Futami H, Hornung R L, Back T T, Bull R, Gruys E, Wiltrout R H
Division of Cancer Treatment, NCI-FCRDC, Frederick, Maryland 21702.
Cancer Res. 1990 Dec 15;50(24):7926-31.
Flavone acetic acid (FAA) is an investigational drug that augments natural killer activity, induces the genes for alpha- and gamma-interferon (IFN) and tumor necrosis factor alpha, and synergizes with recombinant interleukin 2 for the successful treatment of murine renal cancer. However, in most clinical studies of FAA only minimal immunomodulatory effects have been reported. Most of the patients in these studies have also been given sodium bicarbonate to prevent possible nephrotoxicity. The current study was performed to determine whether alkalinization had any effects on FAA-induced immune modulation and therapeutic activity in mice. The results showed that alkalinization inhibited the treatment of murine renal cancer by FAA plus recombinant interleukin 2 such that the survival rate of 84% in nonalkalinized mice was reduced to 0 in mice that were alkalinized during treatment. Alkalinization also significantly inhibited the ability of FAA to augment both splenic and hepatic natural killer activity in a dose-dependent manner. In contrast, alkalinization did not inhibit the ability of polyinosinic:polycytidylic acid and poly-L-lysine stabilized in carboxymethyl cellulose, maleic anhydride divinyl ether, or Propionibacterium acnes to augment liver-associated natural killer activity. By Northern blot analysis, it was shown that the induction of mRNA for IFN-alpha, IFN-gamma, and tumor necrosis factor alpha by FAA in the spleen cells of mice was significantly reduced in alkalinized mice. Consistent with a reduction in the FAA-induced expression of the cytokine genes, alkalinization also resulted in a significant decrease in both the peak serum concentration and duration of detectable IFN activity following FAA treatment. Increasing the dose of FAA in alkalinized mice to 300 mg/kg overcame the deleterious effects of alkalinization for treatment of murine renal cancer by FAA plus recombinant interleukin 2. These results demonstrate that the process of alkalinization inhibits the immunomodulatory and immunotherapeutic effects of FAA in mice and suggest that alkalinization might have similar deleterious effects on FAA-induced immune stimulation in human clinical trials.
黄酮醋酸（FAA）是一种正在研究的药物，它能增强自然杀伤细胞活性，诱导α-和γ-干扰素（IFN）以及肿瘤坏死因子α的基因表达，并与重组白细胞介素2协同作用，成功治疗小鼠肾癌。然而，在大多数FAA的临床研究中，仅报道了最小的免疫调节作用。这些研究中的大多数患者还接受了碳酸氢钠治疗，以预防可能的肾毒性。进行当前这项研究是为了确定碱化是否对FAA诱导的小鼠免疫调节和治疗活性有任何影响。结果表明，碱化抑制了FAA加重组白细胞介素2对小鼠肾癌的治疗效果，使得未碱化小鼠84%的存活率在治疗期间碱化的小鼠中降至0。碱化还以剂量依赖的方式显著抑制了FAA增强脾脏和肝脏自然杀伤细胞活性的能力。相比之下，碱化并不抑制聚肌苷酸：聚胞苷酸和在羧甲基纤维素、马来酸酐二乙烯醚或痤疮丙酸杆菌中稳定的聚-L-赖氨酸增强肝脏相关自然杀伤细胞活性的能力。通过Northern印迹分析表明，在碱化小鼠中，FAA诱导的小鼠脾细胞中IFN-α、IFN-γ和肿瘤坏死因子α的mRNA表达显著降低。与FAA诱导的细胞因子基因表达降低一致，碱化还导致FAA治疗后血清中可检测到的IFN活性的峰值浓度和持续时间显著降低。将碱化小鼠中FAA的剂量增加到300mg/kg可克服碱化对FAA加重组白细胞介素2治疗小鼠肾癌的有害影响。这些结果表明，碱化过程抑制了FAA在小鼠中的免疫调节和免疫治疗作用，并表明碱化在人类临床试验中可能对FAA诱导的免疫刺激有类似的有害影响。
