Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells.
Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells.
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发表时间：
1988-04
影响因子：
3.6
通讯作者：
J. Zamora;H. Pearce;W. T. Beck
中科院分区：
文献类型：
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作者：
J. Zamora;H. Pearce;W. T. Beck
多药耐药性（MDR），以对长春花生物碱和蒽环类药物的耐药性为代表，是一种特征明确的实验现象，可能具有一些临床相关性。维拉帕米、氯喹和相关药物先前已被证明能够增强抗癌药物在多重耐药细胞中的细胞毒性，但这些药物的作用机制尚不清楚。由于这些药物似乎没有共同特征，我们研究了这些和其他化合物“调节”长春花生物碱抗性的能力，以确定它们是否具有任何共同的化学或物理特征。除维拉帕米外，还测试了由吲哚生物碱、溶酶体药物和胺组成的 24 种化合物在我们的人白血病多重耐药细胞系 CEM/VLB100 中增强长春花碱和/或长春新碱细胞毒性的能力。已鉴定出 17 种化合物可将长春花生物碱的细胞毒性提高 5 倍以上。这些包括喹啉类（氯喹、奎宁、钦可尼定和伯氨喹）、吖啶类（吖啶、吖啶橙和奎纳克林）和吲哚生物碱（育亨宾、花花南丁、利血平、毒扁豆碱和长春花生物碱的文多林和长春花碱部分），以及其他 生物碱和胺（氯丙嗪、普萘洛尔、阿托品和色胺）。长春花碱、长春花碱和奎纳克林还增强了阿霉素和替尼泊苷在这些细胞中的细胞毒性，表明这种“调节”并不限于长春花生物碱。我们检查了一些众所周知的溶酶体化合物（甲胺、肾上腺素、苏拉明和台盼蓝），发现它们不能增强长春新碱在 CEM/VLB100 细胞中的细胞毒性，表明溶酶体活性本身并不是调节剂活性所必需的。三维计算机模型允许对长春花碱、文多林和维拉帕米的构象相关同系物进行分子比较，并揭示了结构同源性的三个区域。我们测量了活性和非活性化合物的疏水性（通过油/水分配）并计算了摩尔折射率（通过加性取代基常数法）。我们发现那些在生理 pH 下呈脂溶性且具有相似摩尔折射率的阳离子药物（维拉帕米、奎纳克林、吲哚生物碱和喹啉）最能增强长春花生物碱在我们的多重耐药细胞中的细胞毒性。（摘要截短为 400 字）
Multidrug resistance (MDR), typified by resistance to Vinca alkaloids and anthracyclines, is a well characterized experimental phenomenon that may have some clinical correlates. Verapamil, chloroquine, and related drugs have been shown previously to be capable of enhancing anticancer drug cytotoxicity in multi-drug-resistant cells, but the mechanism(s) by which these agents do this is(are) unclear. Since these agents did not seem to have common features, we studied these and other compounds for their ability to "modulate" Vinca alkaloid resistance in order to determine whether they possessed any common chemical or physical features. In addition to verapamil, 24 compounds, consisting of indole alkaloids, lysosomotropic agents, and amines, were tested for their ability to enhance the cytotoxicity of vinblastine and/or vincristine in our human leukemic multidrug-resistant cell line, CEM/VLB100. Seventeen compounds that enhance the cytotoxicity of the Vinca alkaloids by more than 5-fold have been identified. These include quinolines (chloroquine, quinine, chinchonidine, and primaquine), acridines (acridine, acridine orange, and quinacrine), and indole alkaloids (yohimbine, corynanthine, reserpine, physostigmine, and the vindoline and catharanthine moieties of the Vinca alkaloids), as well as other alkaloids and amines (chlorpromazine, propranolol, atropine, and tryptamine). Vindoline, catharanthine, and quinacrine also enhanced the cytotoxicity of doxorubicin and teniposide in these cells, indicating that this "modulation" was not limited to Vinca alkaloids. We examined some well known lysosomotropic compounds (methylamine, epinephrine, suramin, and trypan blue) and found that they were not able to enhance the cytotoxicity of vincristine in the CEM/VLB100 cells, indicating that lysosomotropic activity per se is not required for modulator activity. Three-dimensional computer modeling permitted molecular comparisons of conformationally related congeners of vinblastine, vindoline, and verapamil and revealed three regions of structural homology. We measured the hydrophobicity (by oil/water partitioning) and calculated the molar refractivity (by the additive substituent constant method) of active and inactive compounds. We found that those cationic agents--verapamil, quinacrine, indole alkaloids, and quinolines--that were lipid soluble at physiologic pH and had similar molar refractivities were best able to enhance the cytotoxicity of the Vinca alkaloids in our multidrug-resistant cells.(ABSTRACT TRUNCATED AT 400 WORDS)