减缓头颈部肿瘤的增殖：多胺类似物BE-4-4-4-4对人鳞状细胞癌的体外生长抑制作用

Slowing proliferation in head and neck tumors: in vitro growth inhibitory effects of the polyamine analog BE-4-4-4-4 in human squamous cell carcinomas.

作者信息

Harari P M, Pickart M A, Contreras L, Petereit D G, Basu H S, Marton L J

机构信息

Department of Human Oncology, University of Wisconsin School of Medicine, Madison, USA.

出版信息

Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):687-94. doi: 10.1016/0360-3016(95)00574-I.

DOI:10.1016/0360-3016(95)00574-I

PMID:7790255

Abstract

PURPOSE

These preclinical studies were carried out to examine the potential of the antiproliferative polyamine analog 1,19-bis-(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) to serve as a therapy adjuvant to radiation for patients with rapidly dividing tumors of the head and neck (H&N).

METHODS AND MATERIALS

Cytostatic and cytotoxic effects of this polyamine analog were investigated in three squamous cell carcinoma (SCC) cell lines derived from human H&N tumors.

RESULTS

Growth inhibition was achieved in all cell lines within 3-4 days of continuous 10 microM drug exposure, and inhibition of cell cycle proliferation kinetics was confirmed via flow cytometry. Cytotoxicity was pronounced (3-4 log cell kill) in the SCC-38 and SCC-4Y cell lines with continuous 10 microM analog exposure over 5 days, and was minimal in the SCC-13Y cell line. No demonstrable effect of BE-4-4-4-4 on single dose radiation survival was identified in any SCC cell line. Ornithine decarboxylase (ODC) activity was rapidly inhibited (1-2 h) following 10 microM BE-4-4-4-4 exposure in all SCC cell lines (approximately 90%), whereas identical exposure to 10 microM difluoromethylornithine (DFMO) induced animal ODC inhibition (approximately 10%). Dose-dependent depletion of endogenous polyamines (putrescine, spermidine, spermine) was achieved in all SCC cell lines following 1 microM and 10 microM BE-4-4-4-4 exposures. Difluoromethylornithine was significantly less potent than BE-4-4-4-4 in its capacity to deplete endogenous polyamines, with no measureable depletion of spermine pools even with 5 mM x 48 h DFMO exposures.

CONCLUSIONS

These data evaluate cytostatic and cytotoxic properties of the polyamine analog BE-4-4-4-4 in human SCCs, and suggest a role for investigation of such agents as an adjuvant to radiation in the therapeutic approach to rapidly dividing human tumors such as those that occur in the H&N.

摘要

目的

开展这些临床前研究，以检验抗增殖多胺类似物1,19 - 双（乙氨基）-5,10,15 - 三氮杂十九烷（BE - 4 - 4 - 4 - 4）作为头颈部（H&N）快速增殖肿瘤患者放疗辅助治疗手段的潜力。

方法与材料

在源自人H&N肿瘤的三种鳞状细胞癌（SCC）细胞系中研究了这种多胺类似物的细胞生长抑制和细胞毒性作用。

结果

持续暴露于10 microM药物3 - 4天内，所有细胞系均实现生长抑制，通过流式细胞术确认了细胞周期增殖动力学受到抑制。在SCC - 38和SCC - 4Y细胞系中，持续5天暴露于10 microM类似物时，细胞毒性显著（3 - 4个对数级的细胞杀伤），而在SCC - 13Y细胞系中细胞毒性最小。在任何SCC细胞系中均未发现BE - 4 - 4 - 4 - 4对单剂量辐射存活有明显影响。在所有SCC细胞系中，暴露于10 microM BE - 4 - 4 - 4 - 4后，鸟氨酸脱羧酶（ODC）活性迅速受到抑制（1 - 2小时）（约90%），而相同暴露于10 microM二氟甲基鸟氨酸（DFMO）仅诱导约10%的ODC抑制。在所有SCC细胞系中，暴露于1 microM和10 microM BE - 4 - 4 - 4 - 4后，内源性多胺（腐胺、亚精胺、精胺）实现了剂量依赖性消耗。二氟甲基鸟氨酸在消耗内源性多胺的能力方面明显弱于BE - 4 - 4 - 4 - 4，即使暴露于5 mM×48小时的DFMO，精胺池也没有可测量的消耗。