Stoppage of blood flow in 3-methylcholanthrene-induced autochthonous primary tumor due to a novel combretastatin A-4 derivative, AC7700, and its antitumor effect.
Stoppage of blood flow in 3-methylcholanthrene-induced autochthonous primary tumor due to a novel combretastatin A-4 derivative, AC7700, and its antitumor effect.
复制标题
新型考布他汀 A-4 衍生物 AC7700 导致 3-甲基胆蒽诱导的原发性肿瘤血流停止及其抗肿瘤作用。
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发表时间：
2001
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影响因子：
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通讯作者：
K. Kubota
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作者：
K. Hori;S. Saito;Y. Sato;K. Kubota
背景
使用几个移植肿瘤在大鼠和小鼠，我们最近表明，急性广泛坏死的肿瘤结节是由全身给药的AC 7700，一种新的combretastatin A-4衍生物，坏死可归因于不可逆的肿瘤血流停止（TBF）。本研究以原发性肿瘤为模型，观察了AC 7700的抗血管和抗肿瘤作用。
材料和方法
在Fischer F344大鼠中通过单次s.c.接种3-甲基胆蒽（MC）（4 mg/0.5 ml/头）。通过氢清除技术测量AC 7700引起的TBF变化。通过组织学和肿瘤生长抑制来评价AC 7700的抗肿瘤作用。
结果
最早的原发性肿瘤出现在MC治疗后77天，最后一个肿瘤出现在273天后（中位数，140天）。一旦肿瘤发生，它们会继续缓慢生长，从未自发消退。指数生长期间肿瘤（n = 34）的平均倍增时间为12.6 +/- 9.0天（平均值+/- SD）（范围：5.4-55.9天）。由于快速静脉注射（0.15 ml/min）10 mg/kg AC 7700，这些生长缓慢的自体肿瘤中的血流量在30 min内从25.2 +/- 15.5降至4.4 +/- 3.2 ml/min/100 g（24个电极）（P < 0.001），并且在6 h的实验期间，降低的TBF未恢复。另一方面，由于0.9%NaCl溶液（10个电极），TBF没有显著变化。此外，TBF在10 mg/kg AC 7700缓慢输注（0.005 ml/min）后立即开始降低，并在AC 7700输注开始后20 min降低约80%（12个电极）。为评价AC 7700对原发性肿瘤的抗肿瘤作用，向荷瘤大鼠静脉注射10 mg/kg AC 7700。虽然在自然过程中，这种肿瘤从未停止生长，但AC 700强烈抑制肿瘤生长（n = 5）。在2例病例中，肿瘤在45天的观察期内从未重新生长。活检和组织学检查结果（n = 5）显示，肿瘤发生广泛坏死，与之前在AC 7700给药后移植肿瘤中观察到的情况相同。
结论
从本实验中，不仅在移植肿瘤中，而且在致癌物诱导的自体原发性肿瘤中，TBF的急性和持续停止导致强烈的抗肿瘤作用。新的抗癌化合物AC 7700可能成为一个非常有用的治疗策略，对难治性癌症。
BACKGROUND
Using several transplanted tumors in rats and mice, we have recently shown that the acute extensive necrosis of tumor nodules is caused by the systemic administration of AC7700, a novel combretastatin A-4 derivative, and that the necrosis can be attributed to irreversible stoppage of tumor blood flow (TBF). In this study, the antivascular and antitumor effects of AC7700 were tested on primary autochthonous tumor.
MATERIAL AND METHODS
Primary sarcomas were induced in Fischer F344 rats by a single s.c. inoculation of 3-methylcholanthrene (MC) (4 mg/0.5 ml/head). Changes in TBF due to AC7700 were measured by hydrogen clearance technique. Antitumor effects of AC7700 were evaluated by histology and tumor growth inhibition.
RESULTS
The earliest primary tumor appeared 77 days after MC treatment and the last tumor appeared after 273 days (median, 140 days). Once tumors occurred, they continued to grow slowly and never regressed spontaneously. The mean doubling time of tumors (n = 34) during exponential growth was 12.6 +/- 9.0 days (mean +/- SD) (range, 5.4-55.9 days). Blood flow in these slow-growing autochthonous tumors decreased highly significantly from 25.2 +/- 15.5 to 4.4 +/- 3.2 ml/min/100 g (24 electrodes)(P < 0.001) within 30 min due to rapid i.v. injection (0.15 ml/min) of 10 mg/kg AC7700 and the decreased TBF did not recover during the experimental period of 6 h. On the other hand, TBF did not change significantly due to 0.9% NaCl solution (10 electrodes). In addition, TBF immediately began to decrease following slow infusion (0.005 ml/min) of 10 mg/kg AC7700 and decreased by approximately 80% (12 electrodes) at 20 min after the start of AC7700 infusion. To evaluate the antitumor effect of AC7700 on the primary tumors, 10 mg/kg AC7700 was injected i.v. to tumor-bearing rats. Although in the natural course, such tumors never stop growing, the tumor growth was strongly inhibited by AC700 (n = 5). In 2 cases, tumors never regrew for the observation period of 45 days. Biopsy and histological findings (n = 5) showed that tumors underwent extensive necrosis, as was observed previously for transplanted tumors following AC7700 administration.
CONCLUSION
From the present experiment it was demonstrated not only in transplanted tumors but also in carcinogen-induced autochthonous primary tumors that acute and sustained stoppage of TBF led to strong antitumor effects. The novel anticancer compound AC7700 might become a very useful therapeutic strategy against refractory cancers.