Buchholz Marie, Strotmann Johanna, Majchrzak-Stiller Britta, Hahn Stephan, Peters Ilka, Horn Julian, Müller Thomas, Höhn Philipp, Uhl Waldemar, Braumann Chris
Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, 44780 Bochum, Germany.
Cancers (Basel). 2022 May 29;14(11):2685. doi: 10.3390/cancers14112685.
Neuroendocrine carcinoma of the pancreas (pNEC) is an aggressive form of neuroendocrine tumor characterized by a rising incidence without an increase in survival rates. GP-2250 is an oxathiazinane derivate possessing antineoplastic effects, especially in combination with Gemcitabine on the pancreatic adenocarcinoma. The cytotoxic effects of the monotherapy of GP-2250 (GP-2250) and Gemcitabine (Gem), as well as the combination therapy of both, were studied in vitro using an MTT-assay on the QGP-1 and BON-1 cell lines, along with in vivo studies on a murine xenograft model of QGP-1 and a patient-derived xenograft model (PDX) of Bo99. In vitro, Gem and GP-2250 showed a dose-dependent cytotoxicity. The combination of GP-2250 and Gemcitabine exhibited highly synergistic effects. In vivo, the combination therapy obtained a partial response in QGP-1, while GP-2250 and Gem showed progressive disease or stable disease, respectively. In Bo99 PDX, the combination therapy led to a partial response, while the monotherapy resulted in progressive disease. No development of secondary resistances was observed, as opposed to monotherapy. This study was the first to evaluate the effects of the emerging substance GP-2250 on pNEC. The substance showed synergism in combination with Gemcitabine. The combination therapy proved to be effective in vitro and in vivo, without the development of secondary resistances.
胰腺神经内分泌癌（pNEC）是一种侵袭性神经内分泌肿瘤，其发病率不断上升，但生存率并未提高。GP - 2250是一种具有抗肿瘤作用的恶二嗪烷衍生物，尤其是与吉西他滨联合使用时对胰腺腺癌有作用。使用MTT法在QGP - 1和BON - 1细胞系上体外研究了GP - 2250单药治疗（GP - 2250）和吉西他滨（Gem）的细胞毒性作用，以及两者的联合治疗，同时在QGP - 1的小鼠异种移植模型和Bo99的患者来源异种移植模型（PDX）上进行了体内研究。在体外，Gem和GP - 2250表现出剂量依赖性细胞毒性。GP - 2250和吉西他滨的联合显示出高度协同作用。在体内，联合治疗在QGP - 1中获得了部分缓解，而GP - 2250和Gem分别显示疾病进展或病情稳定。在Bo99 PDX中，联合治疗导致部分缓解，而单药治疗导致疾病进展。与单药治疗不同，未观察到继发性耐药的发生。本研究首次评估了新型物质GP - 2250对pNEC的作用。该物质与吉西他滨联合显示出协同作用。联合治疗在体外和体内均被证明有效，且未出现继发性耐药。
