Antitumour responses to flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid in immune deficient mice.
Antitumour responses to flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid in immune deficient mice.
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DOI：
10.1038/bjc.1992.228
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发表时间：
1992-07
影响因子：
8.8
通讯作者：
Baguley BC
中科院分区：
文献类型：
--
作者：
Ching LM;Joseph WR;Baguley BC
黄酮-8-乙酸（FAA）是一种合成类黄酮，具有令人印象深刻的临床前活性，但作为单一药物没有临床活性（Kerr & Kaye，1989）。5，6-MeXAA是本实验室开发的FAA的稠合三环类似物（Rewcastle等人，1991年）。与FAA相比，它具有改善的抗肿瘤活性和12倍的剂量效力，是临床试验的候选药物。FAA和5，6-MeXAA与内毒素共有许多特性：它们诱导肿瘤坏死因子（TNF）的合成（North & Havell，1988; Mace等人，1990）和刺激一氧化氮的形成，两者都是在体外（Drapier等人，1988年; Albersen等人，1990）和体内（Stuehr & Marletta，1985; Bauzsen等人，1991年）。这些代理人的行动有两个主要方面。首先，通过诱导TNF，它们促进肿瘤缺血引起的肿瘤血流停止和细胞死亡（Evelhoch等人，1988; North和Havell，1988; Zwi等人，1989; Mahadevan等人，1990年）。其次，巨噬细胞-（Stewart等人，1988）或淋巴细胞（Berendt等，1978）介导的细胞毒性导致残留肿瘤细胞的进一步杀伤。T淋巴细胞介导的免疫性与内毒素的作用有关（Berendt等人，1978）和FAA（Pratesi等人，1990; Bibby等人，1991年）。我们在这里报告，FAA和5，6-MeXAA诱导生长延迟和治愈的结肠38腺癌的T细胞耗竭小鼠，因此可以有效地发挥作用，至少对某些肿瘤，T细胞的独立机制。如前所述（Rewcastle等人，1991年; Albersen等人，1991）、5，6-MeXAA和FAA，当以单剂量方案给予具有可触知的皮下Colon 38肿瘤的BDF（C57 B1/6 J × DBA/2 J）杂交小鼠时，诱导显著的生长延迟和治愈（表I）。为了研究T细胞在该应答中的作用，对裸（无胸腺）和T细胞缺陷胸腺切除（T x B）小鼠进行类似处理。C57 B1/6 nu/nu小鼠（获自MrV. Jansen，奥克兰医学院）和BDF小鼠在恒温恒湿条件下饲养，使用无菌垫料和食物，并遵循机构动物伦理指南。通过在6周龄时切除BDF小鼠的胸腺并在1周后用“钴源”照射（9.5戈伊）来制备T × B小鼠。静脉内注射同基因骨髓细胞（2 x 106），并在骨髓重建后6周将小鼠用于实验。在每次实验结束时，检查所有小鼠的胸腺是否完全切除。通过用伴刀豆球蛋白A（2 μ g/ml; Sigma）培养来自个体小鼠的脾细胞（106个细胞/ml）并在3天后测量氚标记的胸苷摄取来检查T细胞缺乏。T x B小鼠的放射活性低于正常胸腺对照组的5%。将结肠38片段皮下植入。每个实验选择直径为4-8 mm的携带肿瘤的小鼠，并根据肿瘤大小随机分为治疗组和对照组（每组至少5只小鼠）。将FAA（获自美国国家癌症研究所（National Cancer Institute），USA）和5，6-MeXAA的钠盐（在该实验室中合成）溶于5%（w/v）碳酸氢钠中，避光（Rewcastle等人，1990），并以单次ip（腹膜内）剂量给药于治疗组的小鼠。此后每周用卡尺测量肿瘤三次，肿瘤体积计算为0.52 a2 B，其中a和B是肿瘤的短轴和长轴。每次测定肿瘤体积的算术平均值（用于包括已完全回归的数值）和标准误差……
Flavone-8-acetic acid (FAA) is a synthetic flavonoid with impressive preclinical activity but no clinical activity as a single agent (Kerr & Kaye, 1989). 5, 6-MeXAA is a fused tricyclic analogue of FAA developed in this laboratory (Rewcastle et al., 1991). It has improved antitumour activity and 12-fold higher dose potency when compared to FAA, and is a candidate drug for clinical trial. FAA and 5, 6-MeXAA share many properties with endotoxin: they induce the syn-thesis of tumour necrosis factor (TNF)(North & Havell, 1988; Mace et al., 1990) and stimulate the formation of nitric oxide, both in vitro (Drapier et al., 1988; Thomsen et al., 1990) and in vivo (Stuehr & Marletta, 1985; Thomsen et al., 1991). There are two main facets to the action of these agents. Firstly, by inducing TNF they promote the cessation of tumour blood flow and cell death by tumour ischaemia (Evelhoch et al., 1988; North & Havell, 1988; Zwi et al., 1989; Mahadevan et al., 1990). Secondly, macrophage-(Stewart et al., 1988) or lymphocyte (Berendt et al., 1978) mediated cytotoxicity leads to further killing of residual tumour cells. T-lymphocyte mediated immunity has been implicated in the action of both endotoxin (Berendt et al., 1978) and of FAA (Pratesi et al., 1990; Bibby et al., 1991). We report here that FAA and 5, 6-MeXAA induce growth delays and cures of the Colon 38 adenocarcinoma in T-cell depleted mice, and can therefore function effectively, at least against some tumours, by T-cell independent mechanisms. As demonstrated previously (Rewcastle et al., 1991; Thomsen et al., 1991), 5, 6-MeXAA and FAA, when administered in a single dose schedule to BDF,(C57B1/6J x DBA/2J) hybrid mice with palpable subcutaneous Colon 38 tumours, induced substantial growth delays and cures (Table I). In order to investigate the role of T-cells in this response, nude (athymic) and T-cell deficient thymectomised (T x B) mice were subjected to similar treatment. C57B1/6 nu/nu mice (obtained from Mr V. Jansen, Auckland Medical School) and BDF, mice were bred under conditions of constant temperature and humidity, using sterile bedding and food and following institutional animal ethical guidelines. T x B mice were prepared by thymectomising BDF, mice at 6 weeks of age and irradiating (9.5 Gy) 1 week later with a'" Cobalt source. Syngeneic bone marrow cells (2 x 106) were injected intravenously and mice were used for experiments 6 weeks after bone marrow reconstitution. At the end of each experiment, all mice were examined for complete removal of thymic glands. T-cell deficiency was checked by culturing spleen cells (106 cellsml-') from individual mice with con-canavalin A (2pgml-'; Sigma) and measuring tritiated thymidine uptake after 3 days. T x B mice incorporated less than 5% of theradioactivity of that of euthymic controls. Colon 38 fragments were implanted subcutaneously. Mice bearing tumours 4-8 mm in diameter were selected for each experiment and randomised with respect to tumour size into treatment and control groups (at least five mice per group). FAA (obtained from the National Cancer Institute, USA) and the sodium salt of 5, 6-MeXAA (synthesised in this laboratory) were dissolved in 5%(w/v) sodium bicarbonate, protected from light (Rewcastle et al., 1990), and administered as a single ip (intraperitoneal) dose to mice in treat-ment groups. Tumours were measured thereafter three times weekly with callipers and tumour volumes calculated as 0.52 a2b, where a and b were the minor and major axes of the tumour. The arithmetic means (used in order to include those which had completely regressed) and standard errors of the tumour volumes were determined at each time …