Osawa S, Terashima Y, Kimura G, Akimoto M
Department of Urology, Nippon Medical School, Tokyo, Japan.
BJU Int. 1999 Jan;83(1):123-8. doi: 10.1046/j.1464-410x.1999.00911.x.
To examine the antitumour effects of the angiogenesis inhibitor AGM-1470 (TNP-470) on rat urinary bladder tumours induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN).
Fischer-344 rats were allocated to one of four groups of 15 rats each; in group 1, rats were administered AGM-1470 intraperitoneally, with group 2 acting as the control and given only saline; in group 3, AGM-1470 was instillation intravesically and group 4 acting as control (intravesical saline). All rats were given 0.05% BBN in their drinking water for 8 weeks and then given water with no BBN. AGM-1470 was administered at a dose of 30 mg/kg every other day for 6 weeks in group 1 and at 15 mg/kg once a week for 6 weeks in group 3. This treatment was commenced at 21 weeks after the start of BBN treatment, when tumorigenesis was apparent in all rat bladders; approximately 70-80% of the tumours were carcinomas. All rats were killed in the 27th week. The antitumour effects of AGM-1470 on the BBN-induced bladder tumours were evaluated macroscopically and histologically. The inhibitory effect of AGM-1470 on endothelial cell proliferation was assessed in groups 1 and 2 by immunohistochemical staining for Factor VIII-related antigen and by counting the microvessels.
The number and volume of bladder tumours were significantly less in group 1 than group 2. In the latter, at least one bladder tumour developed in each of the 15 rats. Histologically, transitional cell carcinoma (TCC) was found in 13 rats and papilloma in two, with invasive cancer in three of the 13 TCCs. Bladder tumours developed in only four of the 15 rats in group 1. Carcinomas were found in three of these four rats and no invasive cancer was detected. The rats in group 1 had significantly fewer microvessels than the controls. The rats in group 4 also showed slightly but insignificantly less tumour growth and fewer carcinomas. In neither experiment were any major side-effects seen except for mild weight loss after AGM-1470 treatment.
AGM-1470 inhibited the growth and malignant progression of BBN-induced bladder tumours in rats, apparently mainly by the inhibition of tumour vessel development. The intraperitoneal administration of AGM-1470 produced better results than did intravesical instillation. These results suggest that the angiogenesis inhibitor AGM-1470 is a promising agent for the treatment of human bladder cancer.
研究血管生成抑制剂AGM - 1470（TNP - 470）对N - 丁基 - N -（4 - 羟基丁基）亚硝胺（BBN）诱导的大鼠膀胱肿瘤的抗肿瘤作用。
将Fischer - 344大鼠分为四组，每组15只；第1组大鼠腹腔注射AGM - 1470，第2组作为对照组，仅给予生理盐水；第3组膀胱内灌注AGM - 1470，第4组作为对照组（膀胱内灌注生理盐水）。所有大鼠饮用含0.05%BBN的水8周，然后饮用不含BBN的水。第1组每隔一天以30mg/kg的剂量给予AGM - 1470，持续6周；第3组每周以15mg/kg的剂量给予AGM - 1470，持续6周。这种治疗在BBN治疗开始21周后开始，此时所有大鼠膀胱中肿瘤形成明显；约70 - 80%的肿瘤为癌。所有大鼠在第27周处死。通过宏观和组织学评估AGM - 1470对BBN诱导的膀胱肿瘤的抗肿瘤作用。通过对第VIII因子相关抗原进行免疫组织化学染色并计数微血管，评估第1组和第2组中AGM - 1470对内皮细胞增殖的抑制作用。
第1组膀胱肿瘤的数量和体积明显少于第2组。在第2组中，15只大鼠中的每只至少发生了一个膀胱肿瘤。组织学上，13只大鼠发现移行细胞癌（TCC），2只发现乳头状瘤，13例TCC中有3例为浸润性癌。第1组15只大鼠中仅4只发生了膀胱肿瘤。这4只大鼠中有3只发现癌，未检测到浸润性癌。第1组大鼠的微血管明显少于对照组。第4组大鼠的肿瘤生长也略有减少，癌的数量也略有减少，但差异不显著。除了AGM - 1470治疗后体重略有减轻外，两个实验中均未观察到任何主要副作用。
AGM - 1470抑制了BBN诱导的大鼠膀胱肿瘤的生长和恶性进展，显然主要是通过抑制肿瘤血管生成。AGM - 1470腹腔注射产生的效果优于膀胱内灌注。这些结果表明血管生成抑制剂AGM - 1470是治疗人类膀胱癌的一种有前景的药物。
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