Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer

Giovannetti, Elisa; Mey, Valentina; Nannizzi, Sara; Pasqualetti, Giuseppe; Tacca, M. Del; Danesi, Romano

doi:10.1158/1535-7163.mct-06-0004

Cited by 74 publications

(68 citation statements)

References 71 publications

(69 reference statements)

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“…Induction of cell cycle arrest and apoptosis are key events in cytotoxic chemotherapy with agents interfering with DNA synthesis. Because pharmacogenomic considerations become increasingly important in clinical oncology (33), EFEMP1 may be a candidate for pretherapeutic evaluation in medical therapy of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

Seeliger¹,

Čamaj²,

Ischenko³

et al. 2009

Molecular Cancer Research

100

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The progression of pancreatic cancer is dependent on local tumor growth, angiogenesis, and metastasis. EFEMP1, a recently discovered member of the fibulin family, was characterized with regard to these key elements of pancreatic cancer progression. Differential gene expression was assessed by mRNA microarray hybridization in FG human pancreatic adenocarcinoma cells and L3.6pl cells, a highly metastatic variant of FG. In vivo orthotopic tumor growth of EFEMP1-transfected FG cells was examined in nude mice. To assess the angiogenic properties of EFEMP1, vascular endothelial growth factor (VEGF) production of tumor cells, endothelial cell proliferation and migration, and tumor microvessel density were analyzed in response to EFEMP1. Further, tumor cell apoptosis, cell cycle progression, and resistance to cytotoxic agents were quantitated by propidium iodide staining and flow cytometry. In microarray hybridization, EFEMP1 was shown to be significantly up-regulated in L3.6pl cells compared with FG cells. Concordantly, EFEMP1 transfection of FG cells stimulated orthotopic and metastatic tumor growth in vivo. EFEMP1 expression resulted in a stimulation of VEGF production by tumor cells and an increased number of CD31-positive microvessels. Endothelial cell proliferation and migration were not altered by EFEMP1, indicating an indirect angiogenic effect. Further, EFEMP1 expression decreased apoptosis and promoted cell cycle progression in response to serum starvation or exposure to gemcitabine, 5-fluorouracil, and irinotecan. EFEMP1 has protumorigenic effects on pancreatic cancer in vivo and in vitro mediated by VEGF-driven angiogenesis and antiapoptotic mechanisms. Hence, EFEMP1 is a promising candidate for assessing prognosis and individualizing therapy in a clinical tumor setting. (Mol Cancer Res 2009;7(2):189-98)

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Section: Discussionmentioning

confidence: 99%

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

Seeliger¹,

Čamaj²,

Ischenko³

et al. 2009

Molecular Cancer Research

100

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“…Unexpectedly, in our study, both TK-1 and TS expression were low in the majority of hepatocellular carcinomas, pancreatic ductal carcinomas, and renal cell carcinomas, which typically show aggressive behavior and also resistance to cytostatic agents. It is possible that dysregulation of expression of other proteins involved in control of the cell cycle, proliferation, apoptosis, and invasiveness may contribute to this aggressive behavior (32).…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer

Shintani

Urano²,

Takakuwa

et al. 2010

Oncol Rep

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Abstract. Thymidine kinase-1 (TK-1) and thymidylate synthase (TS) are key enzymes for salvage and de novo pyrimidine synthesis, respectively. Numerous studies have suggested that increased TS levels are associated closely with resistance to fluoropyrimidine-based chemotherapy. TAS-102 is a novel drug containing trifluorothymidine, which is phosphorylated by TK-1 to its active monophosphated form, that in turn can inhibit TS. TAS-102 has been shown to exhibit antitumor activity in fluoropyrimidine-resistant human cancer cells. TAS-102 is currently undergoing clinical trials for use in gastrointestinal cancers. In the present study, we used immunohistochemistry to investigate the expression of TK-1 and TS in various types of cancer. TK-1 and TS expression was markedly different between cancer types. High TK-1 expression was detected prominently in gastrointestinal adenocarcinomas and esophageal and uterine squamous cell carcinomas. Gastrointestinal adenocarcinomas and squamous cell uterine carcinomas were often accompanied by high TS expression, indicating activation of pyrimidine synthesis through both the salvage and de novo pathways. These results led us to consider that TAS-102 may also be effective for esophageal and uterine squamous cell carcinomas, as well as for gastrointestinal adenocarcinomas, even in fluoropyrimidineresistant cases with high TS expression. In contrast, thyroid papillary carcinomas, lung adenocarcinomas, hepatocellular carcinomas, pancreatic ductal carcinomas, and renal cell carcinomas, which exhibit low TK-1 expression, may be resistant to TAS-102. In non-small cell lung cancers, high TK-1 expression was demonstrated in squamous cell carcinomas, but not in adenocarcinomas. This result suggests that TAS-102 efficacy and the pyrimidine synthetic pathway may differ depending on histological type. Our results indicate that administration of TAS-102 could be selected on the basis of the immunohistochemical evaluation of TK-1 and

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“…Tumors were measured with vernier calipers twice or thrice weekly. The tumor volume was calculated using the formula, tumor volume (mm 3 ) ¼ (length Â width 2 )/2. Animals were randomly assigned to treatment and control groups when their tumors reached a volume of 75-125 mm 3 after 7 and 10 days post AsPC1 and MiaPaca2 tumor cell implantation, respectively.…”

Section: Adenovirus Vectorsmentioning

confidence: 99%

“…More specifically, gemcitabine is metabolized intracellularly and results in two metabolites: diphosphate and triphosphate nucleosides. Both these metabolites interfere with DNA synthesis 3 and inhibit cell growth. In addition, gemcitabine induces apoptosis in human pancreatic cancer cells through the induction of intracellular reactive oxygen species.…”

Section: Introductionmentioning

confidence: 99%

Combination of human tumor necrosis factor-alpha (hTNF-α) gene delivery with gemcitabine is effective in models of pancreatic cancer

et al. 2009

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Pancreatic adenocarcinoma is an aggressive and highly lethal malignancy. Currently, gemcitabine is commonly used in patients with pancreatic cancer. However, the life expectancy of pancreatic cancer patients remains poor. We explored the possibility of increased anti-tumor activity by combining human tumor necrosis factor-alpha (hTNF-a) with current front-line therapy. Human TNF-a displays potent anti-tumor activity, but its use is limited by the toxicity of systemic administration. We developed a gene delivery approach using intratumoral injections of an adenoviral vector expressing hTNF-a, AdEgr.TNF.11D (TNFerade), to increase local concentrations of hTNF-a within the tumor, thereby maximizing local anti-tumor activity and yet minimizing the systemic toxicities. An ongoing phase III clinical trial is testing the efficacy of AdEgr.TNF.11D-injected intratumorally and combining with chemotherapy in locally advanced pancreatic cancer. In this study, we show that treatment with AdEgr.TNF.11D and gemcitabine results in a high level of hTNF-a expression in human pancreatic cancer cell lines. The combined treatment was well tolerated, highly active and produced marked delays in the growth of human pancreatic xenograft tumors relative to either agent alone. Our results strongly suggest that combination of AdEgr.TNF.11D and gemcitabine may be a potentially useful therapeutic approach for the improved treatment of pancreatic cancer.

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Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer

Cited by 74 publications

References 71 publications

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer

Combination of human tumor necrosis factor-alpha (hTNF-α) gene delivery with gemcitabine is effective in models of pancreatic cancer

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