New targets and challenges in the molecular therapeutics of cancer

被引:27
作者
Eastman, Alan
Perez, Raymond P.
机构
[1] Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Dept Pharmacol & Toxicol, Lebanon, NH 03756 USA
[2] Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Dept Med, Lebanon, NH USA
关键词
drug discovery; gefitinib; imatinib mesylate; oncogene addition; pharmacodynamics; synthetic lethal; UCN-01;
D O I
10.1111/j.1365-2125.2006.02720.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The past 20 years have seen an explosion of information on the molecular changes that lead to cancer. The pathways that have been uncovered include many targets for the development of novel therapeutics. Several such drugs have been approved for clinical use and many additional drugs and targets are now being evaluated in preclinical studies. These new drugs may exhibit impressive therapeutic activity, but this is often restricted to a subpopulation of cancers with a particular molecular change. Moreover, toxicity or even antagonism may result from off-target effects of the drugs. Accordingly, it will be critical to stratify patients for treatment based on the propensity of their tumours to respond. In addition, defining the appropriate dose of targeted agents to administer is challenging; early clinical trial designs must include assays to define the effective biological dose, in addition to more traditional end-points such as the maximum tolerable dose. These and many other challenges exist in the preclinical and clinical development of these drugs.
引用
收藏
页码:5 / 14
页数:10
相关论文
共 35 条
[1]   Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling [J].
Alizadeh, AA ;
Eisen, MB ;
Davis, RE ;
Ma, C ;
Lossos, IS ;
Rosenwald, A ;
Boldrick, JG ;
Sabet, H ;
Tran, T ;
Yu, X ;
Powell, JI ;
Yang, LM ;
Marti, GE ;
Moore, T ;
Hudson, J ;
Lu, LS ;
Lewis, DB ;
Tibshirani, R ;
Sherlock, G ;
Chan, WC ;
Greiner, TC ;
Weisenburger, DD ;
Armitage, JO ;
Warnke, R ;
Levy, R ;
Wilson, W ;
Grever, MR ;
Byrd, JC ;
Botstein, D ;
Brown, PO ;
Staudt, LM .
NATURE, 2000, 403 (6769) :503-511
[2]   The specificities of protein kinase inhibitors: an update [J].
Bain, J ;
McLauchlan, H ;
Elliott, M ;
Cohen, P .
BIOCHEMICAL JOURNAL, 2003, 371 :199-204
[3]   Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts [J].
Berg, T ;
Cohen, SB ;
Desharnais, J ;
Sonderegger, C ;
Maslyar, DJ ;
Goldberg, J ;
Boger, DL ;
Vogt, PK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (06) :3830-3835
[4]   Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase [J].
Bryant, HE ;
Schultz, N ;
Thomas, HD ;
Parker, KM ;
Flower, D ;
Lopez, E ;
Kyle, S ;
Meuth, M ;
Curtin, NJ ;
Helleday, T .
NATURE, 2005, 434 (7035) :913-917
[5]  
Bunch RT, 1996, CLIN CANCER RES, V2, P791
[6]  
Bunch RT, 1997, CELL GROWTH DIFFER, V8, P779
[7]   Timeline - Chemotherapy and the war on cancer [J].
Chabner, BA ;
Roberts, TG .
NATURE REVIEWS CANCER, 2005, 5 (01) :65-72
[8]  
Dagher R, 2002, CLIN CANCER RES, V8, P3034
[9]   Targeting epidermal growth factor receptor - are we missing the mark? [J].
Dancey, JE ;
Freidlin, B .
LANCET, 2003, 362 (9377) :62-64
[10]   Specificity and mechanism of action of some commonly used protein kinase inhibitors [J].
Davies, SP ;
Reddy, H ;
Caivano, M ;
Cohen, P .
BIOCHEMICAL JOURNAL, 2000, 351 (351) :95-105