Thalidomide is an inhibitor of angiogenesis.

Abstract

Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of aniogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antaniogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization ofthafidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally adminsered drug for the treatment of many diverse dease dependent on angiogenesis.Thalidomide is a potent teratogen. It was developed by Chemie Grunenthal in the 1950s as a sedative that appeared so nontoxic in rodent models that a LD50 could not be established. In 1961, McBride (1) and Lenz (2) described the association between limb defects in babies and maternal thalidomide usage. Although humans are exquisitely sensitive to the teratogenic effects of thalidomide, experiments in rodents failed to reveal similar effects (3, 4). Teratogenic effects could be experimentally reproduced by the administration of thalidomide to pregnant rabbits at an oral dose of 100-300 mg per kg per day (5, 6). Over the past 30 years, the mechanism of thalidomide's teratogenicity has been extensively studied but has remained unsolved (7).We now postulate that the limb defects seen with thalidomide were secondary to an inhibition of blood vessel growth in the developing fetal limb bud. The limb bud is unique in requiring a complex interaction of both angiogenesis and vasculogenesis during development (8). Vasculogenesis is the formation of a capillary bed from endothelial cells that have differentiated from mesenchymal precursors. Angiogenesis is the formation of new blood vessels from sprouts ofpreexisting vessels. Therefore, the limb bud would be a particularly vulnerable target to a teratogen that inhibited endothelial cell function. We chose to examine the effect of thalidomide on growing vasculature in the chicken chorioallantoic membrane and in the rabbit cornea. MATERIALS AND METHODSChicken chorioallantoic membrane (CAM) assays were performed as described (9, 10) and the effects on the developing vasculature were recorded at 48 h after implantation of the 0.5% carboxymethylcellulose pellet containing various drugs. Corneal

Oesophageal cancer and cachexia: the effect of short‐term treatment with thalidomide on weight loss and lean body mass

“…The concept of angiogenic therapy was first published in 1971 by Folkman, 25 but it was not until later that the anti-angiogenic effect of thalidomide was described. 26 Eisen et al used low-dose thalidomide as an anti-angiogenic agent in patients with advanced melanoma, ovarian and breast cancer. 27 Thalidomide has a direct effect on the cancer tissue itself through its anti-angiogenic properties.…”

Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo

“…These recent insights disclose new possible therapeutic targets. Interestingly, the anti-angiogenic drug, thalidomide, has been reported to be effective in patients with refractory MM (D'Amato et al, 1994;Singhal et al, 1999). The development of drugs acting on different levels of angiogenesis can thus be considered as a promising pathway.…”

Thalidomide‐induced teratogenesis: History and mechanisms

“…These include rodent and rabbit corneal assays where blood vessels induced in response to a FGF soaked bead are destroyed following thalidomide application (D'Amato et al, 1994; Kenyon et al, 1997). Rat fetuses exposed to thalidomide in late gestation show blood vessel disruption in areas of the brain areas linked to causing autism (Hallene et al, 2006).…”