Keller Gunhild, Schally Andrew V, Nagy Attila, Halmos Gabor, Baker Benjamin, Engel Jorg B
Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70112-1262, USA.
Cancer. 2005 Nov 15;104(10):2266-74. doi: 10.1002/cncr.21402.
Multidrug resistance (MDR) mediated by membrane transporters, such as P-glycoprotein (MDR-1) and MDR-associated protein (MRP), remains a challenge in the therapy of renal cell carcinoma (RCC). Chemotherapy targeted to hormone receptors may provide a new approach to overcome chemoresistance. The cytotoxic analogue of bombesin/gastrin-releasing peptide (GRP), AN-215, consists of a superactive derivative of doxorubicin, AN-201, which is linked to a bombesin analogue carrier: RC-3094.
The authors examined the expression of bombesin/GRP receptors in 3 human RCC cell lines (A-498, ACHN. and 786-0) by using reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis and radioligand-binding assays. They also evaluated the effects of AN-215 and its cytotoxic radical AN-201 in the same RCC models in vivo, and they studied the effects of AN-215 and AN-201 on the expression levels of MDR-1 and subtype 1 of MRP (MRP-1) by using real-time PCR.
A N-215 significantly (P < 0.05) inhibited the growth of A-498, ACHN, and 786-0 RCC xenografted into nude mice by 59.2-67.6%, whereas the cytotoxic radical AN-201 alone had no significant antitumor effects. The efficacy of AN-215 was independent of the expression patterns of MDR-1 and MRP-1 in these RCC cell lines. The induction of MDR-1 by AN-215 was similar (Experiment 2) or weaker (Experiment 1) compared with AN-201. Both AN-215 and AN-201 caused only a minor induction of MRP-1.
The current findings indicated that targeted chemotherapy with cytotoxic bombesin/GRP analogue AN-215 can inhibit the growth of RCC, providing a new treatment modality for patients with advanced RCC.
由膜转运蛋白介导的多药耐药性（MDR），如P-糖蛋白（MDR-1）和多药耐药相关蛋白（MRP），仍然是肾细胞癌（RCC）治疗中的一个挑战。针对激素受体的化疗可能提供一种克服化疗耐药性的新方法。蛙皮素/胃泌素释放肽（GRP）的细胞毒性类似物AN-215，由阿霉素的一种超活性衍生物AN-201组成，它与一种蛙皮素类似物载体RC-3094相连。
作者通过逆转录聚合酶链反应（RT-PCR）分析和放射性配体结合试验，检测了3种人RCC细胞系（A-498、ACHN和786-0）中蛙皮素/GRP受体的表达。他们还在相同的RCC体内模型中评估了AN-215及其细胞毒性自由基AN-201的作用，并通过实时PCR研究了AN-215和AN-201对MDR-1和MRP亚型1（MRP-1）表达水平的影响。
AN-215显著（P < 0.05）抑制移植到裸鼠体内的A-498、ACHN和786-0 RCC的生长，抑制率为59.2% - 67.6%，而单独的细胞毒性自由基AN-201没有显著的抗肿瘤作用。AN-215的疗效与这些RCC细胞系中MDR-1和MRP-1的表达模式无关。与AN-201相比，AN-215对MDR-1的诱导作用相似（实验2）或较弱（实验1）。AN-215和AN-201都只引起MRP-1的轻微诱导。
目前的研究结果表明，用细胞毒性蛙皮素/GRP类似物AN-215进行靶向化疗可以抑制RCC的生长，为晚期RCC患者提供了一种新的治疗方式。
