Extract
Note: Please read the complete
full text with Figures and Tables at
Current status of cancer knowledge
Cancer has been one of the most common causes of human death for a long time. Epidemiological data demonstrated that
there have been nearly 7 million deaths as a result of cancer per year in the past several decades, and it is estimated that there
will be 16 million new cancer cases and 10 million cancer deaths per year by the year of 2020 [World Health Organization].
Despite the efforts of scientists throughout the world for several decades, the mechanism of tumor development has not
yet been completely clarified. Scientists in different research fields have given distinct answers on carcinogenesis respectively.
As to etiology, cancer develops with the accumulation of multi-gene mutations, which are the result of the interaction
between genetic host factors and external agents. Carcinogenic agents can be categorized as physical ones such as
ultraviolet (UV) and ionizing radiation; chemical ones such as asbestos and smoking; biological ones such as certain viral and
bacterial infections; as well as mycotoxins containing food such as aflatoxins causing liver
cancer[1_5]. Research of cancer stem cells, which has been regarded as the origin of cancer, has claimed that the current methods of chemotherapy are
targeting the wrong objects[6]. Scientists on system biology contend that traditional biologists have intensively studied the
individual components of a living organism, and more efforts should be put into the investigation on how these components
interact with each other and form a complex
system[7]. Deregulated cell growth is the defining feature of tumors compared with
normal tissue. Molecular biologists believe that deregulated cell growth occurs as a result of perturbed signal transduction
defined as all cellular signals that modulate cellular behavior or function.
Though great success has been achieved, the war against cancer is complex and hard, and we are still far from winning it.
At present, more and more scientists are beginning to explore the mechanism of carcinogenesis by studying the oncogenic
signal transduction.
Cells receive an external "signal input" from their environment that controls proliferation, differentiation, migration or
death. Such signals come from specific soluble signaling
molecules, from matrix molecules or through direct contacts
with other cells, and are mediated to the receiving cell through
specific receptors. Activation of such receptors initiates a
number of intracellular signaling pathways. The signal
processing elements within the cell make a response that will be
a pattern of reactions manifest as a metabolic, morphologic
or electric "signal output". There has been a notable interest
during the past 25 years in the elucidation of these pathways,
since their perturbation is linked to the development of
serious diseases, including cancer.
Essential signaling pathways involved in tumor development
Cells are organic microsystems with functional
compartments interconnected by complex signal
pathways[8]. Signal transduction has been proven to not only occur through
linear pathways between individual receptors and specific
cellular responses, but rather, there is extensive cross-talk
between different pathways, and the cell thus contains a
network of interacting signaling components. Among those,
numerous signaling pathways are accompanied by the
activation of kinase cascade, which regulates the processes
essential to tumor cell development including cell growth,
differentiation, migration and apoptosis etc. Besides p53,
phosphatase and tensin homolog deleted on chromosome
ten (PTEN) and Rb proteins, which play critical roles in
tumor development and have been extensively studied already,
cell signaling researchers are also working hard to identify
novel targets that act as an Achilles' heel in the signaling
pathway to develop new drugs to inhibit cancer
development and metastasis. Some key pathways associated with
cancer development are briefly summarized as below.
Mitogen activated protein kinase pathways
Mitogen activated protein kinases (MAPKs) are a family
of kinases of different lineages that are thought to be
important in tumor growth and
metastasis[9]. There are three major subfamilies of MAPK: the extracellular-signal-regulated
kinases (ERK); the c-jun N-terminal kinase or stress-activated
protein kinases (JNK or SAPK); and p38 MAPK. All of these
have been proved to play essential roles in the regulation of
intracellular metabolism, gene expression and integral
actions in many aspects including cell growth, differentiation,
apoptosis and cellular responses to external stresses. Lots
of evidence has indicated that overexpression and
activation of MAPKs are extremely important in the development
of cancer[10]. Xu et
al[11] demonstrated that blockage of the
MAPK pathway resulted in the decrease of
cyclooxygenase-2 (COX-2) expression and the inhibition of angiogenesis in
malignant glioma cells indicating the promising prospect of
p38 as a valuable target in brain tumor therapy. Hsiao
et al[12] reported flavanone and 2'-OH flavanone can inhibit
metastasis of lung cancer cells via suppression of the MAPK
pathway and perturb the invasion and metastasis of lung cancer
cells, thereby constituting an adjuvant treatment for
metastasis control.
IKK/NF-κB signaling cascades
IκB kinase/NF-κB (IKK/NF-κB) signaling pathways play
critical roles in a variety of physiological and pathological
processes[13]. NF-κB is a critical nuclear transcriptional
factor that is activated in response to cellular stresses and
regulates the expression of genes involved in cell proliferation
and cell death[14]. When regulated NF-κB activation is
disrupted and cells undergo apoptosis. That is, constitutively
elevated or dysregulated NF-κB activation leads to cell death
in response to stress. Cross talk between NF-κB and c-Jun
N-terminal kinases (JNKs) has been involved in the cell life
and death decision under various stresses. Functional
suppression of JNK activation by NF-κB has been proposed as
a key cellular survival mechanism and contributes to cancer
cells escaping from apoptosis. Huang et
al[15] lately provided a novel scenario of the proapoptotic role of IkappaB kinase
beta (IKKbeta)-NF-κB, which can act as the activator of the
JNK pathway through the induction of GADD45alpha for
triggering mitogen-activated protein kinase kinase 4
(MKK4)/JNK activation. There has been much effort recently to probe
the long-recognized relationship between the pathological
processes of infection, inflammation and cancer. For example
epidemiological studies have shown that 15% of human
deaths from cancer are associated with chronic viral or
bacterial infections. Hence, inhibition of IKK-driven
NF-κB activation offers a strategy for the treatment of different
malignancies and can convert inflammation-induced tumor growth
to inflammation-induced tumor
regression[16].
Wnt signaling pathway
The wnt signal transduction cascade, one of the most
powerful pathways in a cell, was originally described in the
embryogenesis of vertebrates and
non-vertebrates[17]. It is
apparent that wnt signaling causes cancer and that tumor
promotion by this pathway can proceed through a number of
different genetic
defects[18]. Additional mechanisms by which
defects in the regulation of wnt signaling contribute to tumor
progression probably remain undiscovered. The
manifestation of cancer by aberrant wnt
signaling most likely results from inappropriate gene
activation mediated by stabilized
β-catenin. Target genes need not contain
T cell factor/lymphoid enhancer factor (TCF/LEF) binding sites in their
promoters, though, as new potential modes of gene activation
by β-catenin are becoming apparent. Several
target genes of β-catenin signaling have now been identified
and some of their functions are consistent with the control of tumor
cell growth, differentiation and
survival[19]. It has been demonstrated that 80% of colorectal cancers alone reveal activation
of this pathway by either inactivation of the
tumor-suppressor gene adenomatous polyposis
coli or mutation of the proto-oncogene β-catenin. Activation of
Wnt/β-catenin signaling has been found to be important for both initiation and
progression of cancers of different tissues. Therefore, targeted
inhibition of Wnt/β-catenin signaling is a rational and
promising new approach for the therapy of cancers of
various origins[20].
Cytokine related signaling
Cytokines and their signaling effectors act as key
determinants of carcinoma cell behavior. Take transforming growth
factor beta (TGF-β) as an example. The autocrine and paracrine
effects of TGF-β on tumor cells and the tumor
micro-environment exert both positive and negative influences on
cancer development[21]. The TGF-β receptor includes Type I and
Type II subunits, which are serine-threonine kinases and
signal through the Smad family of proteins. Binding of
TGF-β to its cell surface receptor leads to the phosphorylation of
the Type I receptor by Type II. The Type I receptor is then
able to phosphorylate and activate the Smad2 protein. Smad2,
in combination with Smad4, is translocated to the nucleus
where the activated Smad complex recruits other
transcription factors (TF) and together activate the expression of
target genes that mediate the biological effects of
TGF-β. Some of the activated target genes stimulate tumorigenesis.
Accordingly, the TGF-β signaling pathway has been
considered as a promoter of tumor development and a potential
target of cancer therapy in numerous tumor
diseases[22].
Essential role of ROS
It is well accepted that reactive oxygen species (ROS)
play a critical role in tumor metastasis. As a signaling
messenger, ROS are able to oxidize the critical target
molecules such as protein kinase C (PKC) and protein tyrosine
phosphates (PTPs), which are involved in tumor cell invasion.
MAPK and p21 activated protein kinase (PAK) have been
proposed to be regulated by ROS as
well[23]. There are several transcriptional factors such as the activator protein 1
(AP-1), Ets, Smad and Snail regulating a lot of genes relevant
to metastasis. AP-1 and Smad can be activated by PKC
activator and TGF-β1, respectively, in a ROS-dependent manner.
In addition, transcription factor Est-1 can be upregulated by
ROS via an antioxidant response element in the promoter.
The ROS-regulated genes associate with
epithelial-mesenchymal transition (EMT) and metastasis include E-cahedrin,
integrin and matrix metalloproteinase (MMP).
Comprehensive understanding of the ROS-triggered signaling
transduction, transcriptional activation and regulation of
gene expressions will help with devising a strategy for
chemotherapeutic interventions in cancer
therapy[24].
Development of targeted drugs
Many years of intensive research into the underlying
molecular causes of human cancer have aimed to identify
molecular targets of therapeutic importance with the hope
that this would enable the development of selective drugs to
treat malignancy. There are some successful drugs targeted
at the key molecules in the signaling pathway during the last
several years, especially for kinase inhibitors.
DNA targeted drug design was once expected to
generate novel therapeutics. Given that they are effective drugs in
clinical use and have produced significant increases in the
survival of cancer patients when used in combination with
drugs that have different mechanisms of action, researchers
later realized that most pathways can be affected by these
drugs at multiple points and these drugs are extremely toxic
as well[25]. In the past 10 years, identification of the key
protein molecules in cancer signaling as potential therapeutic
targets has led to the emergence of a new era of
target-directed therapies. Some small-molecule protein kinase
inhibitors have shown clinical effects in cancer patients that were
discussed by Speake, Holloway and
Costello[26]. Similarly, molecules are being isolated or designed to inhibit the
activity of other signaling pathways known to be deregulated in
cancer, such as MAPK and PI3K/Akt cascade
etc.[27,28].
In 1998, the monoclonal antibody trastuzumab
(Herce-petin) directed against the receptor tyrosine kinase (RTK)
HER2 was approved for the treatment of breast cancer by
the Food and Drug Administration (FDA) as a milestone of a
next-generation anti-cancer therapeutic. Binding of
trastuzumab to the extracellular domain of RTK induces the
internalization of the receptor, resulting in the
down-regulation of HER 2. Then, inhibition of cell-cycle progression and
antibody-dependent cellular cytotoxicity can be detected
because of immune responses[29]. Moreover, trastuzumab is
able to block cleavage of HER2, which would generate a
membrane-bound truncated receptor that is constitutively
active[30]. Clinical trials showed the positive response in
previous treated and untreated patients with metastatic breast
cancer[31,32]. Prolonged survival of patients treated with
chemotherapy and trastuzumab has been observed on patients
overexpressing HER2 compared with chemotherapy
alone[33].
STI-571 (Imatinib or Gleevec) targets the ABL (Abelson
leukaemia viral oncogene) gene product, a constitutively
active tyrosine kinase that drives the proliferation of
immature myeloid cells[34,35]. STI-571 thus inhibits tyrosine
phosphorylation of the downstream proteins involved in ABL
signal transduction and consequently inhibiting BCR-ABL
positive cells[36]. Preclinical and clinical studies have
verified the remarkable effect of imatinib in the treatment of
chronic myeloid leukemia (CML)[37,38]. It was approved by
the FDA in 2001 for the treatment of CML at all stages after
failure of interferon-α (INF-α) therapy. Furthermore, Imatinib
also shows activity against the tyrosine kinases of c-kit and
platelet-derived growth factor receptor
(PDGFR)[39], so, this drug is also being evaluated in clinical trials for patients with tumors
displaying aberrant activation of these signaling
pathways[40].
Beyond the success of Gleevec and Herceptin, the
development for targeted cancer therapeutics has extended to
epidermal growth factor receptor (EGFR) with Iressa, which
is another excellent example. Iressa is a small-molecule EGFR
inhibitor used in the clinical treatment of patients with
non-small-cell lung cancer (NSCLC). Two pivotal phase II
studies showed positive results for patients with previous treated
advanced[41,42]. However, two phase III trials revealed no
additional increase of survival rate compared with routine
chemotherapy in NSCLC[43,44]. On the whole, it is somewhat
controversial to access the benefits of Iressa, although it
was approved in Japan in 2002 and in US in 2003.
Although targeted drugs have achieved great success in
the initial stage, drug-resistance of these hormones or
antibodies is still inevitable so far. For example, Imatinib
resistance in the clinical setting has been attributed to the point
mutations of the tyrosine kinase[45]. A potential approach to
combating such mutants is to treat patients with a
combination of agents that interact differently with their targets at the
molecular level. Development of multi-target drugs is one of
the ideal choices to solve the problem through a simplified process.
Sorafenib is a kind of novel multi-target anti-cancer drug.
It not only inhibits tumor progress by blocking RAF/ MAP
kinase kinase (MEK)/ extracellular signal-regulated kinase
(ERK) signaling pathways directly, but also prevent
angiogenesis in tumor via the suppression of vascular endothelial
growth factor (VEGF) and PDGF, thus it indirectly inhibits
tumor progress as well[46]. Based on the results of a
randomized phase III clinical trial, sorafenib was approved by the
FDA to treat advanced renal cell carcinoma in 2005.
Another small molecular drug approved by the FDA for
treating gastrointestinal stromal tumor (GIST) and advanced
renal cell carcinoma is sunitinib (Sutent,
SU11248)[47]. Through the inhibition of VEGF-R2, R3, R1,
DGFR-β, KIT, LT-3, RET and their signaling pathways, sunitinib is able to
exert anti-cancer effects and works well in renal cell
carcinoma, GIST, neuroendocrine tumor, sarcoma, thyroid
carcinoma, melanoma, breast cancer, colorectal cancer and
non-small-cell lung cancer.
Challenges and prospect
Clinical development of these successful drugs has
revealed the importance of target selection. In considering
future molecular targets, it is necessary to distinguish between
general versus specific ones. General targets essential for
cell proliferation and survival, such as those affecting the
cell cycle, apoptosis or angiogenesis, are broadly applicable
in cancer, while molecular-specific targets represent a unique
abnormality of the tumor. The success of imatinib elucidates
the importance to identify an appropriate therapeutic target,
preferably an early pathogenetic molecule, so as to treat
patients at an early stage of disease. Beside specificity,
potency, efficacy and biopharma-ceuticals are also key
properties required by molecularly-targeted drug development.
Since many tumors accumulate numerous genetic
alterations and mutations that can arise in response to drug
treatment even in the case of clonal diseases, combinations of
new target-specific drugs have notably enhanced antitumor efficacy[48]. Nevertheless, the use of `cocktails' of
target directed drugs that aim at different hallmark
characteristics of the tumor are likely to be the future of cancer
signaling therapy to achieve maximal therapeutic benefits,
underlining the necessity for a comprehensive characterization of
oncogenic pathways[49].
References
1 Márquez-Garbán DC, Chen HW, Fishbein MC, Goodglick L,
Pietras RJ. Estrogen receptor signaling pathways in human
non-small cell lung cancer. Steroids 2007; 72: 135_43.
2 Graham R, Ogden GR. Alcohol and oral cancer. Alcohol 2005;
35: 169_73.
3 Gençer S, Salepçib T, Özer S. Evaluation of infectious etiology
and prognostic risk factors of febrile episodes in neutropenic
cancer patients. J Infect 2003; 41: 65_72.
4 Ruano-Ravina A, Figueiras A, Barros-Dios JM. Lung cancer and
related risk factors: an update of the literature. Public Health
2003; 107: 149_56.
5 Ponz de Leon M, Roncucci L. The cause of colorectal cancer.
Dig Liver Dis 2000; 32: 426_39.
6 Bapat SA. Evolution of cancer stem cells. Semin Cancer Biol
2006; 3: 204_13.
7 Westerhoff HV, Palsson BO. The evolution of molecular biology
into systems biology. Nat Biotechnol 2004; 22: 1249_52.
8 Wolf B. Cellular signaling: aspects for tumor diagnosis and therapy.
Biomed Tech 2007; 52: 164_8.
9 Binetruy B, Heasley L, Bost F, Caron L, Aouadi M. Concise
review: regulation of embryonic stem cell lineage commitment
by mitogen-activated protein kinases. Stem Cells 2007; 25: 1090_5.
10 Huang C, Jacobson K, Schaller MD. MAP kinases and cell
migration. J Cell Sci 2004; 117: 4619_28.
11 Xu K, Shu HK. EGFR activation results in enhanced
cyclooxy-genase-2 expression through p38 mitogen-activated protein
kinase-dependent activation of the Sp1/Sp3 transcription
factors in human gliomas. Cancer Res 2007; 67: 6121_9.
12 Hsiao YC, Kuo WH, Chen PN, Chang HR, Lin TH, Yang WE,
et al. Flavanone and 2'-OH flavanone inhibit metastasis of lung
cancer cells via down-regulation of proteinases activities and
MAPK pathway. Chem Biol Interact 2007; 167: 193_206.
13 Okamoto T, Sanda T, Asamitsu K. NF-kappa B signaling and
carcinogenesis. Curr Pharm Des 2007; 13: 447_62.
14 Perkins ND. Integrating cell-signalling pathways with NF-kappaB
and IKK function. Nat Rev Mol Cell Biol 2007; 8: 49_62.
15 Song L, Li J, Zhang D, Liu ZG, Ye J, Zhan Q,
et al. IKKbeta programs to turn on the GADD45alpha-MKK4-JNK apoptotic
cascade specifically via p50 NF-kappaB in arsenite response. J
Cell Biol 2006; 175: 607_17.
16 Schulze-Luehrmann J, Ghosh S. Antigen-receptor signaling to
nuclear factor kappa B. Immunity 2006; 25: 701_15.
17 Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14: 1837_51.
18 Lustig B, Behrens J. The Wnt signaling pathway and its role in
tumor development. J Cancer Res Clin Oncol 2003; 129: 199_221.
19 Major MB, Camp ND, Berndt JD, Yi X, Goldenberg SJ, Hubbert
C, et al. Wilms tumor suppressor WTX negatively regulates
WNT/beta-catenin signaling. Science 2007; 316: 1043_6.
20 Herbst A, Kolligs FT. Wnt signaling as a therapeutic target for
cancer. Methods Mol Biol 2007; 361: 63_91.
21 Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor
suppression and cancer progression. Nat Genet 2001; 29: 117_29.
22 Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL,
et al. Inhibition of TGF-beta with neutralizing antibodies prevents
radiation-induced acceleration of metastatic cancer progression.
J Clin Invest 2007; 117: 1305_13.
23 Wu WS. The signaling mechanism of ROS in tumor progression.
Cancer Metastasis Rev 2006; 25: 695_705.
24 Kopnin PB, Agapova LS, Kopnin BP, Chumakov PM.
Repression of sestrin family genes contributes to oncogenic Ras-
induced reactive oxygen species up-regulation and genetic
instabi-lity. Cancer Res 2007; 67: 4671_8.
25 Slapak CA, Kufe DW. Principles of cancer therapy. In: Isselbacher
KJ, editor. Harrison's Principles of Internal Medicine. 14th ed.
New York, McGraw_Hill; 1998. p 523_37.
26 Speake G, Holloway B, Costello G. Recent developments related
to the EGFR as a target for cancer chemotherapy. Curr Opin
Pharmacol 2005; 5: 343_9.
27 Johnson GL, Dohlman HG, Graves LM. MAPK kinase kinases
(MKKKs) as a target class for small-molecule inhibition to
modulate signaling networks and gene expression. Curr Opin Chem
Biol 2005; 9: 325_31.
28 Mitsiades CS, Mitsiades N, Koutsilieris M. The Akt pathway:
molecular targets for anti-cancer drug development. Curr Cancer
Drug Targets 2004; 4: 235_56.
29 Kumar R, Shepard HM, Mendelsohn J. Regulation of
phosphorylation of the c-erbB-2/HER2 gene product by a monoclonal
antibody and serum growth factor(s) in human mammary carcinoma
cells. Mol Cell Biol 1991; 11: 979_86.
30 Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga
J. Trastuzumab (Herceptin), a humanized anti-Her2 receptor
monoclonal antibody, inhibits basal and activated Her2
ectodo-main cleavage in breast cancer cells. Cancer Res 2001; 61: 4744_9.
31 Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S,
Fehrenbacher L, et al. Multinational study of the efficacy and
safety of humanized anti-HER2 monoclonal antibody in women
who have HER2-overexpressing metastatic breast cancer that
has progressed after chemotherapy for metastatic disease. J Clin
Oncol 1999; 17: 2639_48.
32 Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN,
Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a
single agent in first-line treatment of HER2-overexpressing
metastatic breast cancer. J Clin Oncol 2002; 20: 719_26.
33 Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde
A, et al. Use of chemotherapy plus a monoclonal antibody against
HER2 for metastatic breast cancer that overexpresses HER2. N
Engl J Med 2001; 344: 783_92.
34 Muller AJ, Young JC, Pendergast AM, Pondel M, Landau NR,
Littman DR, et al. BCR first exon sequences specifically activate
the BCR/ABL tyrosine kinase oncogene of Philadelphia
chromosome-positive human leukemias. Mol Cell Biol 1991; 11:
1785_92.
35 Deininger MW, Goldman JM, Melo JV. The molecular biology of
chronic myeloid leukemia. Blood 2000; 96: 3343_56.
36 Deininger MW, Goldman JM, Lydon N. The tyrosine kinase
inhibitor CGP57148B selectively inhibits the growth of
BCR-ABL-positive cells. Blood 1997; 90: 3691_8.
37 Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford
JM, et al. Activity of a specific inhibitor of the BCR-ABL
tyrosine kinase in the blast crisis of chronic myeloid leukemia and
acute lymphoblastic leukemia with the Philadelphia chromosome.
N Engl J Med 2001; 344: 1038_42.
38 Kantarjian HM, Cortes JE, O'Brien S, Luthra R, Giles F,
Verstovsek S, et al. Long-term survival benefit and improved
complete cytogenetic and molecular response rates with imatinib
mesylate in Philadelphia chromosome-positive chronic-phase
chronic myeloid leukemia after failure of interferon-alpha. Blood
2004; 104: 1979_88.
39 Druker BJ, Lydon NB. Lessons learned from the development of
an abl tyrosine kinase inhibitor for chronic myelogenous
leukaemia. J Clin Invest 2000; 105: 3_7.
40 Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of
KIT tyrosine kinase activity: a novel molecular approach to the
treatment of KIT-positive malignancies. J Clin Oncol 2002; 20:
1692_703.
41 Silvestri GA, Rivera MP. Targeted therapy for the treatment of
advanced non-small cell lung cancer: a review of the epidermal
growth factor receptor antagonists. Chest 2005; 128: 3975_84.
42 Cohen EE, Kane MA, List MA, Brockstein BE, Mehrotra B, Huo
D, et al. Phase II trial of gefitinib 250 mg daily in patients with
recurrent and/or metastatic squamous cell carcinoma of the head
and neck. Clin Cancer Res 2005; 11: 8418_24.
43 Hirsch FR, Varella-Garcia M, Bunn PA, Franklin WA, Dziadziuszko
R, Thatcher N, et al. Molecular predictors of outcome with
gefitinib in a phase III placebo-controlled study in advanced
non-small-cell lung cancer. J Clin Oncol 2006; 24: 5034_42.
44 Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller
V, et al. Gefitinib in combination with gemcitabine and cisplatin
in advanced non-small-cell lung cancer: a phase III
trial_INTACT 1. J Clin Oncol 2004; 22: 777_84.
45 Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao
PN, et al. Clinical resistance to STI-571 cancer therapy caused
by BCRABL gene mutation or amplification. Science 2001; 293:
876_80.
46 Adjei AA, Molina JR, Mandrekar SJ, Marks R, Reid JR, Croghan
G, et al. Phase I trial of sorafenib in combination with gefitinib in
patients with refractory or recurrent non-small cell lung cancer.
Clin Cancer Res 2007; 13: 2684_91.
47 Wolter P, Dumez H, Schoffski P. Sunitinib and hypothyroidism.
N Engl J Med 2007; 356: 1580.
48 Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde
A, et al. Use of chemotherapy plus a monoclonal antibody against
HER2 for metastatic breast cancer that overexpresses HER2. N
Engl J Med 2001; 344: 783_92.
49 van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M,
et al. Gene expression profiling predicts clinical outcome of breast
cancer. Nature 2002; 415: 530_6.
|
