Involvement of the DNA mismatch repair system in antineoplastic drug resistance

Lage, Hermann; Dietel, Manfred

doi:10.1007/s004320050258

Cited by 108 publications

(53 citation statements)

References 69 publications

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“…As expected, the cisplatin -resistant phenotype remained unaltered in all transfected cell clones because this resistance is commonly caused by alternative resistance mechanisms, e.g., by a modulation of the activity of the DNA mismatch repair system ( overview in Ref. [ 34] ).…”

Section: Discussionsupporting

confidence: 62%

Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2

et al. 2002

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The phenomenon of multidrug resistance ( MDR ) in human cancers is one of the major causes of failure of chemotherapy. A recently identified new member of the superfamily of ATP -binding cassette transporters, breast cancer resistance protein ( BCRP ), was demonstrated to confer an atypical multidrug -resistant phenotype to tumor cells. To overcome the BCRP -mediated drug resistance, a specific anti -BCRP hammerhead ribozyme was introduced into the human gastric carcinoma cell line, EPG85 -257RNOV, exhibiting an atypical MDR phenotype. By this approach, the expression levels of the targeted BCRP -encoding mRNA and the BCRP transport protein were decreased to the low constitutive expression level that was observed in highly drug -sensitive parental gastric carcinoma cells. In addition, in the anti -BCRP ribozyme -treated cells, the cellular drug accumulation was dramatically increased to the level measured in drug -sensitive cells. These effects were accompanied by an extensive reversal of the drug -resistant phenotype of more than 80%. Because additional mechanisms contribute to the multimodal -mediated MDR phenotype exhibited by this gastric carcinoma cell line, the data suggest that the BCRP -mediated contingent to the drug resistance was overcome nearly completely. Moreover, the data indicate that ribozyme -based gene therapy may be clinically applicable in preventing and reversing BCRPmediated atypical MDR.

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Section: Discussionsupporting

confidence: 62%

Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2

et al. 2002

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“…5,27,28,40 In addition, MMR status has been suggested as a mechanism of chemoresistance. 41 Therefore the results of this study may also have clinical significance with respect to diagnosis and treatment of adult GCT.…”

Section: Discussionmentioning

confidence: 80%

Mismatch repair gene expression and genetic instability in testicular germ cell tumor

Velasco

Riquelme

Schultz

et al. 2004

Cancer Biology & Therapy

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ABBREVIATIONSMMR mismatch repair MSI microsatellite instability MSH2 mut-S homolog 2 MLH1 mut-L homolog 1 GCT germ cell tumor LOH loss of heterozygosity ACKNOWLEDGEMENTSThe authors wish to acknowledge support from Fondecyt 1020695 to AV and Baylor College of Medicine Institutional support to FSL. Research Paper Mismatch Repair Gene Expression and Genetic Instability in Testicular Germ Cell Tumor ABSTRACTHuman mismatch repair (MMR) genes encode highly conserved interacting proteins that correct replication errors predisposing to hereditary gastrointestinal and genitourinary malignancies. A subset of sporadic genitourinary tumors also exhibits MMR deficiency and can be identified by measuring the frequency of microsatellite instability (MSI) in cancer cell DNA. We investigated expression of the two most commonly mutated MMR genes, MSH2 and MLH1, in sporadic testicular germ cell tumor (GCT) in order to: (1) determine the expression pattern of MSH2 and MLH1 proteins in normal seminiferous tubules and histologically distinct GCT subtypes, (2) correlate MMR gene expression with genetic instability in GCT and (3) develop a panel of molecular markers that can identify genetically distinct subsets of GCT for prognostic assessment.MSH2 and MLH1 had differential staining patterns in normal seminiferous tubules and malignant tissues. MSH2 was expressed in all stages of spermatogenesis up to but excluding mature sperm whereas MLH1 was predominantly expressed in premeiotic germ cells. All histological GCT subtypes showed differential immunostaining for MSH2 and MLH1 however pure seminoma had statistically significant fewer low MSH2 staining tumors than other subtypes (p = 0.046). Twenty-five percent of GCT exhibited increased frequency of MSI (MSI+ tumors) with 73, 70 and 43% of MSI+ tumors exhibiting low MSH2, low MLH1 or low MSH2 and low MLH1 staining respectively. Fifteen percent of testicular GCT exhibited loss of heterozygosity (LOH) but no MSI (LOH only tumors). Only 28, 17 or 6% of LOH only tumors exhibited low MSH2, low MLH1 or low MSH2 and low MLH1 staining respectively.

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“…Therefore, it is possible that the 6-TG-mediated Ras inactivation cascades down to further inhibit Rac1 activity. It is also possible that the 6-TG-mediated decrease in T-cell proliferation and survival may be because of the DNA-targeting therapeutic action of 6-TG in which incorporation of 6-TG into DNA interferes with the action of the mismatch repair system (7,8,10). Further studies to configure the mechanism of the 6-TG-mediated diminution of the proliferation and survival of T-cells will be necessary.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, 6-TG in DNA can be recognized as a DNA lesion by the mismatch repair system. This recognition results in induction of the apoptosis of acute lymphoblastic leukemia (7)(8)(9)(10). Recent studies show that 6-TGNP derived from 6-TP prodrugs binds to Rac1 to form the 6-TGNP⅐Rac1 complex (5,11).…”

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confidence: 99%

Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function

Shin

Wey

Umutesi

et al. 2016

Journal of Biological Chemistry

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6-Thiopurine (6-TP) prodrugs include 6-thioguanine and azathioprine. Both are widely used to treat autoimmune disorders and certain cancers. This study showed that a 6-thioguanosine triphosphate (6-TGTP), converted in T-cells from 6-TP, targets Rac1 to form a disulfide adduct between 6-TGTP and the redox-sensitive GXXXXGK(S/T)C motif of Rac1. This study also showed that, despite the conservation of the catalytic activity of RhoGAP (Rho-specific GAP) on the 6-TGTP-Rac1 adduct to produce the biologically inactive 6-thioguanosine diphosphate (

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Involvement of the DNA mismatch repair system in antineoplastic drug resistance

Cited by 108 publications

References 69 publications

Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2

Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2

Mismatch repair gene expression and genetic instability in testicular germ cell tumor

Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function

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