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Comparative untargeted proteomic analysis of ADME proteins and tumor antigens for tumor cell lines

Acta Pharmaceutica Sinica B 2018年第2期8卷 252-260页

作者： Xiaomei Gu Qing Xiao Qian Ruan Yuezhong Shu Ashok Dongre Ramaswamy Iyer w.griffith.humphreys Yurong Lai Pharmaceutical Candidate Optimization Bristol-Myers Squibb Company Genomics Bristol-Myers Squibb Company

In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3 B2,H226, Ovcar3 and N87 were extracted and digested with γLys C and trypsin. The resulting peptide lysate were pre-fractionated and subjected to untargeted quantitative proteomics analysis using a high resolution mass spectrometer. The mass spectra were processed by the Max Quant and the protein abundances were estimated using total peak area(TPA) method. A total of 6037 proteins were identified, and the analysis resulted in the identification of 2647 membrane proteins. Of those, tumor antigens and absorption,metabolism, disposition and elimination(ADME) proteins including UDP-glucuronosyltransferase,cytochrome P450, solute carriers and ATP-binding cassette transporters were detected and disclosed significant variations among the cell lines. The principal component analysis was performed for the cluster of cell lines. The results demonstrated that H226 is closely related with N87, while Hep3 B2 aligned with HepG2. The protein cluster of Ovcar3 was apart from that of other cell lines investigated. By providing for the first time quantitative untargeted proteomics analysis, the results delineated the expression profiles of membrane proteins. These findings provided a useful resource for selecting targets of choice for anticancer therapy through advancing data obtained from preclinical tumor cell line models to clinical outcomes.

关键词： Cancer cell lines Untargeted quantitative proteomics Tumor-associated membrane proteins Cytochrome P450 ABC transporters SLC transporters

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Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate,BMS-753493,in CD2F1 mice after systemic administration

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Acta Pharmaceutica Sinica B 2016年第5期6卷 460-467页

作者： Hong Shen Lifei wang weiqi Chen Krista Menard Yang Hong Yuan Tian Samuel J.Bonacorsi w.griffith.humphreys Francis Y.Lee Jinping Gan Pharmaceutical Candidate Optimization Bristol-Myers Squibb Research & Development Discovery Oncology Bristol-Myers Squibb Research & Development Chemistry Bristol-Myers Squibb Research & Development

To assess targeting of an epothilone folate conjugate(BMS-753493) to the folate receptor(FR)-overexpressed tumor in mice bearing both FRt and FR– tumors,a series of experiments were conducted by quantitative whole-body autoradiography(QwBA) and LC–MS/MS following *** of BMS-753493 or its active moiety,BMS-748285 in mice bearing FRt(98M109) and FR–(M109) *** showed [3H]BMS-753493–derived radioactivity was extensively distributed to various *** FR over-expressing 98M109 tumors showed consistently higher level of radioactivity than FR-negative tumors(i.e.,M109 tumors) up to 48 h post dose of [3H]BMS-753493,despite the magnitude of difference between the tumors is relatively small(generally 3 5-fold).The radioactivity level in 98M109 tumors was 2 12-fold of normal tissues except intestine/content at 48 h post *** selective radioactivity uptake into 98M109 tumors over M109 or normal tissues was observed after *** of the active epothilone,[3H]***–MS/MS measurements demonstrated that the concentrations of BMS-748285,presumably from hydrolysis of the folate conjugate,in 98M109 tumors were greater than those in M109 tumors after *** of BMS-753493(2–3-fold) whereas no differential uptake in the tumors following BMS-748285 *** data were consistent with radioactivity *** results demonstrated that the folate conjugation in BMS-753493 enabled moderately preferential distribution of the active epothilone to FR overexpressing 98M109 tumors,thereby supporting targeted delivery of cytotoxics through the folate receptor.

关键词： Folate receptor Tumor selective targeting Folate receptor–expressing tumor Epothilone folate conjugate Tissue distribution Tumor uptake

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