Molecular biology of pancreatic cancer; oncogenes, tumour suppressor genes, growth factors, and their receptors from a clinical perspective

Sakorafas, George H.; Tsiotou, A.G.; Tsiotos, Gregory G.

doi:10.1053/ctrv.1999.0144

Cited by 79 publications

(50 citation statements)

References 215 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Gemcitabine has also been evaluated as a radiosensitizer, and promising results have been achieved in patients with locally advanced pancreatic cancer (19). Human pancreatic cancer overexpresses many growth factors, and their receptors, including EGFR and VEGFR, are thought to play a critical role in driving growth and resistance to chemoradiotherapy and eventually disease relapse (3,4,20). For example, substantial evidence suggests that expression of VEGF is regulated mainly by hypoxia, which is a common feature of most solid tumors, including pancreatic cancers (21).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

Bianco¹,

Giovannetti

Ciardiello³

et al. 2006

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination. Experimental Design: ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1cells and in vivo to MIA PaCa-2 tumor xenografts. The effects of treatments were studied by the evaluation of cytotoxicity, apoptosis, cell cycle, EGFR and Akt phosphorylation, modulation of gene expression of enzymes related to gemcitabine activity (deoxycytidine kinase and ribonucleotide reductase), as well as vascular endothelial growth factor immunohistochemistry and microvessel count. Results: In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation. Moreover, ZD6474 inhibited phosphorylation of EGFR and Akt and triggered cell apoptosis. PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase. In vivo, ZD6474 showed significant antitumor activity alone and in combination with radiotherapy and gemcitabine, and the combination of all three modalities enhanced MIA PaCA-2 tumor growth inhibition compared with gemcitabine alone. Conclusions: ZD6474 decreases EGFR and Akt phosphorylation, enhances apoptosis, favorably modulates gene expression in cancer cells, and acts synergistically with gemcitabine and radiotherapy to inhibit tumor growth. These findings support the investigation of this combination in the clinical setting.Pancreatic cancer is a highly malignant illness that has steadily increased in incidence over recent decades, and it is now the fourth leading cause of death from cancer in the Western world. Despite this, there has been little improvement in prognosis over the past 20 years (1). Due to the delay of clinical symptoms, pancreatic cancer is usually detected at an advanced stage, and survival ranges between 4 and 6 months after diagnosis. Moreover, because of its aggressive biological behavior, this malignancy has a grim prognosis even following surgical resection, and the 5-year survival for all stages of the disease remains below 4% (2). Therefore, pancreatic cancer represents a clinical challenge and novel therapeutic approaches are warranted.Several studies showed that pancreatic cancer is characterized by dysregulation of molecular mechanisms involved in cell proliferation, invasiveness, and angiogenesis (3). Epidermal growth factor receptor (EGFR) is a key driver of cell proliferation, and

show abstract

Section: Discussionmentioning

confidence: 99%

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

Bianco¹,

Giovannetti

Ciardiello³

et al. 2006

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Ductal adenocarcinoma of the pancreas represents the fourth most common cause of cancer-related death, and its incidence is increasing (1). Because of the lack of early symptoms and an aggressive tumor phenotype, pancreatic cancer is often diagnosed at an incurable stage of disease.…”

mentioning

confidence: 99%

“…In recent years, considerable insight into the genetic basis of this malignancy has been achieved. The functional inactivation of tumor suppressor genes such as Smad4, TP53, and MTS1/p16, as well as the activation of distinct oncogenes (e.g., KRAS2), seems to be common in pancreatic cancer (1,2). However, the role of other tumor genes involved in the pathogenesis of pancreatic cancer still needs to be elucidated.…”

mentioning

confidence: 99%

c-MYC Activation in Primary and Metastatic Ductal Adenocarcinoma of the Pancreas: Incidence, Mechanisms, and Clinical Significance

et al. 2002

View full text Add to dashboard Cite

“…En el cáncer de páncreas se han publicado frecuencias de mutación de K-ras que fluctúan entre 70 y 100% 15 , sin diferencias significativas para Tabla 1. Características generales del grupo analizado y su relación con sobrevida y mutación del gen k-ras (n=69) (4) 20% ( …”

Section: Discussionunclassified

“…Ha sido reportada en diferentes órganos con alta frecuencia en tumores de colon, 50% 12 , pulmón, 50% 13 y tiroides, 60% 14 . En el cáncer de páncreas se han comunicado frecuencias de mutación, que varían entre 70 y 100% de los casos 8,9,15 . En el cáncer ampular entre 19 y 70%, para tumores de vía biliar [16][17][18][19][20][21][22] entre 0 y 55% 20,23-27 y entre 0 y 100% para vesícula biliar 6,20,23,25 .…”

Section: N V E S T I G a C I ó Nunclassified

Mutación del gen K-ras en tumores pancreático-biliares

Roa

Anabalón

et al. 2005

Rev. méd. Chile

View full text Add to dashboard Cite

show abstract

Molecular biology of pancreatic cancer; oncogenes, tumour suppressor genes, growth factors, and their receptors from a clinical perspective

Cited by 79 publications

References 215 publications

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

c-MYC Activation in Primary and Metastatic Ductal Adenocarcinoma of the Pancreas: Incidence, Mechanisms, and Clinical Significance

Mutación del gen K-ras en tumores pancreático-biliares

Contact Info

Product

Resources

About