Development of gemcitabine-resistant patient-derived xenograft models of pancreatic ductal adenocarcinoma.
Development of gemcitabine-resistant patient-derived xenograft models of pancreatic ductal adenocarcinoma.
复制标题
胰腺导管腺癌的耐吉西他滨患者衍生的异种移植模型的开发。
DOI：
10.20517/cdr.2020.35
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Yoon KJ
中科院分区：
文献类型：
--
作者：
Miller AL;Garcia PL;Gamblin TL;Vance RB;Yoon KJ
目的：吉西他滨是局部晚期和转移性胰腺导管腺癌（PDAC）的一线药物，但无论是单独使用吉西他滨还是联合使用吉西他滨都不能持久缓解这种肿瘤类型。我们开发了三种体内获得吉西他滨耐药（gemR）的PDAC患者源异种移植（PDX）模型，以确定与体内药物暴露相关的耐药机制并评估新的治疗方法。方法：独立源性PDXs小鼠给予吉西他滨100 mg/kg，每周1次或2次。肿瘤最初有反应，但在治疗后重新生长，并被指定为gemR。我们使用免疫组织化学方法比较了先前与吉西他滨耐药相关的蛋白[核糖核苷酸还原酶亚基M1 （RRM1）、RRM2、人浓缩核苷转运蛋白1 （hCNT1）、人平衡核苷转运蛋白1 （hENT1）、胞苷脱氨酶（CDA）和脱氧胞苷激酶（dCK）]在gemR和各自gemcitabine-naïve亲本肿瘤中的表达。结果：亲代肿瘤和子代肿瘤在肿瘤细胞形态、肿瘤相关基质的数量或干细胞标记物的表达方面没有差异。6种基因标记蛋白的表达在不同的模型中没有一致的模式。RRM1和CDA的增加与体外衍生的gemR模型一致。然而，与预期的hCNT1、hENT1和dCK的减少不同，与亲本肿瘤相比，gemR肿瘤表达的这些gemR标记蛋白没有变化或水平更高。结论：这些模型是第一个体内获得吉西他滨耐药的PDAC PDX模型。数据表明，在体外获得耐药性的模型中确定的机制不太可能是体内获得耐药性的主要机制。正在进行的工作重点是表征尚未确定的gemR机制，并在这些gemR模型中确定具有抗肿瘤功效的药物。
Aim: Gemcitabine is a frontline agent for locally-advanced and metastatic pancreatic ductal adenocarcinoma (PDAC), but neither gemcitabine alone nor in combination produces durable remissions of this tumor type. We developed three PDAC patient-derived xenograft (PDX) models with gemcitabine resistance (gemR) acquired in vivo, with which to identify mechanisms of resistance relevant to drug exposure in vivo and to evaluate novel therapies. Methods: Mice bearing independently-derived PDXs received 100 mg/kg gemcitabine once or twice weekly. Tumors initially responded, but regrew on treatment and were designated gemR. We used immunohistochemistry to compare expression of proteins previously associated with gemcitabine resistance [ribonucleotide reductase subunit M1 (RRM1), RRM2, human concentrative nucleoside transporter 1 (hCNT1), human equilibrative nucleoside transporter 1 (hENT1), cytidine deaminase (CDA), and deoxycytidine kinase (dCK)] in gemR and respective gemcitabine-naïve parental tumors. Results: Parental and gemR tumors did not differ in tumor cell morphology, amount of tumor-associated stroma, or expression of stem cell markers. No consistent pattern of expression of the six gemR marker proteins was observed among the models. Increases in RRM1 and CDA were consistent with in vitro-derived gemR models. However, rather than the expected decreases of hCNT1, hENT1, and dCK, gemR tumors expressed no change in or higher levels of these gemR marker proteins than parental tumors. Conclusion: These models are the first PDAC PDX models with gemcitabine resistance acquired in vivo. The data indicate that mechanisms identified in models with resistance acquired in vitro are unlikely to be the predominant mechanisms when resistance is acquired in vivo. Ongoing work focuses on characterizing unidentified mechanisms of gemR and on identifying agents with anti-tumor efficacy in these gemR models.
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影响因子：
5.7
作者：
Garcia PL;Miller AL;Gamblin TL;Council LN;Christein JD;Arnoletti JP;Heslin MJ;Reddy S;Richardson JH;Cui X;van Waardenburg RCAM;Bradner JE;Yang ES;Yoon KJ
通讯作者：
Yoon KJ
DOI：
10.1016/j.bbrc.2005.05.097
发表时间：
2005-07-22
影响因子：
3.1
作者：
Hausser, HJ;Brenner, RE
通讯作者：
Brenner, RE
影响因子：
3.7
作者：
Jonckheere N;Skrypek N;Merlin J;Dessein AF;Dumont P;Leteurtre E;Harris A;Desseyn JL;Susini C;Frénois F;Van Seuningen I
通讯作者：
Van Seuningen I
影响因子：
9.7
作者：
Kreitzburg KM;Fehling SC;Landen CN;Gamblin TL;Vance RB;Arend RC;Katre AA;Oliver PG;van Waardenburg RCAM;Alvarez RD;Yoon KJ
通讯作者：
Yoon KJ
影响因子：
5.2
作者：
Duong HQ;Hwang JS;Kim HJ;Kang HJ;Seong YS;Bae I
通讯作者：
Bae I