1521-1878/asset/olbannerleft.gif?v=1&s=2845fffff50a3ee70a98eae52f73644aabfc6da8)
Challenges
You have free access to this content
Thalidomide-induced limb defects: resolving a 50-year-old puzzle
Article first published online: 17 NOV 2009
DOI: 10.1002/bies.200900103
Copyright © 2009 Wiley Periodicals, Inc.
Additional Information
How to Cite
Vargesson, N. (2009), Thalidomide-induced limb defects: resolving a 50-year-old puzzle. Bioessays, 31: 1327–1336. doi: 10.1002/bies.200900103
Publication History
- Issue published online: 17 NOV 2009
- Article first published online: 17 NOV 2009
References
- 1
- 2, , . 2004. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 4: 314–22.
- 3, , . 2005. Thalidomide as a novel therapeutic agent: new uses for an old product. Drug Discov Today 10: 107–14.
- 4, . 1992. Recognition of thalidomide defects. J Med Genet 29: 716–23.
- 5. 1988. A short history of thalidomide embryopathy. Teratology 38: 203–15.Direct Link:
- 6, , . 2000. Mechanism of action in thalidomide teratogenesis. Biochem Pharm 59: 1489–99.
- 7, . 2003. Thalidomide: a review of approved and investigational uses. Clin Ther 25: 342–95.
- 8. 1961. Thalidomide and congenital abnormalities. Lancet 2: 1358.
- 9, . 1962. Foetal malformations due to thalidomide. Ger Med Mon 7: 253–58.
- 10
- 11. 1977. Clinical observations on the thalidomide syndrome. Proc R Soc Med 70: 225–27.
- 12, . 1999. Teratogen update: Thalidomide: a review, with a focus on ocular findings and new potential uses. Teratology 60: 306–21.Direct Link:
- 13. 1986. The thalidomide syndrome: risks of exposure and spectrum of malformations. Clin Perinatol 13: 555–73.
- 14. 1965. Teratogenic properties of thalidomide. Br Med J 2: 1064.
- 15, , . 1973. The effect of Thalidomide intake during 113 human pregnancies. Teratology 8: 163–66.Direct Link:
- 16, , , et al. 2004. Thalidomide-derived immunomodulatory drugs as therapeutic agents. Expert Opin Biol Ther 4: 1963–70.
- 17, . 2009. Lenalidomide: a novel anticancer drug with multiple modalities. Expert Opin Pharmacother 10: 125–33.
- 18, . 2003. Thalidomide and its derivatives: emerging from the wilderness. Postgrad Med J 79: 127–32.
- 19, . 2000. Hypothesis: Thalidomide embryopathy – Proposed mechanism of action. Teratology 61: 189–95.Direct Link:
- 20, . 2000. Thalidomide: current and potential applications. Am J Med 108: 487–95.
- 21, , , et al. 1996. Thalidomide, a current teratogen in South America. Teratology 54: 273–77.Direct Link:
- 22, , , et al. 2007. New cases of thalidomide embryopathy in Brazil. Birth Defects Res A Clin Mol Teratol 79: 671–72.Direct Link:
- 23. 1963. Teratogenic effects of thalidomide and related substances. Lancet 1: 723–24.
- 24, , . 2002. Thalidomide metabolism by the CYP2C subfamily. Clin Cancer Res 8: 1964–73.
- 25, , , et al. 1996. Rediscovering Thalidomide: a review of its mechanism of action, side effects and potential uses. J Am Acad Dermatol 35: 969–79.
- 26, , . 1986. Teratogen metabolism: Thalidomide activation is mediated by Cytochrome P-450. Toxicol Appl Pharmacol 82: 175–79.
- 27, , , et al. 2005. Orally administered lenalidomide (CC-5013) is antiangiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvasc Res 69: 56–63.
- 28, , , et al. 2002. 5′-OH thalidomide, a metabolite of thalidomide, inhibits angiogenesis. Ther Drug Monit 24: 104–10.
- 29, , , et al. 2003. Antiangiogenic activity of N-substituted and tetrafluorinated thalidomide analogues. Cancer Res 63: 3189–94.
- 30, , , et al. 2004. Antitumor effects of thalidomide analogs in human prostate cancer xenografts implanted in immunodeficient mice. Clin Cancer Res 10: 4192–97.
- 31, , , et al. 2006. Thalidomide metabolism and hydrolysis: mechanisms and implications. Curr Drug Metab 7: 677–85.
- 32, , , et al. 2006. Importance of the stress kinase p38 in mediating the direct cytotoxic effects of the thalidomide analogue, CPS49, in cancer cells and endothelial cells. Clin Cancer Res 12: 3502–09.
- 33, , , et al. 2004. Comparative molecular field analysis and comparative molecular similarity indices analysis of Thalidomide analogues as angiogenesis inhibitors. J Med Chem 47: 2219–27.
- 34, , , et al. 2009. Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. Proc Natl Acad Sci USA 106: 8573–79.
- 35, , . 1963. Teratogenic effects of thalidomide and related substances. Lancet 1: 552.
- 36. 1966. Early changes in limb buds of chick embryos after thalidomide treatment. J Embryol Exp Morphol 16: 289–300.
- 37, , , et al. 2006. Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells. BMC Cell Biol 7: 17.
- 38, , . 2007. Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signalling pathway. FASEB J 21: 1410–21.
- 39, , . 1965. Teratogenic effect of thalidomide in rabbits, rats, hamsters and mice. Toxicol Appl Pharmacol 7: 268–86.
- 40, , , et al. 1966. Intravenous injection of thalidomide in pregnant rabbits. Science 154: 1362.
- 41, , , et al. 1996. Down-regulation of adhesion receptors on cells of primate embryos as a probable mechanism of the teratogenic action of Thalidomide. Life Sci 58: 295–316.
- 42. 1988. Proposed mechanisms of action in Thalidomide embryopathy. Teratology 38: 229–39.Direct Link:
- 43, , , et al. 1994. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci 91: 4082–85.
- 44, . 2004. A novel hypothesis for thalidomide-induced limb teratogenesis: redox misregulation of the NF-kappaB pathway. Antioxid Redox Signal 6: 1–14.
- 45, , , et al. 2008. Thalidomide induces limb anomalies by PTEN stabilization, Akt suppression, and stimulation of caspase-dependent cell death. Mol Cell Biol 28: 529–38.
- 46, , . 2009. Integrins in cell migration – the actin connection. J Cell Sci 122: 199–206.
- 47, , , et al. 2000. A possible role of N-cadherin in thalidomide teratogenicity. Life Sci 67: 457–61.
- 48. 1998. A developmental model for thalidomide defects. Nature 396: 322–23.
- 49
- 50, , . 1984. Thalidomide deformities and their nerve supply. J Anat 139: 397–410.
- 51, , . 2001. A reciprocal relationship between cutaneous nerves and repairing skin wounds in the developing chick embryo. Dev Biol 238: 27–39.
- 52, , , et al. 2008. Specification of motor axon trajectory by ephrin-B: EphB signaling: symmetrical control of axonal patterning in the developing limb. Neuron 60: 1039–53.
- 53, . 1983. Peripheral nerves do not play a trophic role in limb skeletal morphogenesis. Teratology 27: 159–167.Direct Link:
- 54. 1985. Paths taken by sensory nerve fibres in aneural chick wing buds. J Embryol Exp Morphol 86: 109–24.
- 55. 1972. Chemical structure and teratogenic properties. IV. An outline of a chemical hypothesis for the teratogenic action of thalidomide. Acta Pharm Suec 9: 543–62.
- 56, , , et al. 1997. Thalidomide: lack of mutagenic activity across phyla and genetic endpoints. Mutat Res 396: 45–64.
- 57, , . 2002. Offspring of male and female parents with thalidomide embryopathy: birth defects and functional anomalies. Teratology 66: 115–21.Direct Link:
- 58, , , et al. 2003. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. J Med Genet 40: 473–8.
- 59, . 2004. Mutations in SALL4 in malformed father and daughter postulated previously due to reflect mutagenesis by Thalidomide. Birth Defects Res Part A 70: 550–51.Direct Link:
- 60, , . 1979. The effect of cell killing by X-irradiation on pattern formation in the chick limb. J Embryol Exp Morph 50: 175–98.
- 61, , , et al. 2009. A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning. Nature 460: 400–4.
- 62. 1997. Never ending tales of the mode of action of thalidomide. Teratog Carcinog Mutagen 17: i–ii.Direct Link:
- 63, , . 1999. Developmental model for thalidomide action. Nature 400: 419–20.
- 64. 1985. Teratogen update: clinical aspects of thalidomide embryopathy–a continuing preoccupation. Teratology 32: 133–44.Direct Link:
- 65, . 1969. Dysmelia – a classification and a pattern of malformation in a group of congenital defects of the limbs. J Bone Joint Surg 51B: 399–414.
- 66
- 67, . 2007. Rethinking the proximodistal axis of the vertebrate limb in the molecular era. Genes Dev 21: 1433–42.
- 68, . 2009. Generation of pattern and form in the developing limb. Int J Dev Biol 53: 805–12.
- 69, . 2001. Smad7 misexpression during embryonic angiogenesis causes vascular dilation and malformations independently of vascular smooth muscle cell function. Dev Biol 240: 499–516.
- 70. 2003. Vascularisation of the developing chick limb bud: role of the TGFβ signalling pathway. J Anat 202: 93–103.Direct Link:
- 71. 1998. The roles of FGFs in the early development of vertebrate limbs. Genes Dev 12: 1571–86.
- 72, , . 2002. Functions of FGF signaling from the apical ectodermal ridge in limb development. Nature 418: 501–8.
- 73, , . 2008. Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. Nature 453: 401–5.
- 74, . 1963. The incidence of limb and ear defects since the withdrawal of thalidomide. Lancet 1095–97.
- 75, , , et al. 2000 Thalidomide inhibits angiogenesis in embryoid bodies by the generation of hydroxyl radicals. Am. J. Pathology 156: 151–8.
- 76, , . 1998. Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Biochem Pharmacol 55: 1827–34.
- 77, , . 1965. The metabolism of thalidomide: the fate of thalidomide and some of its hydrolysis products in various species. Br J Pharmacol Chemother 25: 338–51.
- 78, , , et al. 1968. A comparison of the teratogenic activity of thalidomide in rabbits and rats. J Pharmacol Exp Ther 160: 189–200.
- 79, , . 1997. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularisation. Exp Eye Res 64: 971–78.
- 80, , , et al. 2002. Effects of putative hydroxylated thalidomide metabolites on blood vessel density in the chorioallantoic membrane (CAM) assay and on tumor and endothelial cell proliferation. Biol Pharm Bull 25: 597–604.
- 81, , , et al. 2004. Metabolism of thalidomide in liver microsomes of mice, rabbits and humans. J Pharmacol Exp Ther 310: 571–77.
- 82, , , et al. 2003. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 198: 483–9.
- 83, . 2004. Development and pathology of the hyaloid, choroidal and retinal vasculature. Int J Dev Biol 48: 1045–8.
- 84, , , et al. 2004. Valproic acid inhibits angiogenesis in vitro and in vivo. Mol Pharmacol 65: 520–7.
- 85, , . 2002. An in ovo chicken model to study the systemic and localized teratogenic effects of valproic acid. Teratology 66: 153–63.Direct Link:
- 86. 2002. Teratogen-induced limb defects. Am J Med Genet 112: 297–303.Direct Link:
- 87, , . 2009. Roles of angiopoietins in kidney development and disease. J Am Soc Nephrol 20: 239–44.
- 88, , . 2002. Divergent vascular mechanisms downstream of Sry establishe the arterial system in the XY gonad. Dev Biol 244: 418–28.
- 89, . 2005. Common mechanisms of nerve and blood vessel wiring. Nature 436: 193–200.
- 90, , , et al. 2005. Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma. J Clin Oncol 23: 5334–46.
- 91, , , et al. 2005. Thalidomide-induced antiangiogenic action is mediated through depletion of VEGF receptors, and is antagonized by spingosine-1-phosphate. Blood 106: 125–34.
- 92, , , et al. 2005. Antimyeloma activity of two novel N substituted and tetrafluorinated thalidomide analogs. Leukemia 19: 1253–61.
- 93, , , et al. 2002. Misregulation of gene expression in the redox-sensitive NF-kB-dependent limb outgrowth pathway by thalidomide. Dev. Dyn. 255: 186–194.Direct Link:
- 94. 2002. Why study human limb malformations? J Anat 202: 27–35.Direct Link:
- 95, , , et al. 2005. Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nat Genet 37: 468–70.
- 96, , , et al. 2005. Inactivating mutations in ESCO2 cause SC Phocomelia and Roberts syndrome: no phenotype-genotype correlation. Am J Hum Genet 77: 1117–28.
- 97, . 2006. Advances in understanding drug-induced neuropathies. Drug Saf 29: 23–30.
- 98, . 2009. Thalidomide chemotherapy-induced peripheral neuropathy:actual status and new perspectives with thalidomide analogues derivatives. Mini Rev Med Chem 9: 760–68.
- 99, . 2000. A Review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treat Rev 26: 351–62.
- 100, , , et al. 2009. Multiple myeloma. Lancet 374: 324–39.
- 101, , , et al. 2009. The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res 77: 78–86.
- 102, , , et al. 2008. RevAssist: a comprehensive risk minimization programme for preventing fetal exposure to lenalidomide. Drug Saf 31: 743–52.