Modulation of multidrug resistance (MDR) in hematological malignancies

Covelli, A.

doi:10.1093/annonc/10.suppl_6.s53

Cited by 37 publications

(32 citation statements)

References 57 publications

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“…The MDR1 phenotype, associated with resistance to the anthracyclines, is important in this disease and numerous attempts have been made to overcome this resistance with MDR modulators but with mixed results (Covelli, 1999). Our results suggest it may be more pertinent to modulate resistance to the commonly used antimetabolite, ara-C. We have shown it is possible to markedly increase the in vitro sensitivity to ara-C in these blast cells from clinical samples up to 80-fold using the DNA polymerase inhibitor, aphidicolin.…”

Section: Discussionmentioning

confidence: 99%

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Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML

Sargent¹,

Elgie²,

Williamson³

et al. 2001

Br J Cancer

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Summary Treatment failure in AML is often attributed to P-glycoprotein-associated multidrug resistance. However, the importance of increased DNA repair in resistant cells is becoming more apparent. In order to investigate the ability of the DNA repair inhibitor aphidicolin to modulate drug resistance, we continually exposed blasts cells, isolated from 22 patients with AML, to a variety of agents ± 15 µM aphidicolin for 48 hours. Cell survival was measured using the MTT assay. Overall, there was no significant effect of aphidicolin on sensitivity to daunorubicin, doxorubicin, etoposide or fludarabine. However, there was a marked increase in sensitivity to ara-C with a median 4.75-fold increase overall (range 0.8-80-fold; P < 0.005). The effect of aphidicolin was significantly greater in blast cells found resistant in vitro to ara-C (8.9-fold compared to 2.12-fold, P < 0.01). This observation was further validated by the correlation between ara-C LC 50 and extent of modulation effect (P < 0.05). Cells isolated from 10 cord blood samples were also tested in order to establish the haematological toxicity of combining ara-C and aphidicolin. The therapeutic index (LC 50 normal cells/tumour cells) for ara-C + aphidicolin was higher than that for ara-C alone suggesting no increased myelotoxicity for the combination. Increased cytotoxicity without increased haematotoxicity makes the combination of ara-C plus aphidicolin ideal for inclusion in future clinical trials.

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Section: Discussionmentioning

confidence: 99%

“…Multidrug resistance (MDR) associated with overexpression of P-glycoprotein is prevalent in haematological malignancies. Whilst some MDR modulation regimens have shown promise, generally early results have been disappointing (Covelli, 1999).…”

mentioning

confidence: 99%

Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML

Sargent¹,

Elgie²,

Williamson³

et al. 2001

Br J Cancer

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“…Despite treatment with alkylating agents, anthracyclines, corticosteroids, 1,2 and bortezomib 3 as well as high-dose therapy and stem cell transplantation, 4-6 MM remains an incurable disease because of the high resistance to apoptosis and both intrinsic and acquired drug resistance. [7][8][9][10][11][12] Therefore, new therapeutic strategies are needed to improve patient outcome.Preclinical in vitro and in vivo studies showed that arsenic trioxide (ATO) has antimyeloma effects both as a single agent [13][14][15][16] and in combination with glutathione-depleting agents [17][18][19] and/or other antimyeloma agents. 15,20,21 Moreover, the combined results of 3 phase 2 studies in patients with relapsed MM refractory to conventional chemotherapy showed only modest efficacy of ATO as single agent, [22][23][24][25][26][27][28] but combination therapies with ascorbic acid, melphalan, steroids, thalidomide, and bortezomib have shown promising results.…”

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confidence: 99%

Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways

Lunghi

Giuliani

Mazzera

et al. 2008

Blood

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IntroductionMultiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of malignant plasma cells within the bone marrow (BM). Despite treatment with alkylating agents, anthracyclines, corticosteroids, 1,2 and bortezomib 3 as well as high-dose therapy and stem cell transplantation, 4-6 MM remains an incurable disease because of the high resistance to apoptosis and both intrinsic and acquired drug resistance. [7][8][9][10][11][12] Therefore, new therapeutic strategies are needed to improve patient outcome.Preclinical in vitro and in vivo studies showed that arsenic trioxide (ATO) has antimyeloma effects both as a single agent [13][14][15][16] and in combination with glutathione-depleting agents [17][18][19] and/or other antimyeloma agents. 15,20,21 Moreover, the combined results of 3 phase 2 studies in patients with relapsed MM refractory to conventional chemotherapy showed only modest efficacy of ATO as single agent, [22][23][24][25][26][27][28] but combination therapies with ascorbic acid, melphalan, steroids, thalidomide, and bortezomib have shown promising results. [29][30][31][32][33][34] We have previously demonstrated that PD184352 (PD), a highly selective inhibitor of MEK phosphorylation and activation, strikingly enhances ATO-mediated apoptosis in acute myelogenous leukemia (AML) via multiple intrinsic apoptotic pathways activation. [35][36][37] MEK blockade efficiently and selectively sensitizes tumor cells to suboptimal doses of other apoptotic stimuli, including classic cytotoxic treatment (nucleoside analogs, microtubule-targeted drugs, ␥-irradiation), 38-43 biologicals (retinoids, interferons), 44,45 steroids, [46][47][48] and other signal transduction/apoptosis modulators (UCN-01, STI571, Bcl-2 antagonists, Bcl-2 antisense oligonucleotides). [49][50][51][52][53] In this study, we tested the apoptotic activity of ATO combined with MEK inhibitors in MM cells, and we were able to demonstrate that PD enhances ATO-induced cytotoxicity both in vitro and in vivo in a human plasmacytoma xenograft model, through a multiple modulation of apoptotic regulatory proteins, including p53 family proteins, TRAIL receptors, several Bcl-2 family proteins, and caspases, that depend on the functionality of the p53 pathway. MethodsApproval for the study was obtained from the Institutional Review Board of the Department of Clinical Sciences, University of Parma (Parma, Italy). ReagentsATO was purchased from Sigma-Aldrich (St Louis, MO). A 1 mM stock solution was obtained by dissolving ATO in phosphate-buffered saline.Submitted October 3, 2007; accepted June 12, 2008. Prepublished online as Blood First Edition paper, June 26, 2008; DOI 10.1182 DOI 10. /blood-2007 The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on April 27, 2019. by guest www.bloodj...

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“…[63][64][65][66][67] In many studies, P-gp overexpression is associated with a poorer outcome, as is overexpression of some of the other efflux pumps, although the data on P-gp seem to be the strongest in this regard. 64,66 Importantly, P-gpmediated resistance can be reversed in vitro by a variety of drugs, such as cyclosporine, PSC-833 and quinine.…”

Section: Novel Approaches To Treat Leukemia Ra Larson Et Almentioning

confidence: 99%

Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002

Larson

Schiffer

et al. 2003

Leukemia

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Novel approaches have been designed to treat leukemia based on our understanding of the genetic and biochemical lesions present in different malignancies. This meeting report summarizes some of the recent advances in leukemia treatment. Based on the discoveries of cellular oncogenes, chromosomal translocations, monoclonal antibodies, multidrug resistance pumps, signal transduction pathways, genomics/proteonomic approaches to clinical diagnosis and mutations in biochemical pathways, clinicians and basic scientists have been able to identify the particular genetic mutations and signal transduction pathways involved as well as design more appropriate treatments for the leukemia patient. This meeting report discusses these exciting new therapies and the results obtained from ongoing clinical trials. Furthermore, rational approaches to treat complications of tumor lysis syndrome by administration of the recombinant urate oxidase protein, also known as rasburicase, which corrects the biochemical defect present in humans, were discussed. Clearly, over the past 25 years, molecular biology and biotechnology has provided the hematologist/oncologist novel bullets in their arsenal that will allow treatment by design in leukemia.

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Modulation of multidrug resistance (MDR) in hematological malignancies

Cited by 37 publications

References 57 publications

Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML

Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML

Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways

Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002

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