The relation between deoxycytidine kinase activity and the radiosensitising effect of gemcitabine in eight different human tumour cell lines

Pauwels, Bea; Korst, A.E.C.; Pattyn, G; Lambrechts, Hilde; Kamphuis, J.A.E.; Pooter, Christel M J De; Peters, Godefridus J.; Lardon, Filip; Vermorken, Jan B.

doi:10.1186/1471-2407-6-142

Cited by 18 publications

(11 citation statements)

References 46 publications

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“…However, response rates are low and rarely exceed 20% (27,28). Reported DCK enzymatic activity in tumors ranges from 5 to 18 pmol/h per mg of protein, and previous studies have found these values to correlate with sensitivity to dFdC (15,29). The DCK activity in L1210 wt leukemia cells was 0.4 nmol/h per mg, well within the range observed in other tumors.…”

Section: Stratification Of Dck-positive and -Negative Tumors By Usingsupporting

confidence: 66%

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

Laing

Walter²,

Campbell³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Gemcitabine (2 ,2 -difluorodeoxycytidine, dFdC) and cytosine arabinoside (cytarabine, ara-C) represent a class of nucleoside analogs used in cancer chemotherapy. Administered as prodrugs, dFdC and ara-C are transported across cell membranes and are converted to cytotoxic derivatives through consecutive phosphorylation steps catalyzed by endogenous nucleoside kinases. Deoxycytidine kinase (DCK) controls the rate-limiting step in the activation cascade of dFdC and ara-C. DCK activity varies significantly among individuals and across different tumor types and is a critical determinant of tumor responses to these prodrugs. Current assays to measure DCK expression and activity require biopsy samples and are prone to sampling errors. Noninvasive methods that can detect DCK activity in tumor lesions throughout the body could circumvent these limitations. Here, we demonstrate an approach to detecting DCK activity in vivo by using positron emission tomography (PET) and 18

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Section: Stratification Of Dck-positive and -Negative Tumors By Usingsupporting

confidence: 66%

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

Laing

Walter²,

Campbell³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Radiation elevates dCK mRNA and protein levels [ 38 ], and there is a clear correlation between dCK levels and radiosensitizing effects of gemcitabine [ 39 ]. dCK adds the first phosphoryl group to DAC and is the rate-limiting enzyme of the overall process of converting DAC to its triphosphate form that incorporates into DNA [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Differential Regulation of Methylation-Regulating Enzymes by Senescent Stromal Cells Drives Colorectal Cancer Cell Response to DNA-Demethylating Epi-Drugs

Agrawal

Das

Táborská

et al. 2018

Stem Cells International

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The advanced-stage colon cancer spreads from primary tumor site to distant organs where the colon-unassociated stromal population provides a favorable niche for the growth of tumor cells. The heterocellular interactions between colon cancer cells and colon-unassociated fibroblasts at distant metastatic sites are important, yet these cell-cell interactions for therapeutic strategies for metastatic colon cancer remain underestimated. Recent studies have shown the therapeutic potential of DNA-demethylating epi-drugs 5-azacytidine (AZA) and 5-aza-2′-deoxycytidine (DAC) for the treatment of solid tumors. While the effects of these epi-drugs alone or in combination with other anticancer therapies are well described, the influence of stromal cells and their secretome on cancer cell response to these agents remain elusive. In this study, we determined the effect of normal and senescent colon-unassociated fibroblasts and their conditioned medium on colorectal cancer (CRC) cell response to AZA and DAC using a cell-based DNA demethylation reporter system. Our data show that fibroblasts accelerate cell proliferation and differentially regulate the expression of DNA methylation-regulating enzymes, enhancing DAC-induced demethylation in CRC cells. In contrast, the conditioned medium from senescent fibroblasts that upregulated NF-κB activity altered deoxycytidine kinase levels in drug-untreated CRC cells and abrogated DAC effect on degradation of DNA methyltransferase 1. Similar to 2D cultures, senescent fibroblasts increased DNA demethylation of CRC cells in coculture spheroids, in addition to increasing the stemness of CRC cells. This study presents the first evidence of the effect of normal and senescent stromal cells and their conditioned medium on DNA demethylation by DAC. The data show an increased activity of DAC in high stromal cell cocultures and suggest the potential of the tumor-stroma ratio in predicting the outcome of DNA-demethylating epigenetic cancer therapy.

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“…It is also in concordance with other data in the literature which state that gemcitabine radiosensitization is more pronounced in cells with high basal dCK activity. 42 We should note, that Pauwels et al 43 recently reported that dCK activity weakly correlated to gemcitabine radiosensitization. Besides the high basal dCK level, another possible explanation for the radiosensitizing effect of gemcitabine is that irradiation itself can induce dCK activity in Gl261 cells by twofold (G Sa´fra´ny and S De´saknai, personal communication, 2005), which, in turn might further improve gemcitabine metabolism and amplify its toxic effect.…”

Section: -31mentioning

confidence: 90%

Adenoviral vector transduction of the human deoxycytidine kinase gene enhances the cytotoxic and radiosensitizing effect of gemcitabine on experimental gliomas

et al. 2008

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The aim of this work was to improve the cytotoxic and radiosensitizing effects of gemcitabine using a gene-directed enzyme prodrug therapy approach. Murine Gl261, rat C6 and human U373 glioma cell lines were transduced with an adenoviral vector encoding the human deoxycytidine kinase gene (Ad-HudCK). Intracranial tumors were established in C57BL/6 mice and Wistar rats using either wild-type or Ad-HudCK-transduced Gl261 and C6 glioma cells. In vitro growing cells and established tumors were treated with gemcitabine and irradiation either alone or in combination. Deoxycytidine kinase overexpression substantially increased both the toxic and radiosensitizing effects of gemcitabine in each cell line, but the enhancement rate varied: it was mild in the Gl261 cells and much stronger in the C6 and U373 cells. In vivo experiments showed a mild radiosensitizing effect of dCK overexpression both in the Gl261 and C6 models. The combination of dCK overexpression, gemcitabine treatment and irradiation improved the survival rate of C6 bearing rats significantly. In conclusion, overexpression of the dCK gene can improve the cytotoxic and radiosensitizing effect of gemcitabine both in vitro and in vivo in a tumor-specific manner.

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The relation between deoxycytidine kinase activity and the radiosensitising effect of gemcitabine in eight different human tumour cell lines

Cited by 18 publications

References 46 publications

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

Differential Regulation of Methylation-Regulating Enzymes by Senescent Stromal Cells Drives Colorectal Cancer Cell Response to DNA-Demethylating Epi-Drugs

Adenoviral vector transduction of the human deoxycytidine kinase gene enhances the cytotoxic and radiosensitizing effect of gemcitabine on experimental gliomas

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