Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

Jordheim, Lars Petter; Cros, Emeline; Gouy, Marie-Hélène; Galmarini, Carlos M.; Peyrottes, Suzanne; Mackey, John R.; Philouze, Christian; Dumontet, Charles

doi:10.1158/1078-0432.ccr-04-0506

Cited by 59 publications

(46 citation statements)

References 39 publications

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“…This finding showing that sapacitabine retained cytotoxic activity against dCK-deficient L1210 cells strongly suggests that sensitivity to sapacitabine may not only be dependent on dCK expression. The role of dCK in sensitivity to CNDAC and sapacitabine has also been observed in MES-SA-10K, a cell line that derives from MES-SA cell deficient in dCK, selected after repeated passages in the presence of gemcitabine (Galmarini and Green, unpublished observations;Jordheim et al, 2004). Although dCKindependent mechanisms are not yet finally understood, other enzymes such as CDA have been recently shown to play a role in the mechanism of action of sapacitabine (Fleming et al, 2007).…”

Section: Discussionmentioning

confidence: 85%

Antiproliferative effects of sapacitabine (CYC682), a novel 2′-deoxycytidine-derivative, in human cancer cells

et al. 2007

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This study assessed the antiproliferative activity of sapacitabine (CYC682, CS-682) in a panel of 10 human cancer cell lines with varying degrees of resistance or sensitivity to the commonly used nucleoside analogues ara-C and gemcitabine. Growth inhibition studies using sapacitabine and CNDAC were performed in the panel of cell lines and compared with both nucleoside analogues and other anticancer compounds including oxaliplatin, doxorubicin, docetaxel and seliciclib. Sapacitabine displayed antiproliferative activity across a range of concentrations in a variety of cell lines, including those shown to be resistant to several anticancer drugs. Sapacitabine is biotransformed by plasma, gut and liver amidases into CNDAC and causes cell cycle arrest predominantly in the G 2 /M phase. No clear correlation was observed between sensitivity to sapacitabine and the expression of critical factors involved in resistance to nucleoside analogues such as deoxycytidine kinase (dCK), human equilibrative nucleoside transporter 1, cytosolic 5 0 -nucleotidase and DNA polymerase-a. However, sapacitabine showed cytotoxic activity against dCK-deficient L1210 cells indicating that in some cells, a dCK-independent mechanism of action may be involved. In addition, sapacitabine showed a synergistic effect when combined with gemcitabine and sequence-specific synergy with doxorubicin and oxaliplatin. Sapacitabine is therefore a good candidate for further evaluation in combination with currently used anticancer agents in tumour types with unmet needs.

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Section: Discussionmentioning

confidence: 85%

Antiproliferative effects of sapacitabine (CYC682), a novel 2′-deoxycytidine-derivative, in human cancer cells

et al. 2007

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“…The murine leukemic lines (L1210 wt and L1210-10K) (14) were a gift from Charles Dumontet (Université Claude Bernard Lyon I, Lyon, France). The human lymphoma line CCRF-CEM and its ara-C-resistant DCKnegative derivative line (CEM-R) (26) were provided by Margaret Black (Washington State University).…”

Section: Methodsmentioning

confidence: 99%

“…To investigate the relationship between FAC retention and DCK activity, we used isogenic cell lines expressing various levels of DCK. The L1210 model consists of the DCK-positive wild-type (L1210 wt) line and the DCK-deficient subline L1210-10K (14). We used retroviral transduction to restore DCK expression in the L1210-10K cells (L1210-10KϩDCK; Fig.…”

Section: Fac Retention In Leukemic Cells Is Critically Dependent On Dckmentioning

confidence: 99%

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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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“…IC 50 values were determined by methylthiazoletetrazolium assay from concentration-effect curves generated using Microsoft Excel as previously described (20).…”

Section: Cytotoxicity Studiesmentioning

confidence: 99%

Silencing of Tubulin Binding Cofactor C Modifies Microtubule Dynamics and Cell Cycle Distribution and Enhances Sensitivity to Gemcitabine in Breast Cancer Cells

Hage‐Sleiman

Herveau

Matera

et al. 2011

Molecular Cancer Therapeutics

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Tubulin binding cofactor C (TBCC) is essential for the proper folding of a-and b-tubulins into microtubule polymerizable heterodimers. Because microtubules are considered major targets in the treatment of breast cancer, we investigated the influence of TBCC silencing on tubulin pools, microtubule dynamics, and cell cycle distribution of breast cancer cells by developing a variant MCF7 cells with reduced content of TBCC (MCÀ). MCÀ cells displayed decreased content in nonpolymerizable tubulins and increased content of polymerizable/microtubule tubulins when compared with control MP6 cells. Microtubules in MCÀ cells showed stronger dynamics than those of MP6 cells. MCÀ cells proliferated faster than MP6 cells and showed an altered cell cycle distribution, with a higher percentage in S-phase of the cell cycle. Consequently, MCÀ cells presented higher sensitivity to the S-phase-targeting agent gemcitabine than MP6 cells in vitro. Although the complete duration of mitosis was shorter in MCÀ cells and their microtubule dynamics was enhanced, the percentage of cells in G 2 -M phase was not altered nor was there any difference in sensitivity to antimicrotubule-targeting agents when compared with MP6 cells. Xenografts derived from TBCC variants displayed significantly enhanced tumor growth in vivo and increased sensitivity to gemcitabine in comparison to controls. These results are the first to suggest that proteins involved in the proper folding of cytoskeletal components may have an important influence on the cell cycle distribution, proliferation, and chemosensitivity of tumor cells. Mol Cancer Ther; 10(2); 303-12. Ó2011 AACR.

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Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

Cited by 59 publications

References 39 publications

Antiproliferative effects of sapacitabine (CYC682), a novel 2′-deoxycytidine-derivative, in human cancer cells

Antiproliferative effects of sapacitabine (CYC682), a novel 2′-deoxycytidine-derivative, in human cancer cells

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

Silencing of Tubulin Binding Cofactor C Modifies Microtubule Dynamics and Cell Cycle Distribution and Enhances Sensitivity to Gemcitabine in Breast Cancer Cells

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