Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model

被引:52
作者
Wacheck, V
Heere-Ress, E
Halaschek-Wiener, J
Lucas, T
Meyer, H
Eichler, HG
Jansen, B
机构
[1] Univ Vienna, Sch Expt Oncol Mol Pharmacol, Dept Clin Pharmacol, A-1090 Vienna, Austria
[2] Univ Vienna, Dept Dermatol, Div Gen Dermatol, A-1090 Vienna, Austria
来源
JOURNAL OF MOLECULAR MEDICINE-JMM | 2001年 / 79卷 / 10期
基金
奥地利科学基金会;
关键词
gastric cancer; antisense oligonucleotides; Bcl-2; chemoresistance; apoptosis;
D O I
10.1007/s001090100251
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
We used Bcl-2 antisense oligonucleotides (G3139) to chemosensitize human gastric cancer by downregulation of Bcl-2 expression in vivo. Oligonucleotides and cisplatin were administered systemically in a human gastric cancer SCID mouse model, and Bcl-2 expression, apoptosis, tumor size, and survival were assessed. Used alone, G3139 treatment led to downregulation of Bcl-2 and moderate tumor reduction compared to saline control. G3139 combined with cisplatin treatment markedly enhanced the antitumor effect of cisplatin (70% tumor size reduction vs. cisplatin alone), associated with increased apoptosis measured in tumor biopsy specimens. Combined treatment with G3139 and cisplatin prolonged survival of the tumor-bearing SCID mice by more than 50% without adding significant drug-related toxicity. Treatment with Bcl-2 antisense oligonucleotides is thus a promising novel approach to enhance antitumor activity of cisplatin or other drugs used in gastric cancer therapy and warrants further evaluation in clinical trials.
引用
收藏
页码:587 / 593
页数:7
相关论文
共 38 条
[1]  
Ajani JA, 1998, ONCOLOGY-NY, V12, P44
[2]   Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer [J].
Boku, N ;
Ohtsu, A ;
Shimada, Y ;
Shirao, K ;
Seki, S ;
Saito, H ;
Sakata, Y ;
Hyodo, I .
JOURNAL OF CLINICAL ONCOLOGY, 1999, 17 (01) :319-323
[3]  
Carpentier AF, 1999, CANCER RES, V59, P5429
[4]   BCL-2 FAMILY: Regulators of cell death [J].
Chao, DT ;
Korsmeyer, SJ .
ANNUAL REVIEW OF IMMUNOLOGY, 1998, 16 :395-419
[5]  
Cotter Finbarr E., 1999, Seminars in Hematology, V36, P9
[6]  
de Menezes DEL, 2000, CLIN CANCER RES, V6, P2891
[7]   The role of chemotherapy in the management of gastric cancer [J].
De Vivo, R ;
Pignata, S ;
Palaia, R ;
Parisi, V ;
Daniele, B .
JOURNAL OF CLINICAL GASTROENTEROLOGY, 2000, 30 (04) :364-371
[8]   Apoptosis and chemotherapy resistance [J].
Hickman, JA .
EUROPEAN JOURNAL OF CANCER, 1996, 32A (06) :921-926
[9]   BCL-2 IS AN INNER MITOCHONDRIAL-MEMBRANE PROTEIN THAT BLOCKS PROGRAMMED CELL-DEATH [J].
HOCKENBERY, D ;
NUNEZ, G ;
MILLIMAN, C ;
SCHREIBER, RD ;
KORSMEYER, SJ .
NATURE, 1990, 348 (6299) :334-336
[10]  
Inada T, 1998, ANTICANCER RES, V18, P2003