Biological Activity
lenalidomideis a derivative of thalidomide introduced in 2004. lenalidomide (revlimid, cc-5013) is a tnf-α secretion inhibitor with ic50 of 13 nm.
in vitro
lenalidomide strongly induces il-2 and sil-2r production. lenalidomide-induced tyrosine phosphorylation of cd28 on t cells is followed by a down-stream activation of nf-κb [2]. lenalidomide and pomalidomide inhibits autoubiquitination of crbn in hek293 t cells expressing thalidomide-binding competent wild-type crbn, but not thalidomide-binding defective crbn (yw/aa). overexpression of crbn wild-type protein, but not crbn (yw/aa) mutant protein, in kms12 myeloma cells, amplifies pomalidomide-mediated reductions in c-myc and irf4 expression and increases in p21(waf-1) expression. long-term selection for lenalidomide resistance in h929 myeloma cell lines is accompanied by a reduction in crbn, while in df15r myeloma cells resistant to both pomalidomide and lenalidomide, crbn protein is undetectable [3].
in vivo
pharmacokinetic studies evaluated doses of 0.5, 1.5, 5, and 10 mg/kg iv and 0.5 and 10 mg/kg doses for ip and oral routes. liquid chromatography-tandem mass spectrometry was used to quantify lenalidomide in plasma, brain, lung, liver, heart, kidney, spleen, and muscle [4]. treatment with either thalidomide or lenalidomide attenuated weight loss, enhanced motor performance, decreased motor neuron cell death, and significantly increased the life span in g93a transgenic mice [5].
IC 50
value: 13 nm [1] lenalidomideis a derivative of thalidomide introduced in 2004. lenalidomide (revlimid, cc-5013) is a tnf-α secretion inhibitor with ic50 of 13 nm. in vitro: lenalidomide strongly induces il-2 and sil-2r production. lenalidomide-induced tyrosine phosphorylation of cd28 on t cells is followed by a down-stream activation of nf-κb [2]. lenalidomide and pomalidomide inhibits autoubiquitination of crbn in hek293 t cells expressing thalidomide-binding competent wild-type crbn, but not thalidomide-binding defective crbn (yw/aa). overexpression of crbn wild-type protein, but not crbn (yw/aa) mutant protein, in kms12 myeloma cells, amplifies pomalidomide-mediated reductions in c-myc and irf4 expression and increases in p21(waf-1) expression. long-term selection for lenalidomide resistance in h929 myeloma cell lines is accompanied by a reduction in crbn, while in df15r myeloma cells resistant to both pomalidomide and lenalidomide, crbn protein is undetectable [3]. in vivo: pharmacokinetic studies evaluated doses of 0.5, 1.5, 5, and 10 mg/kg iv and 0.5 and 10 mg/kg doses for ip and oral routes. liquid chromatography-tandem mass spectrometry was used to quantify lenalidomide in plasma, brain, lung, liver, heart, kidney, spleen, and muscle [4]. treatment with either thalidomide or lenalidomide attenuated weight loss, enhanced motor performance, decreased motor neuron cell death, and significantly increased the life span in g93a transgenic mice [5]. toxicity: international staging system iii received a combination therapy of lenalidomide (15 mg, day 1 - 21) with dexamethasone (40 mg, day 1, 8, 15, 22). after 4 days on chemotherapy, he experienced worsened dyspnea and was urgently hospitalized because of acute respiratory failure [6].
