Hofsli E, Nissen-Meyer J
Cell Research Laboratory, Institute of Cancer Research, University of Trondheim, Norway.
Cancer Res. 1990 Jul 1;50(13):3997-4002.
The phenomenon of multidrug resistance implies that a wide spectrum of structurally and functionally unrelated chemotherapeutic drugs are recognized and processed by the molecular system which protects multidrug-resistant (MDR) cells against lipophilic cytotoxic drugs. This suggests that lipophilic agents with low toxicity may also be recognized and processed by this molecular system. At high concentrations these agents might saturate the system, thereby reversing multidrug resistance. In support of this hypothesis, 19 (73%) of 26 arbitrarily chosen lipophilic drugs were in this study found to increase the accumulation of actinomycin D in MDR WEHI 164 cells. The most potent of these drugs were also shown to sensitize these cells to the cytotoxic effect of actinomycin D and doxorubicin. There was a good correlation between the ability of the lipophilic drugs to induce an increased accumulation of actinomycin D in MDR cells and their ability to sensitize these cells to the cytotoxic effect of chemotherapeutic drugs. The ability to reverse drug resistance appeared to be additive, since increased accumulation of actinomycin D was also obtained by combining low concentrations of various lipophilic drugs. This may be a way to reduce the in vivo toxic effect of the lipophilic drugs yet still obtain a reversal of drug resistance. When MDR cells were exposed to lipophilic drugs which reversed drug resistance, the synergistic cytotoxic effect of actinomycin D and tumor necrosis factor was obtained at reduced actinomycin D concentrations.
多药耐药现象意味着多种结构和功能不相关的化疗药物被保护多药耐药（MDR）细胞免受亲脂性细胞毒性药物影响的分子系统识别和处理。这表明低毒性的亲脂性药物也可能被该分子系统识别和处理。在高浓度时，这些药物可能会使该系统饱和，从而逆转多药耐药。为支持这一假设，在本研究中发现，26种随机选择的亲脂性药物中有19种（73%）能增加放线菌素D在MDR WEHI 164细胞中的蓄积。这些药物中最有效的还被证明能使这些细胞对放线菌素D和阿霉素的细胞毒性作用敏感。亲脂性药物在MDR细胞中诱导放线菌素D蓄积增加的能力与其使这些细胞对化疗药物细胞毒性作用敏感的能力之间存在良好的相关性。逆转耐药的能力似乎具有相加性，因为通过联合低浓度的各种亲脂性药物也能增加放线菌素D的蓄积。这可能是一种降低亲脂性药物体内毒性作用但仍能逆转耐药的方法。当MDR细胞暴露于能逆转耐药的亲脂性药物时，在降低放线菌素D浓度的情况下可获得放线菌素D和肿瘤坏死因子的协同细胞毒性作用。
