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1. Introduction
Thalidomide was initially synthesized as a non-addictive, non-barbiturate sedative by the German pharmaceutical company Chemie-Grünenthal in the late 1950's. It was discovered to be an effective antiemetic and was then used to control symptoms of nausea and vomiting in pregnant women. It was not until 1961 that thalidomide was validated as the cause of the largest man-made medical disaster in history with an estimated 10,000 children in 46 countries born with birth defects. Subsequently, thalidomide was withdrawn from most countries. In the following decades, the immunomodulatory and antiangiogenic effects of thalidomide were discovered and recognised as a novel indication for treatment with thalidomide. In 1965, Sheskin (1) serendipitously discovered that the immunomodulatory effects of thalidomide could be used to successfully cure erythema nodosum leprosum. In 1994, D'Amato et al (2) discovered that orally administered thalidomide inhibits angiogenesis induced by basic fibroblast growth factor (FGF) in a rabbit cornea micropocket assay. Due to these mechanisms, thalidomide was used to treat multiple myeloma and shown to be highly effective (3). To date, studies have been performed to examine the efficacy of thalidomide in the treatment of solid tumors, such as prostate cancer, glioblastoma and squamous cell carcinoma of the neck (4–8).
In 2005, Jain suggested that certain antiangiogenic agents can also 'normalize' the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery (9). Subsequently, several studies of thalidomide suggested that it reduces tumor vessel density and tumor interstitial fluid pressure, while improving perfusion and oxygenation in preclinical fibrosarcoma and liver carcinoma models. Although the time of improved oxygenation only lasted for 2–4 days of thalidomide treatment (10), it demonstrated that thalidomide probably temporarily reversed tumor vessels towards a more normal phenotype. In vitro, thalidomide analogs also inhibited proliferative effects on human umbilical vein endothelial cells (11). These studies explored the vascular remodeling effect of thalidomide without associating vascular normalization with effects on immune cells. The immunomodulatory properties of thalidomide have been the focus of mechanistic studies of the therapeutic effects of thalidomide in patients with different types of cancer (12–14). The potent immunomodulatory activity of thalidomide mainly alters the secretion and activity of various cytokines (12–18). To some extent, these cytokines control the balance between pro-angiogenic...