, and possibly TNF and interferon gamma may be responsible for the excessive VEGF production,¹⁵ causing vascular proliferation and blood vessel invasion of the synovial lining in RA with acidic fibroblast growth factor (FGF) and basic FGF involved in synoviocyte proliferation, synovial hyperplasia, and apoptotic resistance.^16,17 The multitargeted angiogenic receptor tyrosine kinase inhibitor, PTK787/ZK222584, was able to suppress RA severity and cause a dose-dependent reduction in new blood vessel formation in mice models.¹⁸ As angiogenesis plays a role in a multitude of malignant and benign conditions, preclinical studies are further exploring new indications for these novel antiangiogenic agents.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: S. Gail Eckhardt, Pfizer (C) Stock Ownership: None Honoraria: S. Gail Eckhardt, Pfizer Research Funding: S. Gail Eckhardt, Pfizer Expert Testimony: None Other Remuneration: None

REFERENCES

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2. Woolf CJ, Mannion RJ: Neuropathic pain: Aetiology, symptoms, mechanisms, and management. Lancet 353:1959-1964, 1999[CrossRef][Medline]

3. Ribeiro RA, Vale ML, Ferreira SH, et al: Analgesic effect of thalidomide on inflammatory pain. Eur J Pharmacol 391:97-103, 2000[CrossRef][Medline]

4. Rowbotham MC: Pharmacologic management of complex regional pain syndrome. Clin J Pain 22:425-429, 2006[CrossRef][Medline]

5. Vale ML, Cunha FQ, Brito GA, et al: Anti-nociceptive effect of thalidomide on zymosan-induced experimental articular incapacitation. Eur J Pharmacol 536:309-317, 2006[CrossRef][Medline]

6. George A, Marziniak M, Schafers M, et al: Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin. Pain 88:267-275, 2000[CrossRef][Medline]

7. Sommer C, Marziniak M, Myers RR: The effect of thalidomide treatment on vascular pathology and hyperalgesia caused by chronic constriction injury of rat nerve. Pain 74:83-91, 1998[CrossRef][Medline]

8. Min JK, Han KY, Kim EC, et al: Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res 64:644-651, 2004[Abstract/Free Full Text]

9. Szabo IL, Pai R, Soreghan B, et al: NSAIDs inhibit the activation of egr-1 gene in microvascular endothelial cells. A key to inhibition of angiogenesis? J Physiol Paris 95:379-383, 2001[CrossRef][Medline]

10. Tarnawski AS, Jones MK: Inhibition of angiogenesis by NSAIDs: Molecular mechanisms and clinical implications. J Mol Med 81:627-636, 2003[CrossRef][Medline]

11. Veves A, King GL: Can VEGF reverse diabetic neuropathy in human subjects? J Clin Invest 107:1215-1218, 2001[Medline]

12. Duh E, Aiello LP: Vascular endothelial growth factor and diabetes: The agonist versus antagonist paradox. Diabetes 48:1899-1906, 1999[Abstract]

13. Kaiser PK: Antivascular endothelial growth factor agents and their development: Therapeutic implications in ocular diseases. Am J Ophthalmol 142:660-668, 2006[CrossRef][Medline]

14. Ng EW, Shima DT, Calias P, et al: Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 5:123-132, 2006[CrossRef][Medline]

15. Malemud CJ: Growth hormone, VEGF and FGF: Involvement in rheumatoid arthritis. Clin Chim Acta 375:10-19, 2007[CrossRef][Medline]

16. Kim WU, Kang SS, Yoo SA, et al: Interaction of vascular endothelial growth factor 165 with neuropilin-1 protects rheumatoid synoviocytes from apoptoticdeath by regulating Bcl-2 expression and Bax translocation. J Immunol 177:5727-5735, 2006[Abstract/Free Full Text]

17. Yoo SA, Bae DG, Ryoo JW, et al: Arginine-rich anti-vascular endothelial growth factor (anti-VEGF) hexapeptide inhibits collagen-induced arthritis and VEGF-stimulated productions of TNF-alpha and IL-6 by human monocytes. J Immunol 174:5846-5855, 2005[Abstract/Free Full Text]

18. Grosios K, Wood J, Esser R, et al: Angiogenesis inhibition by the novel VEGF receptor tyrosine kinase inhibitor, PTK787/ZK222584, causes significant anti-arthritic effects in models of rheumatoid arthritis. Inflamm Res 53:133-142, 2004[CrossRef][Medline]

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Related Correspondence

• Sunitinib Malate and Multiple Receptor Tyrosine Kinases Inhibitors: Are They Also Novel Drugs for Chronic and Neurophatic Pain?
  Luigi Di Lorenzo
  JCO 2007 25: 2858-2859 [Full Text]

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