Oki E, Sakaguchi Y, Toh Y, Oda S, Maehara Y, Yamamoto N, Sugimachi K
Cancer Centre of Kyushu University Hospital, Fukuoka, Japan.
Br J Cancer. 1998 Sep;78(5):625-30. doi: 10.1038/bjc.1998.552.
Various types of anti-neoplastic agents induce apoptosis in vitro, but less is known of the role of this mode of cell death in tumours treated in vivo. We examined the induction of apoptosis by oral anti-neoplastic agents, tegafur and uracil (UFT, a combined preparation of 1 mol tegafur and 4 mol uracil), and the relationship of effects on tumour growth. Seven different human gastrointestinal tumour xenografts were transplanted into nude mice, including two colon adenocarcinomas (KM20C and Col-1), three gastric carcinomas (SC-6, St-40 and 4-1ST) and two pancreatic carcinomas (PAN-4 and PAN-12), followed by oral administration of UFT (24 mg kg(-1) day(-1)) for 9 days. The percentage of apoptotic cells in each tumour was scored in histological sections, chronologically, using a molecular biological-histochemical system and growth inhibition was examined in each tumour. A significant growth inhibition by UFT was observed for all tumours, except PAN-12. In KM20C and SC-6, growth inhibition rates were 61.7% and 60.6% respectively. Quantitative assay for apoptosis showed a remarkable induction of apoptosis in KM20C (4.2%) and SC-6 (3.5%), which were relatively sensitive to UFT. In addition, KM20C and SC-6 showed a higher incidence of spontaneous apoptosis. In five other tumours, which responded to a lesser extent than KM20C and SC-6, UFT altered little the changes in apoptosis (less than 2%) and spontaneous apoptosis was relatively low. Thus, tumours with a higher apoptosis induced by UFT had a higher response to UFT. Apoptosis observed in tumours might serve as a predictor of a preferable response to UFT.
多种类型的抗肿瘤药物在体外可诱导细胞凋亡，但对于这种细胞死亡方式在体内肿瘤治疗中的作用，人们了解得较少。我们研究了口服抗肿瘤药物替加氟尿嘧啶（UFT，1摩尔替加氟与4摩尔尿嘧啶的复方制剂）诱导细胞凋亡的情况，以及其对肿瘤生长的影响关系。将7种不同的人胃肠道肿瘤异种移植物接种到裸鼠体内，包括2种结肠腺癌（KM20C和Col-1）、3种胃癌（SC-6、St-40和4-1ST）以及2种胰腺癌（PAN-4和PAN-12），随后口服UFT（24毫克/千克/天），持续9天。使用分子生物学 - 组织化学系统，按时间顺序对各肿瘤组织切片中的凋亡细胞百分比进行评分，并检测各肿瘤的生长抑制情况。除PAN-12外，所有肿瘤均观察到UFT对其有显著的生长抑制作用。在KM20C和SC-6中，生长抑制率分别为61.7%和60.6%。凋亡定量分析显示，对UFT相对敏感的KM20C（4.2%）和SC-6（3.5%）中出现了明显的凋亡诱导现象。此外，KM20C和SC-6的自发凋亡发生率较高。在另外5种对UFT反应程度低于KM20C和SC-6的肿瘤中，UFT对凋亡变化的影响较小（小于2%），且自发凋亡率相对较低。因此，UFT诱导凋亡率较高的肿瘤对UFT的反应性更高。肿瘤中观察到的凋亡可能作为预测对UFT良好反应的指标。
