Marques-Santos L F, Harab R C, de Paula E F, Rumjanek V M
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil.
Cancer Lett. 1999 Mar 22;137(1):99-106. doi: 10.1016/s0304-3835(98)00348-6.
P-glycoprotein (Pgp) has been widely associated with the multidrug resistance phenotype. Nevertheless, this protein has been detected in many normal tissues and cells, including liver, kidney, endothelial cells that constitute the hematological barrier of the brain and testes, and cells from the immune system. Many in vitro models have been used to study drugs that modulate Pgp activity and the multidrug resistance phenomenon. In the present work, we investigate the in vivo effects of resistance-modulating agents on lymphoid organs. Rhodamine 123 (Rho123), a well-known Pgp substrate, was administered to mice, and the fluorescence level in thymus and lymph node cells measured. The fluorescence level on these organs showed a dose-dependent response. Cyclosporin A (CSA), Verapamil (VP) and Trifluoperazine (TFP), three resistance-modulating agents, were administered to mice 1 h prior to 1 mg/kg Rho123 administration. Surprisingly, VP (10 mg/kg) and TFP (750 microg/kg) did not modulate Rho123 retention by thymus and lymph node cells. CSA (50 mg/kg) was the only drug that increased the fluorescence level in both organs. These results point out to the need of a wider study on the in vivo effects of resistance-modulating agents in different organs and systems.
P-糖蛋白（Pgp）已被广泛认为与多药耐药表型相关。然而，在许多正常组织和细胞中都检测到了这种蛋白质，包括肝脏、肾脏、构成血脑屏障的内皮细胞和睾丸，以及免疫系统的细胞。许多体外模型已被用于研究调节Pgp活性和多药耐药现象的药物。在本研究中，我们调查了耐药调节剂对淋巴器官的体内作用。将著名的Pgp底物罗丹明123（Rho123）给予小鼠，并测量胸腺和淋巴结细胞中的荧光水平。这些器官上的荧光水平呈现出剂量依赖性反应。在给予1 mg/kg Rho123前1小时，将三种耐药调节剂环孢素A（CSA）、维拉帕米（VP）和三氟拉嗪（TFP）给予小鼠。令人惊讶的是，VP（10 mg/kg）和TFP（750 μg/kg）并未调节胸腺和淋巴结细胞对Rho123的保留。CSA（50 mg/kg）是唯一能增加两个器官中荧光水平的药物。这些结果表明需要对耐药调节剂在不同器官和系统中的体内作用进行更广泛的研究。
