Schwartsmann G, Pinedo H M, Leyva A
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Eur J Cancer Clin Oncol. 1987 Jun;23(6):739-43. doi: 10.1016/0277-5379(87)90271-9.
Two sublines of HL-60 cells differing markedly in their ability to undergo differentiation to granulocytes after treatment with retinoic acid (RA), dimethyl sulfoxide (DMSO) and the pyrimidine analog, 5-aza-2'-deoxycytidine (azadCyd) were studied. The sensitive subline (HL-60 S) responded well to 1 microM RA, 1% DMSO and 1 microM azadCyd, showing 89 +/- 5%, 46 +/- 5% and 29 +/- 6% mature nitroblue tetrazolium (NBT)-positive cells, respectively. However, the resistant subline (HL-60 R) showed only modest maturational effects (12 +/- 3%, 11 +/- 2% and 9 +/- 2%, respectively) after treatment with the same agents. Using the HL-60 R as a model for resistance to differentiation induction in the HL-60 cell line, studies were carried out to determine whether the combined use of RA, DMSO and azadCyd could reverse the resistance of these tumor cells to the induction of maturation expressed by the individual agents. When these agents were given in any combination of 2, a minor increase in differentiation induction was detected (13 +/- 6% or less NBT-positive cells). However, when all 3 agents were combined (RA + DMSO + azaCyd), resistance was completely reversed (89 +/- 7% mature NBT-positive cells). In addition, different degrees of concentration-dependence of each agent in the combination were observed. The RA + DMSO + azadCyd combination caused a maximal accumulation of NBT-positive cells after 72 to 96 hr of incubation. These results show that the lack of competence for induction of differentiation in resistant HL-60 cells can be completely reversed by the above ternary drug combination. However, the mechanism responsible for this synergistic effect must await further elucidation of the molecular mechanisms by which such agents act.
研究了HL-60细胞的两个亚系，它们在用维甲酸（RA）、二甲基亚砜（DMSO）和嘧啶类似物5-氮杂-2'-脱氧胞苷（氮杂胞苷）处理后向粒细胞分化的能力有显著差异。敏感亚系（HL-60 S）对1微摩尔RA、1%DMSO和1微摩尔氮杂胞苷反应良好，分别有89±5%、46±5%和29±6%的成熟硝基蓝四氮唑（NBT）阳性细胞。然而，抗性亚系（HL-60 R）在用相同药物处理后仅表现出适度的成熟效应（分别为12±3%、11±2%和9±2%）。以HL-60 R作为HL-60细胞系中抗分化诱导的模型，进行研究以确定RA、DMSO和氮杂胞苷联合使用是否能逆转这些肿瘤细胞对各单一药物诱导成熟的抗性。当以任意两种药物组合给药时，检测到分化诱导有轻微增加（NBT阳性细胞为13±6%或更低）。然而，当三种药物联合使用（RA+DMSO+氮杂胞苷）时，抗性被完全逆转（89±7%成熟NBT阳性细胞）。此外，观察到联合使用中每种药物不同程度的浓度依赖性。RA+DMSO+氮杂胞苷组合在孵育72至96小时后导致NBT阳性细胞最大程度积累。这些结果表明，抗性HL-60细胞中缺乏分化诱导能力可通过上述三元药物组合完全逆转。然而，这种协同效应的机制必须等待进一步阐明这些药物作用的分子机制。
