Kawai K, Kawamata H, Kemeyama S, Rademaker A, Oyasu R
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611-3008.
Cancer Res. 1994 May 15;54(10):2630-2.
Chronic inflammation of the urinary tract is a significant risk factor for the development of urinary bladder cancer in man. Previously we have shown that acute and chronic inflammation induced by repeated intravesical instillation of killed Escherichia coli (KEC) strikingly enhanced N-methyl-N-nitrosourea (MNU)-initiated bladder carcinogenesis in our heterotopically transplanted rat urinary bladder model. We conducted the present study to determine whether delayed onset of KEC treatment can still enhance carcinogenesis of the MNU-initiated urothelium and whether continuous KEC treatment is necessary for the development of tumors. After the initiation of carcinogenesis in heterotopically transplanted bladders by the instillation of a single dose (0.25 mg) of MNU, animals were divided into several groups, for which weekly KEC treatment (5 x 10(8) cells suspended in 0.5 ml of phosphate-buffered 2.1% NaCl solution) was begun 1, 5, and 18 weeks later and continued until termination of the experiment at 31 weeks. In addition, animals received 4-week KEC treatment, which was started 1 or 5 weeks after MNU administration. Treatment with KEC alone or MNU alone induced few tumors. Maximal tumor development was demonstrated in the group receiving KEC treatment continuously throughout the experimental period. Delaying the onset of continuous KEC treatment by 4 weeks resulted in a significant decrease in the number of tumors (P = 0.006). However, a substantial number of tumors were induced even when KEC treatment was delayed as many as 18 weeks, as compared to tumor development in the group receiving MNU only (P = 0.007). The tumor volume (size) was not different between continuous and short-term KEC treatment groups. We conclude that (a) although a large number of cells undergo promutagenic DNA damage by a single dose of MNU, the amounts are reduced quickly during the subsequent 4 weeks; but that (b) a substantial number of genetically altered cells remain for a long time and can be promoted to tumors when stimulated by a chronic inflammatory stimulus; and that (c) the duration of KEC treatment determines the number, but not the volume, of tumors.
泌尿道慢性炎症是人类膀胱癌发生的一个重要危险因素。此前我们已经表明，在我们的异位移植大鼠膀胱模型中，通过反复膀胱内灌注灭活大肠杆菌（KEC）诱导的急性和慢性炎症显著增强了N-甲基-N-亚硝基脲（MNU）引发的膀胱癌发生。我们进行本研究以确定KEC治疗延迟开始是否仍能增强MNU引发的尿路上皮癌发生，以及持续KEC治疗对于肿瘤发生是否必要。在通过单次灌注剂量为0.25mg的MNU启动异位移植膀胱的致癌作用后，将动物分为几组，分别在1、5和18周后开始每周进行KEC治疗（5×10⁸个细胞悬浮于0.5ml磷酸盐缓冲的2.1%氯化钠溶液中），并持续至31周实验结束。此外，动物接受4周的KEC治疗，在给予MNU后1或5周开始。单独使用KEC或单独使用MNU治疗诱导出的肿瘤很少。在整个实验期间持续接受KEC治疗的组中显示出最大程度的肿瘤发生。将持续KEC治疗开始时间延迟4周导致肿瘤数量显著减少（P = 0.006）。然而，与仅接受MNU的组中的肿瘤发生相比，即使KEC治疗延迟多达18周，仍诱导出大量肿瘤（P = 0.007）。持续和短期KEC治疗组之间的肿瘤体积（大小）没有差异。我们得出结论：（a）尽管单次剂量的MNU会使大量细胞发生促诱变DNA损伤，但在随后的4周内损伤量会迅速减少；但（b）大量基因改变的细胞会长期留存，并且在受到慢性炎症刺激时可被促进形成肿瘤；以及（c）KEC治疗的持续时间决定肿瘤的数量而非体积。
