Massart C, Gibassier J, Raoul M, Denais A, Maugendre S, Darcel F, Lucas C
Laboratoires d'Hormonologie-Enzymologie, CHU de Pontchaillou, Rennes, France.
Anticancer Drugs. 1996 May;7(3):321-30. doi: 10.1097/00001813-199605000-00013.
In medullary carcinoma of the thyroid (MTC), drug resistance remains the major obstacle to effective chemotherapy. In this work, we studied the effect of S9788 on doxorubicin (DOX) efficiency in a MTC cell line (TT cells) injected in nude mice. After two passages, TT cells were injected in 40 nude mice divided into four groups [controls and groups receiving DOX alone (10 mg/kg), S9788 alone (50 mg/kg) or both DOX + S9788]. The weight of the mice, tumoral volume (TV), doubling time (DT) of the tumor and survival time of mice were evaluated in each group. In addition, the efficiency of DOX with or without S9788 was assessed by the inhibition of tumoral growth and specific growth delay. In vitro, glycoprotein P 170 (P-gp) was detected on tissular sections and on tumoral cells by immunocytochemistry or flow cytometry with several monoclonal antibodies: JSB1, MRK 16, C219 and UIC2. In vivo the weight of the mice decreased slightly with DOX and dropped dramatically with DOX + S9788. The DT of the tumors increased with DOX over controls (22.5 +/- 8.5/12.7 +/- 3.9 days) and showed a higher value with DOX + S9788 (29.2 +/- 11.4 days). Inhibition of tumoral growth, 89% with DOX, fell to 47.6% with DOX + S9788. Specific growth delay increased with the double treatment (130 versus 75% with DOX alone). In vitro, P-gp was not detected on tissular sections and cells whatever the method and the antibody used. In conclusion, S9788 potentiates the efficiency of DOX treatment in vivo. The absence of P-gp may result from the absence of translation of the MDR1 gene. The reversal effect of S9788 may involve another resistance mechanism such as the MDR Sister of MRP.
在甲状腺髓样癌（MTC）中，耐药性仍然是有效化疗的主要障碍。在本研究中，我们研究了S9788对注射于裸鼠体内的MTC细胞系（TT细胞）中阿霉素（DOX）疗效的影响。传代两次后，将TT细胞注射到40只裸鼠体内，分为四组[对照组以及单独接受DOX（10mg/kg）、单独接受S9788（50mg/kg）或同时接受DOX + S9788的组]。评估每组小鼠的体重、肿瘤体积（TV）、肿瘤倍增时间（DT）和小鼠存活时间。此外，通过抑制肿瘤生长和特定生长延迟来评估有或没有S9788时DOX的疗效。在体外，通过免疫细胞化学或流式细胞术，使用几种单克隆抗体（JSB1、MRK 16、C219和UIC2）在组织切片和肿瘤细胞上检测糖蛋白P 170（P-gp）。在体内，单独使用DOX时小鼠体重略有下降，而同时使用DOX + S9788时体重急剧下降。与对照组相比，DOX使肿瘤的DT增加（22.5±8.5/12.7±3.9天），DOX + S9788时DT更高（29.2±11.4天）。肿瘤生长抑制率，DOX为89%，DOX + S9788时降至47.6%。联合治疗使特定生长延迟增加（单独使用DOX时为75%，联合治疗时为130%）。在体外，无论使用何种方法和抗体，在组织切片和细胞上均未检测到P-gp。总之，S9788可增强DOX在体内的治疗效果。未检测到P-gp可能是由于MDR1基因未翻译。S9788的逆转作用可能涉及另一种耐药机制，如MRP的MDR姐妹基因。
