Lan L B, Ayesh S, Lyubimov E, Pashinsky I, Stein W D
Biochemistry Department, Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel.
Cancer Chemother Pharmacol. 1996;38(2):181-90. doi: 10.1007/s002800050468.
We determined the kinetic parameters that describe the effect of 20 different modulators of the multidrug resistance pump on the reversal of cytotoxin accumulation in a resistant strain of P388 leukemia cells (P388/ADR), and on the reversal of cell killing for these cells. When measured by a direct comparison of the amplitude of the pertinent protocol (accumulation or cell killing), the Ki for reversal of accumulation was generally some four or five times larger than that for reduction of cytotoxicity. We showed that this was only an apparent discrepancy, since a full theoretical analysis of the two protocols allowed the intrinsic Ki to be obtained for the two procedures and these computed Ki values were then almost identical. We found that for six of the modulators studied (namely, cyclosporin A, quinidine, dipyridamole, propafenone, mefloquine, tamoxifen) the extent of pump reversal should be better than 90% at tolerated plasma levels culled from the literature.
我们测定了动力学参数，这些参数描述了20种不同的多药耐药泵调节剂对P388白血病耐药细胞株（P388/ADR）中细胞毒素蓄积逆转的影响，以及对这些细胞杀伤逆转的影响。当通过直接比较相关实验方案（蓄积或细胞杀伤）的幅度来测量时，蓄积逆转的Ki通常比细胞毒性降低的Ki大四五倍。我们表明这只是一个明显的差异，因为对这两个实验方案进行全面的理论分析可以得到这两个过程的内在Ki，然后这些计算出的Ki值几乎相同。我们发现，对于所研究的六种调节剂（即环孢素A、奎尼丁、双嘧达莫、普罗帕酮、甲氟喹、他莫昔芬），从文献中选取的耐受血浆水平下，泵逆转程度应优于90%。
