Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?

被引:257
作者
Reuter, CWM [1 ]
Morgan, MA [1 ]
Bergmann, L [1 ]
机构
[1] Univ Ulm, Dept Internal Med Hematol & Oncol 3, D-89081 Ulm, Germany
关键词
D O I
10.1182/blood.V96.5.1655.h8001655_1655_1669
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
A series of alterations in the cellular genome affecting the expression or function of genes controlling cell growth and differentiation is considered to be the main cause of cancer, These mutational events include activation of oncogenes and inactivation of tumor suppressor genes. The elucidation of human cancer at the molecular level allows the design of rational, mechanism-based therapeutic agents that antagonize the specific activity of biochemical processes that are essential to the malignant phenotype of cancer cells. Because the frequency of RAS mutations is among the highest for any gene in human cancers, development of inhibitors of the Ras-mitogen-activated protein kinase pathway as potential anticancer agents is a very promising pharmacologic strategy. Inhibitors of Ras signaling have been shown to revert Ras-dependent transformation and cause regression of Ras-dependent tumors in animal models. The most promising new class of these potential cancer therapeutics are the farnesyltransferase inhibitors, The development of these compounds has been driven by the observation that oncogenic Ras function is dependent upon posttranslational modification, which enables membrane binding. In contrast to many conventional chemotherapeutics, farnesyltransferase inhibitors are remarkably specific and have been demonstrated to cause no gross systemic toxicity in animals, Some orally bioavailable inhibitors are presently being evaluated in phase II clinical trials. This review presents an overview on some inhibitors of the Ras signaling pathway, including their specificity and effectiveness in vivo. Because Ras signaling plays a crucial role in the pathogenesis of some hematologic malignancies, the potential therapeutic usefulness of these inhibitors is discussed. (C) 2000 by The American Society of Hematology.
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收藏
页码:1655 / 1669
页数:15
相关论文
共 231 条
[21]   Identification of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis:: A possible explanation for divergent clinical behavior [J].
Büttner, C ;
Henz, BM ;
Welker, P ;
Sepp, NT ;
Grabbe, J .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1998, 111 (06) :1227-1231
[22]  
Byrne JL, 1998, BRIT J HAEMATOL, V100, P256
[23]  
CAMP LA, 1994, J BIOL CHEM, V269, P23212
[24]   Phosphoinositide kinases [J].
Carpenter, CL ;
Cantley, LC .
CURRENT OPINION IN CELL BIOLOGY, 1996, 8 (02) :153-158
[25]   Protein prenyltransferases [J].
Casey, PJ ;
Seabra, MC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (10) :5289-5292
[26]  
CASEY S, 1992, ONCOGENE, V12, P2525
[27]  
CATLING AD, 1995, MOL CELL BIOL, V15, P5214
[28]   Selective inhibition of ras-transformed cell growth by a novel fatty acid-based chloromethyl ketone designed to target was endoprotease [J].
Chen, YL .
ANTICANCER MOLECULES: STRUCTURE, FUNCTION, AND DESIGN, 1999, 886 :103-108
[29]  
Clark Geoffrey J., 1995, P17
[30]  
CORRADINI P, 1993, BLOOD, V81, P2708