Hofsli E, Nissen-Meyer J
Cell Research Laboratory, Institute of Cancer Research, University of Trondheim, Regionsykehuset, Norway.
Int J Cancer. 1989 Mar 15;43(3):520-5. doi: 10.1002/ijc.2910430330.
WEHI 164 murine fibrosarcoma cells were rendered multidrug-resistant (MDR) by culture in the presence of actinomycin D. In addition to resistance to actinomycin D, the cells acquired resistance to doxorubicin, mitomycin, vincristine and cycloheximide. The fact that development of resistance to one type of lipophilic chemotherapeutic drug also results in resistance to other structurally unrelated lipophilic drugs suggests that non-toxic lipophilic agents may interfere with drug resistance by saturating the pathway by which MDR-cells inhibit drug cytotoxicity. We show that the antibiotic erythromycin significantly reverses the resistance of MDR WEHI 164 cells to doxorubicin and actinomycin D. In addition to cross-resistance to chemotherapeutic drugs, 3 out of 4 actinomycin D-resistant WEHI 164 cell lines also showed higher resistance to tumour necrosis factor (TNF) than the parental WEHI 164 cells. However, whereas verapamil, a calcium antagonist known to reverse multidrug-resistance, rendered resistant cells more sensitive to chemotherapeutic drugs, it protected the cells from killing by TNF, suggesting that drug resistance and TNF resistance may not be directly connected. A synergistic cytotoxic effect of TNF and actinomycin D was obtained on both the parental and the MDR cells. However, higher concentrations of TNF and actinomycin D were required to obtain a cytotoxic effect in the MDR cells, reflecting actinomycin D and TNF resistance in these cells.
通过在放线菌素D存在的情况下培养，将WEHI 164小鼠纤维肉瘤细胞诱导为多药耐药（MDR）细胞。除了对放线菌素D耐药外，这些细胞还获得了对阿霉素、丝裂霉素、长春新碱和环己酰亚胺的耐药性。对一种亲脂性化疗药物产生耐药性也会导致对其他结构不相关的亲脂性药物产生耐药性，这一事实表明，无毒亲脂性药物可能通过使MDR细胞抑制药物细胞毒性的途径饱和来干扰耐药性。我们发现抗生素红霉素能显著逆转MDR WEHI 164细胞对阿霉素和放线菌素D的耐药性。除了对化疗药物的交叉耐药性外，4株放线菌素D耐药的WEHI 164细胞系中有3株对肿瘤坏死因子（TNF）的耐药性也高于亲代WEHI 164细胞。然而，已知能逆转多药耐药性的钙拮抗剂维拉帕米虽然能使耐药细胞对化疗药物更敏感，但却能保护细胞免受TNF的杀伤，这表明耐药性和TNF耐药性可能没有直接联系。TNF和放线菌素D对亲代细胞和MDR细胞均有协同细胞毒性作用。然而，在MDR细胞中需要更高浓度的TNF和放线菌素D才能获得细胞毒性作用，这反映了这些细胞对放线菌素D和TNF的耐药性。
