Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

Bocci, Guido; Fioravanti, Anna; Orlandi, Paola; Bernardini, Nunzia; Collecchi, Paola; Tacca, M. Del; Danesi, Romano

doi:10.1038/sj.bjc.6602720

Cited by 73 publications

(74 citation statements)

References 44 publications

(43 reference statements)

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“…Treatment in accordance with the characteristics of the pancreatic cancer cells is needed. Many studies have reported the effectiveness of combination treatment of anticancer drug and inhibitor or gene transduction (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). There is no treatment that is effective for all carcinomas with various characteristics.…”

Section: Discussionmentioning

confidence: 99%

Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase?

Funamizu

Okamoto²,

Kamata³

et al. 2009

Oncol Rep

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Abstract. The prognosis of pancreatic cancer remains poor, and the standard first-line chemotherapy with gemcitabine (GEM) has a response rate of less than 20%. Since expression of deoxycytidine kinase (dCK) seems important for improvement of GEM sensitivity, overexpression of dCK was investigated using pancreatic cancer cell lines (Panc-1, MIAPaCa-2 and BxPC-3). dCK gene was introduced into the cell lines by retrovirus and changes in IC50 were examined. Sensitivity of two pancreatic cancer cell lines to GEM elevated dramatically in comparison with control cells, but change of sensitivity remained at 1.8 times in BxPC-3. Since addition of tetrahydro uridine (THU), an inhibitor of deoxycytidine deaminase (CDA), increased the sensitivity 54-fold, overexpression of CDA seems to be the mechanism for improvement of the sensitivity. In conclusion, dCK is a key enzyme of GEM, but resistance of GEM is not improved in all pancreatic cancer cells by overexpression of dCK. Combination treatment based on expression of GEM metabolism-related gene may become an effective therapy in the future. IntroductionThe prognosis of pancreatic cancer remains poor, for which surgery remains the only potentially curative treatment. This poor prognosis relates to the advanced disease stage at the time of diagnosis and to its profound resistance to existing therapies. Gemcitabine (GEM) is a cytotoxic pyrimidine deoxynucleoside analogue, with activity against several solid tumors such as cancers of the pancreas, lung, breast and ovary. GEM is transported into the cell mostly by human equilibrative and concentrative nucleoside transporters (hENT and hCNT, respectively). Cells deficient in hENT1 are highly resistant to GEM (1), while hCNT1 transfection increases GEM sensitivity in pancreatic cancer cell lines (2). This drug is activated by deoxycytidine kinase (dCK), and phosphorylates a monophosphate, diphosphate and triphosphate (dFdCTP). dCK is the rate-limiting enzyme in the transformation of nucleoside analogs, and the increase in dCK activity may improve the efficacy of GEM (3,4). dFdCTP is mainly incorporated into DNA leading to masked chain termination. In addition, its active metabolite can inhibit ribonucleotide reductase (RR), resulting in a decrease in deoxynucleoside triphosphate (dNTP) pools that are required for DNA repair and synthesis as well as inhibition of DNA polymerase. GEM is inactivated by deamination and catalyzed by deoxycytidine deaminase (CDA) (Fig. 1). Mechanism of intrinsic resistance to GEM in carcinomas remains unclear although that of acquired resistance to the drug in pancreatic carcinoma has been intensively studied. Some of these studies have disclosed a decrease in dCK activity (2), increased activity of CDA (5), and increased RR activity (6,7). The aim of this study was to prove whether overexpression of dCK by retrovirus vector improves the therapeutic efficacy of GEM for pancreatic cancer. Materials and methodsReagent and chemicals. GEM (difluorodeoxycytidine, dFdC) was a generous gift of Eli Lilly (Indi...

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Section: Discussionmentioning

confidence: 99%

Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase?

Funamizu

Okamoto²,

Kamata³

et al. 2009

Oncol Rep

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“…To quantify cyclin D1 mRNA, RNA (1 µg) was reverse transcribed as previously described [25] and the resulting cDNA was diluted (2:3) and then amplified by QRT-PCR with the Applied Biosystems 7900HT sequence detection system. Cyclin D1, validated primer was purchased from Applied Biosystems (Assay ID Hs00277039_m1).…”

Section: Quantification Of Cyclin D1 Gene and Protein Expression In Ementioning

confidence: 99%

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

Bocci¹,

Fioravanti²,

Motta³

et al. 2011

Biochemical Pharmacology

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Aims. To demonstrate the antiproliferative and pro-apoptotic activity of the novel pyrazolopyrimidine derivative multiple tyrosine kinase inhibitor CLM3, alone and in combination with SN-38 (the active metabolite of irinotecan), on endothelial and tumour cells and to show its mechanism of action.Methods. Proliferation and apoptotic assays were performed on microvascular endothelial (HMVECd) and lung (A549) and thyroid cancer (8305C, TT) cell lines exposed to CLM3 and to the simultaneous combination with SN38 for 72h. Cell-based phospho-VEGFR-2, phospho-EGFR and phospho-RET inhibition assays were performed and ERK1/2 and Akt phosphorylation were quantified by ELISA kits. Conclusions.The pyrazolopyrimidine derivative CLM3 demonstrated a highly significant and promising antiproliferative and proapoptotic activity, alone and in combination with SN-38, for activated endothelial and cancer cell cells. These effects are mainly due to its inhibition of phosphorylation of VEGFR-2, EGFR and RET tyrosine kinases and their related signalling pathways.

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“…for 10 min and washed with PBS; the resulting pellet was immediately frozen in liquid nitrogen and stored at À801C. Briefly, RNA (1 mg) was reverse transcribed (Bocci et al, 2005a) and the resulting cDNA was diluted (2 : 3) and then amplified by QRT-PCR with the Applied Biosystems 7900HT sequence detection system. Vascular endothelial growth factorand TSP-1-validated primers were purchased from Applied Biosystems (Assay ID Hs00170236_m1 and Hs00173626_m1, respectively).…”

Section: Assessment Of Human Vegf and Tsp-1 Gene Expression And Plasmmentioning

confidence: 99%

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

et al. 2008

Self Cite

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The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapyrefractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m À2 day À1 (n ¼ 7), 2.8 mg m À2 day À1 (n ¼ 5) and 4.2 mg m À2 day À1 (n ¼ 8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C ss ) of SN-38 were between 1 and 3.3 ng ml À1 . From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4±30.1 and 130.4±9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m À2 day À1 dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities 4grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations.

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Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

Cited by 73 publications

References 44 publications

Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase?

Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase?

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

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