Hassan H T, Veit A, Maurer H R
Department of Haematology, University of Cambridge Clinical School, England, UK.
J Cancer Res Clin Oncol. 1991;117(3):227-31. doi: 10.1007/BF01625429.
All-trans-retinoic acid, hexamethylene bisacetamide and 5-azacytidine are inducers of granulocytic differentiation of HL-60 human myeloid leukaemic cells, which eventually leads to inhibition of cell proliferation. The effect of graded concentrations of all-trans-retinoic acid (RA) (1 nM-1 microM), hexamethylene bisacetamide (HMBA) (0.5-4 mM) and/or 5-azacytidine (5azaC) (1 nM-1 mM), alone and in combination with each other on colony formation and growth of HL-60 cells was studied in agar capillary clonogenic micro assays in order to identify new potential therapeutic regimens for elderly patients with acute myeloid leukaemia. ED90 concentrations, inducing 90% inhibition of colony formation for RA, HMBA and 5azaC, were 128 nM, 2.7 mM and 40 microM, respectively. The drug interactions between these differentiating agents were analysed by Berenbaum's general algebraic solution. The combinations: RA + HMBA, 5azaC + HMBA and RA + 5azaC were significantly synergistic in inhibiting HL-60 colony formation. Their interaction indices were 0.62, 0.83, and 0.97, respectively, at a specific effect level of 15%. The addition of 1 mM HMBA to 100 nM 5azaC- and 1 nM RA-treated cultures significantly increased the colony-formation inhibition from only 2.6% and 7.0% to 46.4%, and 43.1%, respectively. Also, HMBA showed marked synergism with RA and 5azaC in inhibiting colony growth. The interaction indices (I) of HMBA + RA and HMBA + 5azaC were 0.013 and 0.009, respectively, at the same specific level of 15%. Moreover, the triple combination of RA + HMBA + 5azaC showed synergism in inhibiting both the colony formation (I = 0.7) and colony growth (I = 0.4) at the same specific level of 15%. Since RA, HMBA and 5azaC were effective when administered alone in phase I clinical trials of myeloid leukaemic patients, their synergistic combinations could provide shorter and less toxic courses of treatment in elderly myeloid leukaemic patients. I is less than 1, = 1 or greater than 1 in synergistic, additive or antagonistic interactions, respectively.
全反式维甲酸、六甲撑双乙酰胺和5-氮杂胞苷是HL-60人髓性白血病细胞粒细胞分化的诱导剂，最终导致细胞增殖受到抑制。为了确定针对老年急性髓性白血病患者的新的潜在治疗方案，在琼脂毛细管克隆形成微量试验中研究了分级浓度的全反式维甲酸（RA）（1 nM - 1 microM）、六甲撑双乙酰胺（HMBA）（0.5 - 4 mM）和/或5-氮杂胞苷（5azaC）（1 nM - 1 mM）单独及相互组合对HL-60细胞集落形成和生长的影响。RA、HMBA和5azaC诱导90%集落形成抑制的ED90浓度分别为128 nM、2.7 mM和40 microM。这些分化剂之间的药物相互作用通过贝伦鲍姆的一般代数解法进行分析。组合：RA + HMBA、5azaC + HMBA和RA + 5azaC在抑制HL-60集落形成方面具有显著的协同作用。在15%的特定效应水平下，它们的相互作用指数分别为0.62、0.83和0.97。向用100 nM 5azaC和1 nM RA处理的培养物中添加1 mM HMBA，可使集落形成抑制率分别从仅2.6%和7.0%显著提高到46.4%和43.1%。此外，HMBA在抑制集落生长方面与RA和5azaC表现出明显的协同作用。在相同的15%特定水平下，HMBA + RA和HMBA + 5azaC的相互作用指数（I）分别为0.013和0.009。此外，RA + HMBA + 5azaC的三联组合在相同的15%特定水平下在抑制集落形成（I = 0.7）和集落生长（I = 0.4）方面均表现出协同作用。由于RA、HMBA和5azaC在髓性白血病患者的I期临床试验中单独给药时有效，它们的协同组合可为老年髓性白血病患者提供更短且毒性更小的治疗疗程。在协同、相加或拮抗相互作用中，I分别小于1、等于1或大于1。
