Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, 33081, Aviano, Italy.
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via L. Giorgieri 1, 34127, Trieste, Italy.
Sci Rep. 2020 May 29;10(1):8773. doi: 10.1038/s41598-020-65424-z.
We here explore the soluble Human Leukocyte Antigen-G (sHLA-G) expression level as clinical biomarker in metastatic colorectal cancer (mCRC). To this aim the sHLA-G protein was measured in plasma samples of 40 patients with mCRC treated with the FOLFIRI (irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and leucovorin (LV)) regimen. The results suggest a link between HLA-G levels and irinotecan (CPT-11) pharmacokinetic, leading to hypothesize a molecular interaction between sHLA-G and CPT-11. This interaction was confirmed experimentally by fluorescence spectroscopy. HLA-G is known to exist in a number of polymorphs that affect both the protein expression levels and its peptide-binding cleft. The interaction between HLA-G polymorphs and CPT-11 was explored by means of computational modelling, confirming the hypothesis that CPT-11 could actually target the peptide binding cleft of the most common HLA-G polymorphs.
我们在这里探讨可溶性人类白细胞抗原-G（sHLA-G）作为转移性结直肠癌（mCRC）的临床生物标志物的表达水平。为此，我们测量了 40 名接受 FOLFIRI（伊立替康（CPT-11）联合 5-氟尿嘧啶（5-FU）和亚叶酸（LV））方案治疗的 mCRC 患者的血浆样本中的 sHLA-G 蛋白。结果表明 HLA-G 水平与伊立替康（CPT-11）药代动力学之间存在联系，从而假设 sHLA-G 与 CPT-11 之间存在分子相互作用。荧光光谱实验证实了这种相互作用。已知 HLA-G 存在多种多态性，影响蛋白质表达水平及其肽结合裂隙。通过计算建模研究了 HLA-G 多态性与 CPT-11 之间的相互作用，证实了 CPT-11 实际上可以靶向最常见的 HLA-G 多态性的肽结合裂隙的假设。
