Mechanisms of resistance to nucleoside analogue chemotherapy in mantle cell lymphoma: a molecular case study

Reiman, Tony; Ka, Graham; Wong, Jiemin; Belch, AR; Coupland, Robert; Young, James D.; Cass, CE; Mackey,

doi:10.1038/sj.leu.2402579

Cited by 12 publications

(7 citation statements)

References 5 publications

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“…For example, 1 MCL patient who was resistant to nucleoside analogs demonstrated abundant hENT-1, dCK, and minimal 5Ј-nucleotidases, but it was still resistant on presentation to fludarabine and dFdC. 48 Moreover, alterations in genes such as ataxia telangiectasia mutated and p53 may influence resistance to nucleoside analogues, 49 particularly in MCL given the high rate of changes in DNA damage pathways. 21,22 It is also likely that the prior chemotherapy regimens patients received will have had an effect on the sensitivity to the MI-63-dFdC combination, particularly in those who received regimens incorporating DNA-damaging agents.…”

Section: Discussionmentioning

confidence: 99%

HDM-2 inhibition suppresses expression of ribonucleotide reductase subunit M2, and synergistically enhances gemcitabine-induced cytotoxicity in mantle cell lymphoma

Jones

Baladandayuthapani

Neelapu

et al. 2011

Blood

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Mantle cell lymphoma (MCL) usually responds well to initial therapy but is prone to relapses with chemoresistant disease, indicating the need for novel therapeutic approaches. Inhibition of the p53 E3 ligase human homolog of the murine double minute protein-2 (HDM-2) with MI-63 has been validated as one such strategy in wild-type (wt) p53 models, and our genomic and proteomic analyses demonstrated that MI-63 suppressed the expression of the ribonucleotide reductase (RNR) subunit M2 (RRM2). This effect occurred in association with induction of p21 and cell-cycle arrest at G 1 /S and prompted us to examine combinations with the RNR inhibitor 2,2-difluoro-2-deoxycytidine (gemcitabine). The regimen of MI-63-gemcitabine induced enhanced, synergistic antiproliferative, and proapoptotic effects in wtp53 MCL cell lines. Addition of exogenous dNTPs reversed this effect, whereas shRNAmediated inhibition of RRM2 was sufficient to induce synergy with gemcitabine. Combination therapy of MCL murine xenografts with gemcitabine and MI-219, the in vivo analog of MI-63, resulted in enhanced antitumor activity. Finally, synergy was seen with MI-63-gemcitabine in primary patient samples that were found to express high levels of RRM2 compared with MCL cell lines. These findings provide a framework for translation of the rational combination of an HDM-2 and RNR inhibitor to the clinic for patients with relapsed wtp53 MCL. (Blood. 2011; 118(15):4140-4149) IntroductionMantle cell lymphoma (MCL) is a B-cell lymphoma that accounts for 6% to 8% of lymphoid malignancies and typically harbors the t(11;14) translocation, resulting in aberrant cyclin D1 expression and cell-cycle dysregulation. 1 MCL patients present with a spectrum of disease types ranging from slow, indolent growing malignancies to more aggressive variants, such as the blastoid phenotype. It is characterized clinically by good initial responses to induction chemotherapy, but later it almost invariably relapses with a more aggressive course, 1 making it an attractive model for novel drug development. 2,3 One such novel agent is the proteasome inhibitor bortezomib that was shown to be active against MCL in a phase 1 trial 4 and then approved for treatment of relapsed disease after multicenter studies fully demonstrated its activity. [5][6][7] Other drugs that have shown promise against MCL include novel agents such as the mammalian target of rapamycin inhibitors temsirolimus 8 and everolimus, 9 the immunomodulatory drug lenalidomide, 10,11 and more traditional cytotoxics such as (2Ј,2Ј-difluoro-2Ј-deoxycytidine (gemcitabine, dFdC). 12,13 dFdC is an effective, broad-spectrum anticancer agent with activity in many malignancies, including as a single agent and in combination for non-Hodgkin lymphoma. 14 It is transported into the cell mainly through the human equilibrative nucleoside transporter (hENT)-1, 15 where it is metabolized by deoxycytidine kinase (dCK) into its 2 active forms, dFdC-diphosphate and dFdCtriphosphate (dFdCTP). 16 The cytotoxic effects of dFdC are because of...

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Section: Discussionmentioning

confidence: 99%

HDM-2 inhibition suppresses expression of ribonucleotide reductase subunit M2, and synergistically enhances gemcitabine-induced cytotoxicity in mantle cell lymphoma

Jones

Baladandayuthapani

Neelapu

et al. 2011

Blood

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“…61 A lack of correlation between hENT1 mRNA levels and drug transport activity has also been described for the hENT1 transporter in MCL cells. 80 For some reason, little CNT-type transport activity is found in CLL and other B-cell lymphomas, although mRNA for hCNT2 and hCNT3 have been detected. Expression of hCNT2 seems better preserved in cells from CLL patients, but this is not a suitable transporter for fludarabine, thus making hENT1and hENT2 key players in the uptake of this drug in lymphoproliferative diseases.…”

Section: What Role Do Nucleoside Transporters Play In Nucleoside-derimentioning

confidence: 99%

Nucleoside transporters in chronic lymphocytic leukaemia

et al. 2004

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“…From a population of 21 CLL patients previously described, 22 we selected 3 fludarabine-naive patients whose CLL samples had the highest expression of hCNT3 message. Peripheral blood was collected in heparinized tubes.…”

Section: Plasma Membrane Hcnt3 Activity In Cll Cellsmentioning

confidence: 99%

“…After centrifugation, cells at the interface were washed twice and resuspended in PBS. Suspension nucleoside transport studies were performed as previously described 22 for assay of sodium-dependent nucleoside uptake mediated by hCNT3. In brief, cells were washed twice with the appropriate transport buffer (Na ϩ or N-methyl-D-glucamine) and then processed immediately or incubated with 100 M dilazep at room temperature for 20 minutes before the transport assay.…”

Section: Plasma Membrane Hcnt3 Activity In Cll Cellsmentioning

confidence: 99%

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Quantitative analysis of nucleoside transporter and metabolism gene expression in chronic lymphocytic leukemia (CLL): identification of fludarabine-sensitive and -insensitive populations

Mackey

Galmarini

Graham

et al. 2005

Blood

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Mechanisms of resistance to nucleoside analogue chemotherapy in mantle cell lymphoma: a molecular case study

Cited by 12 publications

References 5 publications

HDM-2 inhibition suppresses expression of ribonucleotide reductase subunit M2, and synergistically enhances gemcitabine-induced cytotoxicity in mantle cell lymphoma

HDM-2 inhibition suppresses expression of ribonucleotide reductase subunit M2, and synergistically enhances gemcitabine-induced cytotoxicity in mantle cell lymphoma

Nucleoside transporters in chronic lymphocytic leukaemia

Quantitative analysis of nucleoside transporter and metabolism gene expression in chronic lymphocytic leukemia (CLL): identification of fludarabine-sensitive and -insensitive populations

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