Antitumour activity of the novel immune modulator 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice lacking the interferon-gamma receptor

被引:22
作者
Pang, JH [1 ]
Cao, Z [1 ]
Joseph, WR [1 ]
Baguley, BC [1 ]
Ching, LM [1 ]
机构
[1] Univ Auckland, Sch Med, Canc Res Lab, Auckland, New Zealand
关键词
DMXAA; tumour necrosis factor; interferon-gamma receptor; lipopolysaccharide; knockout; antitumour; colon; 38;
D O I
10.1016/S0959-8049(98)00050-1
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antitumour agent currently undergoing clinical evaluation, appears to mediate its antitumour effects through immune modulation and the production of cytokines. We used mice with a targeted disruption of the interferon-gamma (IFN-gamma) receptor gene as a model to evaluate the role of the host response to IFN-gamma in the antitumour action of DMXAA on colon 38 tumours. A feature of the results was that while DMXAA treatment induced both IFN-gamma and tumour necrosis factor (TNF) in serum, the increase was >20-fold higher in IFN-gamma R-0/0 mice than in wild-type mice. In contrast, mRNA levels for IFN-gamma and TNF were similar in the two mouse strains, suggesting that the concentrations of these cytokines were controlled by a post-transcriptional mechanism. Serum nitrate levels, used as a measure of nitric oxide production, were increased by DMXAA, but to a similar extent in both strains of mice. Complete regressions of colon 38 tumours were obtained in response to DMXAA in the knockout mice, although the dose required for 100% cure was higher and the reduction in tumour volume occurred more slowly than in the wild-type counterparts. The results demonstrate that the host response to IFN-gamma is not essential for an antitumour response. Similar results were obtained in mice that were immunosuppressed by treatment with cyclosporin A before treatment with DMXAA. The results are consistent with the concept that the antitumour activity of DMXAA involves complex immunomodulation, probably with significant redundancy in contributing cytokines. (C) 1998 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:1282 / 1289
页数:8
相关论文
共 41 条
[1]   LIGAND-INDUCED AUTOREGULATION OF IFN-GAMMA RECEPTOR-BETA CHAIN EXPRESSION IN T-HELPER CELL SUBSETS [J].
BACH, EA ;
SZABO, SJ ;
DIGHE, AS ;
ASHKENAZI, A ;
AGUET, M ;
MURPHY, KM ;
SCHREIBER, RD .
SCIENCE, 1995, 270 (5239) :1215-1218
[2]   Immunomodulatory actions of xanthenone anticancer agents [J].
Baguley, BC ;
Ching, LM .
BIODRUGS, 1997, 8 (02) :119-127
[3]   INHIBITION OF GROWTH OF COLON-38 ADENOCARCINOMA BY VINBLASTINE AND COLCHICINE - EVIDENCE FOR A VASCULAR MECHANISM [J].
BAGULEY, BC ;
HOLDAWAY, KM ;
THOMSEN, LL ;
ZHUANG, L ;
ZWI, LJ .
EUROPEAN JOURNAL OF CANCER, 1991, 27 (04) :482-487
[4]   ANTITUMOR-ACTIVITY OF FLAVONE ACETIC-ACID (NSC-347512) IN MICE - INFLUENCE OF IMMUNE STATUS [J].
BIBBY, MC ;
PHILLIPS, RM ;
DOUBLE, JA ;
PRATESI, G .
BRITISH JOURNAL OF CANCER, 1991, 63 (01) :57-62
[5]   Cellular responses to interferon-gamma [J].
Boehm, U ;
Klamp, T ;
Groot, M ;
Howard, JC .
ANNUAL REVIEW OF IMMUNOLOGY, 1997, 15 :749-795
[6]  
CHING LM, 1994, CANCER RES, V54, P870
[7]   INDUCTION OF NATURAL-KILLER ACTIVITY BY XANTHENONE ANALOGS OF FLAVONE ACETIC-ACID - RELATION WITH ANTITUMOR-ACTIVITY [J].
CHING, LM ;
JOSEPH, WR ;
LI, Z ;
ATWELL, GJ ;
REWCASTLE, GW ;
DENNY, WA ;
BAGULEY, BC .
EUROPEAN JOURNAL OF CANCER, 1991, 27 (01) :79-83
[8]   ANTITUMOR RESPONSES TO FLAVONE-8-ACETIC ACID AND 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID IN IMMUNE DEFICIENT MICE [J].
CHING, LM ;
JOSEPH, WR ;
BAGULEY, BC .
BRITISH JOURNAL OF CANCER, 1992, 66 (01) :128-130
[9]   INHIBITION OF CYTOKINE PRODUCTION BY CYCLOSPORINE-A AND TRANSFORMING GROWTH-FACTOR-BETA [J].
ESPEVIK, T ;
FIGARI, IS ;
SHALABY, MR ;
LACKIDES, GA ;
LEWIS, GD ;
SHEPARD, HM ;
PALLADINO, MA .
JOURNAL OF EXPERIMENTAL MEDICINE, 1987, 166 (02) :571-576
[10]   CYTOKINE INDUCTION AND THERAPEUTIC SYNERGY WITH INTERLEUKIN-2 AGAINST MURINE RENAL AND COLON CANCERS BY XANTHENONE-4-ACETIC ACID-DERIVATIVES [J].
FUTAMI, H ;
EADER, LA ;
BACK, TT ;
GRUYS, E ;
YOUNG, HA ;
WILTROUT, RH ;
BAGULEY, BC .
JOURNAL OF IMMUNOTHERAPY, 1992, 12 (04) :247-255