Liang Y, Hannan C J, Chang B K, Schoenlein P V
Department of Radiology, Research and Nuclear Medicine, Medical College of Georgia, Augusta 30912, USA.
Anticancer Res. 1997 May-Jun;17(3C):2083-8.
Tumor cell resistance to many unrelated anticancer drugs is a major obstacle during cancer chemotherapy. One mechanism of drug resistance is thought to be due to the efflux of anticancer drugs caused by P-glycoprotein. In recent years, magnetic fields have been found to enhance the potency of anticancer drugs, with favorable modulation of cancer therapy. In this study, KB-ChR-8-5-11, a multidrug resistant (MDR) human carcinoma subline, was used as a model to evaluate the ability of pulsed magnetic fields (PMF) to modulate the potency of daunorubicin (DNR) in vivo and to determine the appropriate order of exposure to drugs and PMF using an in vitro cytotoxicity assay. Solenoid coils with a ramped pulse current source were used at 250 pulses per second for both in vivo and in vitro experiments. For the in vivo study, KB-ChR-8-5-11 cells were inoculated into thymic Balbc-nu/nu female mice. Treatment was begun when the average tumor volume reached 250-450 mm3. Treatment consisted of whole body exposure to PMF for one hour, followed immediately by intravenous (i.v.) injection of 8 mg/kg DNR designated as day 0, and repeated on days 7 and 14. Among the various groups, significant differences in the tumor volume were found between PMF + saline and PMF + DNR groups (p = 0.0107) at 39 days and 42 days (p = 0.0101). No mice died in the PMF alone group, and no toxicity attributable to PMF was found during the experimental period. For the in vitro studies, the sulforhodamine blue (SRB) cytotoxicity assay was used to determine the effect of the sequence which cells are exposed to PMF and/or DNR. Cells were exposed to PMF either before (pre-PMF) or after (post-PMF) drug was added. Results showed that the IC50 was significantly different between controls and pre-PMF + DNR groups (P = 0.0096, P = 0.0088). The IC50 of the post-PMF + DNR group was not found to be significantly different from control groups. Thus, the data in this report demonstrates that PMF enhanced the potency of DNR against KB-ChR-8-5-11 xenograft in vivo, while the efficacy of DNR was potentiated in vitro by PMF exposure only when PMF exposure occurred in the presence of drug. The data in vitro suggest that the mechanism by which PMFs modulate DNR's potency may be by inhibition of the efflux pump, P-glycoprotein. Further work to determine conditions for maximum modulation of drug potency by PMFs is warranted.
肿瘤细胞对多种不相关抗癌药物产生耐药性是癌症化疗过程中的主要障碍。耐药的一种机制被认为是由P-糖蛋白引起的抗癌药物外排所致。近年来，已发现磁场可增强抗癌药物的效力，并对癌症治疗产生有利调节作用。在本研究中，多药耐药（MDR）人癌细胞系KB-ChR-8-5-11被用作模型，以评估脉冲磁场（PMF）在体内调节柔红霉素（DNR）效力的能力，并通过体外细胞毒性试验确定药物与PMF的合适暴露顺序。体内和体外实验均使用带有斜坡脉冲电流源的螺线管线圈，每秒250个脉冲。在体内研究中，将KB-ChR-8-5-11细胞接种到胸腺裸鼠Balbc-nu/nu雌性小鼠体内。当平均肿瘤体积达到250 - 450立方毫米时开始治疗。治疗包括全身暴露于PMF 1小时，随后立即静脉注射（i.v.）8毫克/千克DNR（指定为第0天），并在第7天和第14天重复。在各个组中，在第39天和第42天，PMF +生理盐水组与PMF + DNR组之间的肿瘤体积存在显著差异（p = 0.0107）（p = 0.0101）。单独PMF组无小鼠死亡，且在实验期间未发现归因于PMF的毒性。在体外研究中，使用磺基罗丹明B（SRB）细胞毒性试验来确定细胞暴露于PMF和/或DNR的顺序的影响。细胞在添加药物之前（PMF预处理）或之后（PMF后处理）暴露于PMF。结果显示，对照组与PMF预处理 + DNR组之间的IC50存在显著差异（P = 0.0096，P = 0.0088）。未发现PMF后处理 + DNR组的IC50与对照组有显著差异。因此，本报告中的数据表明，PMF增强了DNR对体内KB-ChR-8-5-11异种移植瘤的效力，而仅当在有药物存在时暴露于PMF，DNR在体外的疗效才会增强。体外数据表明，PMF调节DNR效力的机制可能是通过抑制外排泵P-糖蛋白。有必要进一步开展工作以确定PMF最大程度调节药物效力的条件。
