Warmann Steven W, Heitmann Heike, Teichmann Birgit, Gratz Klaus Friedrich, Ruck Peter, Hunger Mona, Fuchs Jörg
Department of Pediatric Surgery, University of Tübingen, Tübingen, Germany.
Pediatr Hematol Oncol. 2005 Jul-Aug;22(5):373-86. doi: 10.1080/08880010590964192.
Multidrug resistance (MDR) contributes to limited treatment results in human hepatoblastoma (HB). The MDR1 gene and its product P-glycoprotein (P-gP) has been identified as important factor in this development. In other tumors, P-gP modulation leads to a restored chemosensitivity of the cells. The aim of this study was to analyze the P-gP-modulating effects of PSC 833, a cyclosporine derivate, and verapamil on the chemotherapy of HB in vivo. HB from 2 patients were transplanted subcutaneously into nude mice NMRI (nu/nu). Animals were divided into 7 groups: Group 1 (Control); Group 2 (CDDP); Group 3 (DOXO); Group 4 (DOXO + verapamil); Group 5 (DOXO + PSC 833); Group 6 (CDDP + verapamil); and Group 7 (CDDP + PSC 833). If DOXO was administered (regardless of the combination), the dose was two times 60 mg/m2. If CDDP was administered, the dose was two times 27 mg/m2. When the chemosensitizers were administered, the doses for PSC 833 and for verapamil were four times 5 mg/kg body-weight. In the combined treatment groups the chemosensitizers were given ten minutes prior to CDDP and DOXO. Tumor volume developments and a-fetoprotein (AFP) alterations were assessed. Relative expression levels of the MDR1 gene after treatment were determined using a semiquantitative rT-PCR approach. In a mixed HB, both chemosensitizers combined with DOXO or CDDP produced a significant reduction of tumor growth (p = .0001-.00063) and AFP levels (p = .0006-.0128) compared to tumors treated with DOXO or CDDP only. Treatment results were identical to those in a less differentiated pure embryonal HB, but only in one case (DOXO + PSC 833, p = .031) significant. The chemosensitizers had no influence on the MDR1 gene expression. MDR1 modulators improve the efficiency of DOXO and CDDP treatment in xenotransplanted HB. They do not induce a further increase of drug resistance in the tumors. The data provide evidence that chemosensitizers might improve treatment results in patients with advanced or relapsed HB.
多药耐药（MDR）导致人类肝母细胞瘤（HB）的治疗效果有限。MDR1基因及其产物P-糖蛋白（P-gP）已被确定为这一过程中的重要因素。在其他肿瘤中，P-gP调节可使细胞的化疗敏感性恢复。本研究的目的是分析环孢素衍生物PSC 833和维拉帕米对HB体内化疗的P-gP调节作用。将2例患者的HB皮下移植到NMRI裸鼠（nu/nu）体内。动物分为7组：第1组（对照组）；第2组（顺铂）；第3组（阿霉素）；第4组（阿霉素+维拉帕米）；第5组（阿霉素+PSC 833）；第6组（顺铂+维拉帕米）；第7组（顺铂+PSC 833）。如果给予阿霉素（无论联合用药情况），剂量为60mg/m²的两倍。如果给予顺铂，剂量为27mg/m²的两倍。当给予化学增敏剂时，PSC 833和维拉帕米的剂量均为5mg/kg体重的四倍。在联合治疗组中，化学增敏剂在顺铂和阿霉素给药前10分钟给予。评估肿瘤体积变化和甲胎蛋白（AFP）改变。使用半定量逆转录聚合酶链反应（rT-PCR）方法测定治疗后MDR1基因的相对表达水平。在混合性HB中，与仅用阿霉素或顺铂治疗的肿瘤相比，两种化学增敏剂与阿霉素或顺铂联合使用均使肿瘤生长（p = 0.0001 - 0.00063）和AFP水平（p = 0.0006 - 0.0128）显著降低。治疗结果与低分化纯胚胎性HB中的结果相同，但仅在1例中（阿霉素+PSC 833，p = 0.031）显著。化学增敏剂对MDR1基因表达无影响。MDR1调节剂可提高阿霉素和顺铂对异种移植HB的治疗效果。它们不会诱导肿瘤产生进一步的耐药性增加。数据表明化学增敏剂可能改善晚期或复发性HB患者的治疗效果。
