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Search for the new, endogenous compound with multidrug resistance modulating activity and its application to cancer chemotherapy

寻找具有多药耐药调节活性的新型内源性化合物及其在癌症化疗中的应用

基本信息

批准号：
11672169
负责人：
TAKANO Mikihisa
金额：
$ 2.3万
依托单位：
Hiroshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

P-Glycoprotein (P-gp) is a drug efflux pump and confers multidrug resistance to cancer cells. In order to reverse multidrug resistance, compounds having the inhibitory potency on P-gp is now actively searched. On one hand, P-gp in normal tissues is important as a determinant of drug handling in the body. In the present study, the function of P-gp under disease states was examined, and the involvement of endogenous P-gp inhibitors was shown. In addition, to find out the new multidrug resistance modulators, we attempted to identify the endogenous P-gp inhibitors.In-vivo P-gp function was examined in acute renal or hepatic failure rats, by measuring the handling of rhodamine 123, a P-gp substrate, in various tissues. Interestingly, the function of P-gp was suppressed not only in target injury tissue but also in other tissues. The expression levels of P-gp in these tissues did not decrease, rather increased in injury tissue. In addition, the inhibitory potency of the plasma from disease rats on P-gp was stronger than that from normal rats, indicating the involvement of endogenous P-gp inhibitors. In fact, the plasma concentration of corticosterone, an endogenous P-gp-related compound, increased in disease rats. In volunteers with normal kidney function, endogenous P-gp inhibitors were found to be excreted into the urine, one of which was identified to be equilin, an estrogen. During the study, di-2-ethylhexyl phthalate (DEHP), which is assumed to be an endocrine disrupting chemicals (EDCs), was found in the urine, though DEHP itself did not have direct inhibitory effect on P-gp. Further studies on endogenous P-gp inhibitors would help to identify new and useful multidrug resistance modulators for cancer chemotherapy.

P-糖蛋白(P-gp)是一种药物外排泵，对肿瘤细胞具有多药耐药性。为了逆转多药耐药，目前正在积极寻找对P-gp具有抑制作用的化合物。一方面，正常组织中的P-gp作为体内药物处理的决定因素是重要的。本研究对P-gp在疾病状态下的功能进行了研究，并证明了内源性P-gp抑制物的参与。此外，为了寻找新的多药耐药调节剂，我们试图鉴定内源性P-gp抑制剂。通过测量P-gp底物罗丹明123在不同组织中的处理情况，在急性肾或肝功能衰竭大鼠体内检测P-gp的功能。有趣的是，P-gp的功能不仅在靶损伤组织中被抑制，而且在其他组织中也被抑制。P-gp在这些组织中的表达水平并没有下降，而是在损伤组织中表达增加。此外，疾病大鼠血浆对P-gp的抑制作用强于正常大鼠，提示内源性P-gp抑制物参与了P-gp抑制作用。事实上，疾病大鼠的血浆皮质酮浓度增加，皮质酮是一种内源性P-gp相关化合物。在肾功能正常的志愿者中，发现内源性P-gp抑制物被排泄到尿液中，其中一种被确认为雌激素马林。在研究过程中，在尿液中发现了邻苯二甲酸二乙基己酯(DEHP)，虽然DEHP本身对P-gp没有直接抑制作用，但它被认为是一种内分泌干扰物(EDCs)。对内源性P-gp抑制剂的进一步研究将有助于寻找新的有效的肿瘤化疗多药耐药调节剂。