Levels of expression of the mdr1 gene and glutathione S-transferase genes 2 and 3 and response to chemotherapy in multiple myeloma

Linsenmeyer, Martha E.; Jefferson, Sara; Wolf, M.; Matthews, Janice R.; Board, Philip G.; Woodcock, David M.

doi:10.1038/bjc.1992.95

Cited by 55 publications

(31 citation statements)

References 20 publications

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“…Melphalan, included in this category, is one of the most frequently used chemotherapeutic agents in the initial treatment of MM. The mRNA levels for the genes GST-2 and mdr1 significantly correlate in MM, supporting the theory that resistant tumors have several concurrent mechanisms of chemoresistance (7).…”

supporting

confidence: 57%

DNA Topoisomerase IIα in Multiple Myeloma: A Marker of Cell Proliferation and Not Drug Resistance

et al. 2001

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DNA topoisomerase II␣ (topo II␣) is the target for a number of antineoplastic agents. Down-regulation of this enzyme is one form of drug resistance. Topo II␣ is also involved in DNA replication and transcription and serves as an indicator of proliferation rate in many human malignancies. This study examines whether topo II␣ is one of the mechanisms of chemoresistance commonly observed in multiple myeloma (MM) or alternatively, whether topo II␣ is associated with tumor cell proliferation. Bone marrow (BM) biopsy sections from 72 cases of MM, stratified according to proliferative activity (bromodeoxyuridine uptake), were immunostained for topo II␣. Immunoreactivity with an additional marker of drug resistance, glutathione-Stransferase , and the proliferation marker Ki-67 were also examined. Topo II␣ was expressed in 26 (36%) cases and correlated strongly with proliferative activity (P < .001). A role for drug resistance could not be supported, given this strong relationship with proliferation and the finding that glutathione-S-transferase expression in 57 (78%) cases was independent of topo II␣ immunoreactivity. Topo II␣ was identified in 91 to 100% of highly proliferative tumors, as evaluated by bromodeoxyuridine uptake or Ki-67 reactivity, respectively. Proliferation also correlated with the histologic grade of the MM. Therefore, topo II␣ immunoreactivity is primarily a marker of cell proliferation in MM and as such is likely to have prognostic significance. Highly proliferative tumors are most likely to be sensitive to chemotherapeutic protocols using anti-topo II␣ agents.

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confidence: 57%

DNA Topoisomerase IIα in Multiple Myeloma: A Marker of Cell Proliferation and Not Drug Resistance

et al. 2001

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“…Although patients with MM at presentation have a low percentage of tumor cells that express MDR1 protein, this percentage increases up to 50% in patients after chemotherapy (27,28). These findings suggest that efforts should focus on overcoming some of the problems associated with paclitaxel-based therapy, including issues with formulation, administration, and susceptibility to resistance conferred by the drug-efflux protein P-glycoprotein.…”

Section: Discussionmentioning

confidence: 99%

Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo

Cho

Katz

et al. 2005

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

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26-Trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B [Fludelone (Flu)] has shown broad antitumor activity in solid tumor models. In the present study, we showed, in vitro, that Flu significantly inhibited multiple myeloma (MM) cell proliferation (with 1-15 nM IC 50), whereas normal human bone marrow stromal cells (HS-27A and HS-5 lines) were relatively resistant (10-to 15-fold higher IC 50). Cell-cycle analysis demonstrated that Flu caused G2͞M phase arrest and induced cell apoptosis. After Flu treatment, caspase-3, -8, and -9 were activated, cytochrome c and second mitochondrial-derived activator of caspase were released to the cytosol, and c-Jun N-terminal kinase was activated, indicating that mitochondria were involved in the apoptosis. Flu toxicity to human hematopoietic stem cells was evaluated by CD34 ؉ cell-apoptosis measurements and hematopoietic-progenitor assays. There was no significant toxicity to noncycling human CD34 ؉ cells. We Epothilones have emerged as a highly promising family of microtubule-stabilizing agents. The epothilones have higher solubility in water than paclitaxel and are poorer substrates for the P-glycoprotein, proving more effective than paclitaxel against tumors showing multidrug resistance (5, 6). Epothilones also have a simpler molecular architecture, which has allowed for the total synthesis of the natural epothilones and many synthetic analogs.Our group achieved the total synthesis, and the structure-activity relationship evaluation, of several epothilones (9-11). This work soon led to the synthesis of 12,13-desoxyepothilone B (dEpoB), which proved highly effective in various in vivo xenograft tumor models (10, 11). More recently, we reported the total synthesis of (E)-9,10-dehydro-12, 13-desoxyepothilone B (9) and 26-trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B, named Fludelone (Flu) (12). In mice, Flu appears to have a particularly broad therapeutic index in vivo. It seems to be curative over a range of tumor types, without tumor relapse upon suspension of treatment. Moreover, Flu is orally available and is completely curative against human tumor xenografts by parenteral and oral therapy. In addition, treatment with Flu gave complete tumor remission against Taxol-resistant tumors (10, 12). These very promising antitumor data were obtained in s.c. solid tumor models; however, drug efficacy in orthotopic models has not been investigated. In the present study, we focused on the evaluation of the anti-multiplemyeloma (MM) effects of the second generation analog Flu, in comparison with dEpoB, in a disseminated MM model. Our data demonstrated that Flu had a profound antitumor activity in human MM both in vitro and in vivo, indicating that this compound might be a promising agent against MM, particularly in late-stage refractory disease. Materials and MethodsCell Lines and Primary Specimens. For information about cell lines and primary specimens, see Supporting Materials and Methods, which is published as supporting information on the PNAS web site.Reagents. Flu and dEpoB...

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“…On the other hand, it was shown that overexpression of P-gp is responsible for the resistance to a new second generation proteasome inhibitor, carflizomib (Hawley et al, 2013). MRP1 overexpression generally was not detected in MM cells (Lynsenmeyer et al, 1992;Marie, 2001). LRP expression was detected in approximately half of MM patients and is associated with a poor response to melphalan-based induction chemotherapy (Lokhorts et al, 1996).…”

Section: Differential Expression Levels Of Abc Transporter Protein Famentioning

confidence: 99%

An update on molecular biology and drug resistance mechanisms of multiple myeloma

Mutlu

Kiraz

Gündüz

et al. 2015

Critical Reviews in Oncology/Hematology

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Multiple myeloma (MM), a neoplasm of plasma cells, is the second most common hematological malignancy. Incidance rates increase after age 40. MM is most commonly seen in men and African-American population. There are several factors to this, such as obesity, environmental factors, family history, genetic factors and monoclonal gammopathies of undetermined significance (MGUS) that have been implicated as potentially etiologic. Development of MM involves a series of complex molecular events, including chromosomal abnormalities, oncogene activation and growth factor dysregulation. Chemotherapy is the most commonly used treatment strategy in MM. However, MM is a difficult disease to treat because of its marked resistance to chemotherapy. MM has been shown to be commonly multidrug resistance (MDR)-negative at diagnosis and associated with a high incidence of MDR expression at relapse. This review deals with the molecular aspects of MM, drug resistance mechanisms during treatment and also possible new applications for overcoming drug resistance. © 2015 Elsevier Ireland Ltd

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Levels of expression of the mdr1 gene and glutathione S-transferase genes 2 and 3 and response to chemotherapy in multiple myeloma

Cited by 55 publications

References 20 publications

DNA Topoisomerase IIα in Multiple Myeloma: A Marker of Cell Proliferation and Not Drug Resistance

DNA Topoisomerase IIα in Multiple Myeloma: A Marker of Cell Proliferation and Not Drug Resistance

Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo

An update on molecular biology and drug resistance mechanisms of multiple myeloma

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