Thalidomide derivatives and the immune system 6. Effects of two derivatives with no obvious teratogenic potency on the pattern of integrins and other surface receptors on blood cells of marmosets
“…Although thalidomide did not alter the expression of E-selectin, ICAM-1, or VCAM-1 on resting HIMEC, it was associated with inhibition of the upregulation of all three of these CAM following induction with TNF-␣/LPS. These findings are in agreement with Nogueira and coworkers (30), who demonstrated that thalidomide did not alter CAM expression in resting HUVEC. However, in contrast with the others who have reported increases in ICAM-1, density on TNF-␣ activated endothelial cells in response to increasing concentrations of thalidomide (17).…”
The glutamic acid derivative thalidomide is a transcriptional inhibitor of TNF-alpha but is also known to affect human blood vessels, which may underlie its teratogenicity. Thalidomide has been used in the treatment of refractory Crohn's disease (CD), but the therapeutic mechanism is not defined. We examined the effect of thalidomide on primary cultures of human intestinal microvascular endothelial cells (HIMEC), the relevant endothelial cell population in inflammatory bowel disease (IBD), to determine its effect on endothelial activation, leukocyte interaction, and VEGF-induced angiogenesis. HIMEC cultures were pretreated with thalidomide before activation with either TNF-alpha/LPS or VEGF. A low-shear-stress flow adhesion assay with either U-937 or whole blood was used to assess HIMEC activation following TNF-alpha/LPS, and a Wright's stain identified adherent leukocytes. Expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) was assessed using radioimmunoassay. Effects of thalidomide on NF-kappaB activation, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression in TNF-alpha/LPS-activated HIMEC were determined by RT-PCR and Western blotting. Thalidomide blocked adhesion of both U-937 and whole blood leukocytes by 50% in HIMEC, inhibiting binding of all classes of leukocytes. Thalidomide also blocked NF-kappaB and cell adhesion molecule expression in HIMEC. In marked contrast, thalidomide did not affect either iNOS or COX-2 expression, two key molecules that play a role in the downregulation of HIMEC activation. VEGF-induced HIMEC transmigration, growth, proliferation, tube formation, and Akt phosphorylation were significantly inhibited by thalidomide. In summary, thalidomide exerted a potent effect on HIMEC growth and activation, suggesting that it may also function via an endothelial mechanism in the treatment of CD.
“…Although thalidomide did not alter the expression of E-selectin, ICAM-1, or VCAM-1 on resting HIMEC, it was associated with inhibition of the upregulation of all three of these CAM following induction with TNF-␣/LPS. These findings are in agreement with Nogueira and coworkers (30), who demonstrated that thalidomide did not alter CAM expression in resting HUVEC. However, in contrast with the others who have reported increases in ICAM-1, density on TNF-␣ activated endothelial cells in response to increasing concentrations of thalidomide (17).…”
The glutamic acid derivative thalidomide is a transcriptional inhibitor of TNF-alpha but is also known to affect human blood vessels, which may underlie its teratogenicity. Thalidomide has been used in the treatment of refractory Crohn's disease (CD), but the therapeutic mechanism is not defined. We examined the effect of thalidomide on primary cultures of human intestinal microvascular endothelial cells (HIMEC), the relevant endothelial cell population in inflammatory bowel disease (IBD), to determine its effect on endothelial activation, leukocyte interaction, and VEGF-induced angiogenesis. HIMEC cultures were pretreated with thalidomide before activation with either TNF-alpha/LPS or VEGF. A low-shear-stress flow adhesion assay with either U-937 or whole blood was used to assess HIMEC activation following TNF-alpha/LPS, and a Wright's stain identified adherent leukocytes. Expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) was assessed using radioimmunoassay. Effects of thalidomide on NF-kappaB activation, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression in TNF-alpha/LPS-activated HIMEC were determined by RT-PCR and Western blotting. Thalidomide blocked adhesion of both U-937 and whole blood leukocytes by 50% in HIMEC, inhibiting binding of all classes of leukocytes. Thalidomide also blocked NF-kappaB and cell adhesion molecule expression in HIMEC. In marked contrast, thalidomide did not affect either iNOS or COX-2 expression, two key molecules that play a role in the downregulation of HIMEC activation. VEGF-induced HIMEC transmigration, growth, proliferation, tube formation, and Akt phosphorylation were significantly inhibited by thalidomide. In summary, thalidomide exerted a potent effect on HIMEC growth and activation, suggesting that it may also function via an endothelial mechanism in the treatment of CD.
“…In this case, a dissociation of teratogenic profile from effects on inflammations and immune reactions might not be easily achievable [42][43][44][45].…”
Section: Teratogenicity Hypothesismentioning
confidence: 92%
“…carbonyl group by a thiocarbonyl, aiming to elucidate the contribution of four amide carbonyl groups of thalidomide (1) to its biological activity. The action of thiothalidomide (36)(37)(38)(39)(40) and analogs (41)(42)(43)(44)(45)(46) to inhibit TNF-α secretion was assessed in human peripheral blood mononuclear cells (PBMC), and the results obtained indicated that monothiothalidomide (36) and 3-thiothalidomide (37) have only marginal activity at 30 µM with inhibition of 31% and 23%, respectively [79]. In contrast, the dithiothalidomides derivatives 38 and 39 exhibited more potent inhibitory activities with IC 50 values of 20 µM and 11 µM, respectively (Fig.…”
Thalidomide ([2-(2,6-dioxo-hexahydro-3-(R,S)-pyridinyl)-1,3-isoindolinedione]), well known by its teratogenic effect, caused birth defects in up to 12,000 children in the 1960s. More recently, this drug was approved by the US Food and Drug Administration for the treatment of erythema nodosum leprosum, under restricted-use program, and a variety of new possible therapeutic applications have been described. This article will accomplish a review of medicinal chemistry aspects of thalidomide and state of the art in the development of new anti-inflammatory and immunomodulator drug candidates designed using thalidomide as lead-compound.
“…12 This latter observation is in accordance with reports demonstrating that thalidomide alters expression of various adhesion receptors on white blood cells in healthy volunteers and in marmosets. [13][14][15] In vivo thalidomide may also exert an antimyeloma effect through stimulation of antimyeloma immune responses by induction of natural killer (NK) cell-mediated myeloma cell lysis 16 or by acting as a costimulatory signal to induce cytotoxic responses in T lymphocytes. 17 The molecular targets of thalidomide are also not well understood; it has been shown to generate reactive oxygen species that damage DNA and may be responsible for the drug's teratogenic and antiangiogenic activity.…”
To determine the mechanism of thalidomide's antimyeloma efficacy, we studied the drug's activity in our severe combined immunodeficiency-human (SCIDhu) host system for primary human myeloma. In this model, tumor cells interact with the human microenvironment to produce typical myeloma manifestations in the hosts, including stimulation of neoangiogenesis. Because mice are not able to metabolize thalidomide efficiently, SCID-hu mice received implants of fetal human liver fragments under the renal capsule in addition to subcutaneous implants of the fetal human bone. Myeloma cell growth in these mice was similar to their growth in hosts without liver implant, as assessed by change in levels of circulating human immunoglobulins and by histologic examinations. Thalidomide given daily by peritoneal injection significantly inhibited myeloma growth in 7 of 8 experiments, each with myeloma cells from a different patient, in hosts implanted with human liver. In contrast, thalidomide exerted an antimyeloma effect only in 1 of 10 mice without liver implants. Microvessel density in the untreated controls was higher than in thalidomide-responsive hosts but not different from nonresponsive ones. Expression of vascular endothelial growth factor by myeloma cells and by other cells in the human bone, determined immunohistochemically, was not affected by thalidomide treatment in any experiment. Our study suggests that thalidomide metabolism is required for its antimyeloma efficacy. Although response to thalidomide was strongly associated with decreased microvessel density, we were unable to conclude whether reduced microvessel density is a primary result of thalidomide's antiangiogenic activity or is secondary to a lessened tumor burden. (Blood. 2002;100:4162-4168)
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