Imam H, Eriksson B, Lukinius A, Janson E T, Lindgren P G, Wilander E, Oberg K
Department of Medicine, University Hospital, Uppsala, Sweden.
Acta Oncol. 1997;36(6):607-14. doi: 10.3109/02841869709001323.
The extent of apoptosis identified by in situ DNA nick end labelling (TUNEL) on tissue samples obtained from patients with neuroendocrine tumors was correlated with the clinical outcome in patients treated with high-dose somatostatin analog (lanreotide 12 mg/day), n = 8, or other biotherapy including interferon-alpha (IFN-alpha), n = 4, low-dose somatostatin analog (octreotide or lanreotide), n = 3, or a combination of both, n = 1. Biopsies were obtained before the start of treatment and/or after 6 months and 12 months. After 6 months of treatment, 5 patients receiving high-dose somatostatin analog showed a biochemical response (decrease in different neuroendocrine tumor markers) and 4 of these showed an increase in apoptotic index (AI: percentage of apoptotic cells) by 1.94 +/- 1.71%. At 12 months, AI was also increased in patients with a biochemical response (4.22 +/- 3.93%). However, none showed a decrease in tumor size on computerized tomography (CT) and none of the patients treated with low-dose somatostatin analog or IFN-alpha showed any significant increase in AI during treatment. In an experimental model, nude mice were xenografted with the neuroendocrine cell line (BON-1). From the 2nd day of tumor implantation, they received treatment with either placebo, high-dose octreotide, IFN-alpha, or a combination of both, for 28 days. In mice receiving treatment with high-dose octreotide (300 microg/kg, t.i.d) there was a threefold increase in apoptotic cells as compared to the placebo group (p = 0.0084), while the combination group had few cells with ultra-structural changes indicating apoptosis and the IFN-alpha treated group showed no significant changes. However, tumor growth inhibition was more pronounced in the combination group (p = 0.0011). This probably denotes that tumor growth inhibition could be achieved more efficiently by blocking the cell cycle than by inducing apoptosis. We concluded that treatment with high-dose somatostatin analogs may induce apoptosis in neuroendocrine tumors, while this is not found during treatment with low-dose somatostatin analogs or IFN-alpha. We also found that an increase in AI during high-dose somatostatin analog treatment was correlated with the biochemical response, but not with the tumor size as detected by CT in patients or with the tumor mass in the experimental model.
通过原位DNA缺口末端标记法（TUNEL）对神经内分泌肿瘤患者的组织样本进行凋亡检测，其凋亡程度与接受高剂量生长抑素类似物（兰瑞肽12毫克/天，n = 8）、或其他生物疗法（包括α干扰素（IFN-α），n = 4）、低剂量生长抑素类似物（奥曲肽或兰瑞肽），n = 3、或两者联合治疗（n = 1）的患者的临床结局相关。在治疗开始前和/或6个月及12个月后获取活检样本。治疗6个月后，5名接受高剂量生长抑素类似物治疗的患者出现生化反应（不同神经内分泌肿瘤标志物降低），其中4名患者的凋亡指数（AI：凋亡细胞百分比）增加了1.94±1.71%。在12个月时，出现生化反应的患者的AI也有所增加（4.22±3.93%）。然而，计算机断层扫描（CT）显示无一例患者肿瘤大小减小，接受低剂量生长抑素类似物或IFN-α治疗的患者在治疗期间AI均未出现显著增加。在一个实验模型中，将神经内分泌细胞系（BON-1）异种移植到裸鼠体内。从肿瘤植入的第2天起，它们接受安慰剂、高剂量奥曲肽、IFN-α或两者联合治疗，持续28天。与安慰剂组相比，接受高剂量奥曲肽（300微克/千克，每日三次）治疗的小鼠凋亡细胞增加了三倍（p = 0.0084），而联合治疗组几乎没有超微结构变化表明凋亡的细胞，IFN-α治疗组无显著变化。然而，联合治疗组的肿瘤生长抑制更为明显（p = 0.0011）。这可能表明，通过阻断细胞周期比诱导凋亡能更有效地实现肿瘤生长抑制。我们得出结论，高剂量生长抑素类似物治疗可能诱导神经内分泌肿瘤细胞凋亡，而低剂量生长抑素类似物或IFN-α治疗期间未发现这种情况。我们还发现，高剂量生长抑素类似物治疗期间AI的增加与生化反应相关，但与患者CT检测到的肿瘤大小或实验模型中的肿瘤质量无关。
