Original Article
Expression of the Gene for Multidrug-Resistance–Associated Protein and Outcome in Patients with Neuroblastoma
N Engl J Med 1996; 334:231-238January 25, 1996
- Abstract
Background
Overexpression of the gene for the multidrug-resistance–associated protein (MRP) has been linked with resistance to chemotherapeutic agents (multidrug resistance) in vitro. The expression of MRP by neuroblastoma cells correlates with N-myc oncogene amplification, a well-established prognostic indicator in patients with neuroblastoma.
Methods
To relate MRP gene expression to established prognostic markers and the clinical outcome of neuroblastoma, we analyzed MRP expression in specimens of primary tumors from 60 patients with neuroblastoma.
Results
Levels of MRP gene expression were significantly higher in tumors with N-myc amplification than in tumors without such amplification (P<0.001). High levels of MRP expression were strongly associated with reductions in both survival and event-free survival (P<0.001) in the overall study population and in subgroups of patients without N-myc amplification and patients with localized disease. For the overall study population, the five-year cumulative survival rates in the groups with high and low levels of MRP expression were 57 percent (95 percent confidence interval, 37 to 78 percent) and 94 percent (95 percent confidence interval, 86 to 100 percent), respectively. In contrast, expression of the MDR1 multidrug-resistance gene was not predictive of survival or event-free survival. After adjustment by multivariate analysis for the effects of N-myc amplification and other prognostic indicators, high levels of MRP expression retained significant prognostic value for poor survival (relative hazard, 14.9; P = 0.01) and poor event-free survival (relative hazard, 9.7; P = 0.004), whereas N-myc amplification had no prognostic value.
Conclusions
High levels of MRP gene expression in patients with neuroblastoma correlate strongly with poor outcome. The findings suggest that expression of this multidrug-resistance gene accounts for the association between N-myc amplification and reduced survival.
Media in This Article
Figure 1
Cumulative Survival of 60 Patients with Neuroblastoma.Figure 2
Expression of the MRP and MDR1 Genes and Cumulative Survival in 60 Patients with Neuroblastoma.Article Activity
- Article
Neuroblastoma is the most common solid tumor of early childhood.1 Patients with localized disease have a favorable prognosis, but the majority of children with neuroblastoma present with metastases and have poor prognoses despite intensive multimodal therapy.2 Treatment failure in these patients is largely attributable to resistance to a diverse range of structurally and functionally unrelated cytotoxic drugs. Resistance to multiple chemotherapeutic agents (multidrug resistance) is particularly apparent in patients whose tumors show amplification of the N-myc oncogene, one of the most powerful indicators of poor outcome in neuroblastoma.3 The mechanisms by which such amplification influences the phenotype of neuroblastoma are unclear.
Multidrug resistance has been intensively investigated in the laboratory. Among the underlying mechanisms, the best-known involves the MDR1 gene, which encodes P-glycoprotein.4 Although a number of studies have suggested a role for MDR1 in the chemoresistance associated with certain cancers,4 the contribution of this gene to the multidrug-resistant phenotype of neuroblastoma is controversial.5-10 Recently, another gene, the gene for multidrug-resistance–associated protein (MRP), has also been found to confer a multidrug-resistant phenotype in vitro.11-13 The MRP gene, located on chromosome 16p13.1,14 encodes a 190-kd membrane-bound glycoprotein that, like P-glycoprotein, mediates resistance to a range of drugs made from natural products, including the vinca alkaloids, anthracyclines, and epipodophyllotoxins.12,15 We recently reported increased MRP expression in neuroblastomas with amplification of the N-myc oncogene and decreased MRP expression after the differentiation of neuroblastoma cells in vitro.16 In the present study, we examined the relation between MRP expression and clinical outcome in patients with neuroblastoma. We found a significant association between high levels of MRP expression and poor outcome and showed that this relation is independent of N-myc amplification.
Methods
Patients and Tumor Specimens
Samples of 60 primary neuroblastoma tumors from untreated patients were obtained from either the Neuroblastoma Tumor Bank of the Pediatric Oncology Group or the Prince of Wales Children's Hospital in Sydney, Australia. The samples from the United States were sent to the investigators for analysis after the proposed study had been reviewed and approved by the Neuroblastoma Biology Subcommittee of the Pediatric Oncology Group. Because insufficient information was available for all patients to be classified uniformly according to the staging criteria of the International Neuroblastoma Staging System,17 the Pediatric Oncology Group tumors were classified according to the staging system used by that group, which was based on the results of resection of the neuroblastoma,18 and the tumors from the hospital were classified according to the system of Evans et al., which was based on the anatomical site of the tumor.19 Among the 28 Pediatric Oncology Group tumors, there were 3 in stage A, 4 in stage B, 12 in stage C, 7 in stage D, and 2 in stage DS; the 32 tumors from the hospital comprised 8 in stage I (including 5 ganglioneuroblastomas), 5 in stage II, 8 in stage III, 9 in stage IV, and 2 in stage IVS. The clinical stages of the tumors were then classified as favorable (Evans stages I, II, and IVS and Pediatric Oncology Group stages A, B, and DS) or unfavorable (Evans stages III and IV and Pediatric Oncology Group stages C and D). Before the study, the number of copies of the N-myc oncogene per haploid genome were determined independently in each tumor by Southern blot analysis, with quantitation of the extent of amplification by serial dilution of DNA.20,21 A tumor with more than 3 copies of N-myc was considered to have N-myc amplification; 13 of the tumors studied (7 in stages III or C and 6 in stages IV or D) had N-myc amplification, with from 8 to 200 copies. Data on histologic classification according to the system of Shimada et al.22 were available for less than half the tumors; therefore, this factor was not analyzed.
All the patients received their diagnoses from December 1984 through September 1994 and were treated in a manner specific to their tumor stage. In the group from the hospital, patients in stages I, II, and IVS were treated with surgical resection of the primary tumor alone or with surgery and six months of chemotherapy with vincristine and cyclophosphamide; patients in stages III and IV received three months of chemotherapy (with teniposide, doxorubicin, cisplatin, vincristine, and cyclophosphamide),23 delayed resection of the primary tumor, and radiation therapy at the primary site. Patients in stage III whose tumors had N-myc amplification and patients in stage IV subsequently received supralethal chemoradiotherapy and autologous bone marrow transplantation, as described elsewhere,24 whereas all other patients in stage III completed 12 months of chemotherapy with the same agents that were used preoperatively.
Among the patients from the Pediatric Oncology Group, those in stage A were treated with surgery alone. Before 1987, all infants under one year of age who had unresectable tumors (those in stages B, C, and D) and all children one year of age or older with stage B disease were treated with five cycles of cyclophosphamide and doxorubicin. Infants in stage DS were also treated in this way or observed without treatment. Among infants with disease diagnosed after 1987 and unresectable tumors, those with hyperdiploid tumors were treated with cyclophosphamide and doxorubicin, whereas those with diploid tumors received cisplatin and teniposide. Older children with stage C disease received cyclophosphamide–doxorubicin alone or combined with cisplatin–teniposide, and in some cases also with radiation. Children with stage D disease were treated with the same pairs of drugs, given in alternation or together in pulses.25-30
Overall, eight patients underwent autologous bone marrow transplantation as part of their therapy. The responses of all the patients were assessed according to internationally accepted criteria,17 and outcomes were determined as of June 1995. The median period of follow-up for the surviving patients was 33 months (range, 7 to 120), whereas the median time from diagnosis to death among the patients with treatment failure was 9 months (range, 2 to 23). The outcome measures studied were survival, defined as the time from diagnosis to death, and event-free survival, defined as the time from diagnosis to the first major event (relapse, failure to enter remission, or death). Among the patients who survived and those who survived without events, survival and event-free survival, respectively, were defined as the time from diagnosis to the last follow-up and were treated as censored observations. Although the Australian and American institutions differed in their treatment protocols, there was no significant difference between the two groups of patients in overall survival or event-free survival. Moreover, multivariate analysis indicated that the inclusion of the treatment center as a variable had no prognostic value.
Analysis of Gene Expression by the Polymerase Chain Reaction
The competitive assay of RNA by the polymerase chain reaction (RNA PCR assay) that we used is a well-established method of analyzing gene expression in a range of tumor tissues, including neuroblastoma.16,31-34 The total amount of RNA in cytoplasm was isolated from frozen tumor tissue,35 and complementary DNA (cDNA) was synthesized from 1-μg aliquots of RNA with random hexanucleotide primers and Moloney murine leukemia virus reverse transcriptase.31 Aliquots of cDNA corresponding to 50 ng of RNA were amplified for 30 cycles in a final volume of 25 μl with 1 unit of Taq polymerase. After an initial period of denaturation for 3 minutes at 94°C, the cycling conditions consisted of 45 seconds at 94°C, 45 seconds at 55°C, and 90 seconds at 72°C. Each target gene sequence (MRP, MDR1, or TRK) was amplified with a control gene sequence (β2-microglobulin) with gene-specific oligonucleotide primers, as described elsewhere.16,31,33 After electrophoresis of the PCR products on 12 percent polyacrylamide gel and staining with ethidium bromide, the bands were visualized and photographed under ultraviolet transillumination. Densitometric analysis was performed with photographic negatives,16,33,36 and the ratio between the expression of the target gene and that of the control gene was determined for each sample by dividing the densitometrically determined volume of the target electrophoretic band by that of the control band. The level of expression of a given gene in an individual tumor (the PCR ratio) was defined as the average of the ratios for that gene obtained in competitive RNA PCR analyses performed on at least three occasions. All the PCR analyses were performed with the investigators unaware of the patients' survival status and outcome.
Statistical Analysis
Differences between groups of tumor specimens in the PCR ratios for specific target genes were assessed by two-sided Student's t-tests. In the survival analyses, the PCR ratios for specific genes in each tumor were categorized as low or high, according to the following procedures. For the TRK gene, tumor specimens were classified as having low expression if a TRK-specific PCR product was either absent or barely detectable (PCR ratio, <0.1) and as having high expression if the PCR ratio was >0.1 (range among the specimens studied that had high expression, 0.13 to 1.68). For the MRP and MDR1 genes, there was no clear demarcation between tumors with low expression and those with high expression; therefore, we used a different method of classification. Gene expression in an individual tumor was considered high if the PCR ratio for the gene in question exceeded the mean ratio for all 60 specimens. The decision to dichotomize the values obtained for MRP and MDR1 expression around the mean PCR ratios was made a priori, not after examination of the results of the survival analysis.
The survival analysis was performed according to the method of Kaplan and Meier, and outcome was compared between subgroups by two-tailed log-rank tests for univariate comparisons. Associations between the patients' clinical characteristics and the molecular characteristics of the tumor specimens were examined by Fisher's exact test. A Cox proportional-hazards regression model was used in the multivariate analysis. Statistical analyses were performed with StatView 4.1 (Abacus Concepts, Berkeley, Calif.) or SAS software (version 6.08, SAS Institute, Cary, N.C.). Results are expressed as means ±SE, and probabilities of survival and relative hazards are given with 95 percent confidence intervals.
Results
Clinical and Molecular Characteristics
To determine whether the 60 patients whose tumors we studied were representative of patients with neuroblastoma in general, we analyzed survival in relation to four well-established prognostic signs (Figure 1AFigure 1
Cumulative Survival of 60 Patients with Neuroblastoma., Figure 1B, Figure 1C, Figure 1D, and Table 1Table 1
Relation of Age and Tumor Stage at Diagnosis to the Molecular Characteristics of the Tumors in the 60 Study Patients with Neuroblastoma.). The results were consistent with previous studies.20,37,38 Amplification of the N-myc oncogene was seen in 22 percent of patients, all of whom had advanced-stage disease at diagnosis, and N-myc amplification was associated with significantly reduced survival (P = 0.002) (Figure 1A). High levels of expression of the TRK proto-oncogene, which encodes a receptor for nerve growth factor, were present in 80 percent of patients and were strongly associated with improved survival (P = 0.007) (Figure 1B), as reported elsewhere.37 TRK gene expression in tumors with amplification of the N-myc oncogene was significantly lower (median PCR ratio, 0.0) than in tumors without N-myc amplification (median ratio, 0.681; P = 0.001). Infants, 90 percent of whom (26 of 29 patients) expressed high levels of the TRK gene, had significantly better survival than older children (P = 0.02) (Figure 1C). Tumor stage was a powerful prognostic indicator (P<0.001) (Figure 1D), with no deaths among patients with favorable tumor stages. The proportion of patients with unfavorable tumor stages (60 percent) was similar to that in other large series of patients with neuroblastoma.20,38,39 However, in this study there was a smaller proportion (27 percent) of patients with stage IV or D tumors than would have been expected with consecutive enrollment,20,38,39 because of the frequent diagnosis of stage IV or D disease by analysis of bone marrow and urinary catecholamines, without biopsy of the primary tumor. When we studied event-free survival, N-myc amplification, TRK expression, and tumor stage continued to have significant prognostic value (data not shown). The characteristics of our study population with respect to well-established prognostic indicators and outcome were thus representative of patients with neuroblastoma in general.Expression of MRP and MDR1
We detected expression of the MRP gene in all 60 tumors obtained at diagnosis (mean [±SE] PCR ratio, 0.403±0.034). As in our earlier study,16 levels of MRP expression in samples of neuroblastoma with N-myc amplification (mean PCR ratio, 0.628±0.074) were significantly higher than those in tumors without amplification (mean ratio, 0.340±0.034; P<0.001). There was an intermediate level of MRP expression (PCR ratio, 0.534±0.022) in the human neuroblastoma cell line, SK-N-SH, which we used for reference. MRP was expressed at significantly higher levels in tumors with unfavorable clinical stages (mean PCR ratio, 0.483±0.047) than in tumors with favorable stages (mean ratio, 0.282±0.040; P = 0.004), a finding that supported a trend noted earlier.16 No significant differences in levels of MRP expression were found between tumors from children younger than one year at diagnosis and tumors from older children, or between tumors with high levels of TRK expression and those with low levels. The MDR1 gene was expressed in 56 of the tumors (93 percent; mean PCR ratio, 0.199±0.026). In contrast to MRP, MDR1 was expressed at lower levels in tumors with N-myc amplification (mean PCR ratio, 0.115±0.033) than in tumors without such amplification (mean ratio, 0.222±0.031), although the difference was not statistically significant (P = 0.09).
Gene Expression and Outcome
Figure 2AFigure 2
Expression of the MRP and MDR1 Genes and Cumulative Survival in 60 Patients with Neuroblastoma. and Figure 2B shows cumulative survival according to levels of expression of the MRP and MDR1 genes. High levels of MRP expression were strongly associated with reduced survival (Figure 2A). For the overall study population, the five-year cumulative survival rates in the groups with high and low levels of MRP expression were 57 percent (95 percent confidence interval, 37 to 78 percent) and 94 percent (95 percent confidence interval, 86 to 100 percent), respectively. Event-free survival was also associated with expression of the MRP gene; the five-year rates of event-free survival in the groups with high and low levels of MRP expression were 46 percent (95 percent confidence interval, 25 to 66 percent) and 91 percent (95 percent confidence interval, 82 to 100 percent), respectively. In contrast, there was no difference in either survival (Figure 2B) or event-free survival with respect to the level of expression of MDR1.To determine whether the prognostic value of MRP expression was independent of the influence of the N-myc oncogene and other established prognostic indicators, we performed multivariate analyses. When outcome was adjusted for the effect of N-myc amplification, high levels of MRP expression remained a significant indicator of both poor survival (relative hazard, 5.7; 95 percent confidence interval, 1.1 to 30.8) and poor event-free survival (relative hazard, 6.2; 95 percent confidence interval, 1.6 to 24.5) (Table 2Table 2
Multivariate Cox Regression Analysis of Prognostic Factors in Neuroblastoma.). One important result in the multivariate analysis was that N-myc amplification had no prognostic value, a sign that MRP expression accounted for the prognostic value of N-myc amplification. In three separate analyses, the relation between MRP expression and outcome was adjusted for the effects of age, TRK expression, and tumor stage. In each case, high levels of MRP expression remained a significant independent predictor of poor survival and poor event-free survival, with hazard ratios ranging from 4.9 to 9.1. When the four established prognostic indicators — namely, N-myc amplification, age at diagnosis, TRK expression, and tumor stage — were combined with MRP gene expression as variables in the Cox regression model, high levels of MRP expression remained the most powerful indicator of poor survival (relative hazard, 14.9; 95 percent confidence interval, 1.8 to 126.5) and poor event-free survival (relative hazard, 9.7; 95 percent confidence interval, 2.0 to 46.0), independently of all other prognostic indicators (Table 2). With the exception of age, no other variable in this study had significant predictive power in determining outcome, although the upper limits of the confidence intervals for the relative-hazard estimates were too high for us to rule out substantial independent contributions by the other prognostic factors.Additional analyses supported the strength of the association between MRP expression and outcome. When the MRP values were dichotomized post hoc around the median PCR ratio for the 60 tumors (0.34) rather than the mean ratio, MRP expression remained significantly predictive of both survival (relative hazard, 5.9; 95 percent confidence interval, 1.3 to 27.1) and event-free survival (relative hazard, 5.2; 95 percent confidence interval, 1.5 to 18.4). When the tumors were divided into quartiles according to ascending levels of MRP expression, the cumulative rates of event-free survival for the quartiles were 93, 87, 72, and 38 percent, indicating a correlation between increasing levels of MRP expression and the increasing risk of a poor outcome. This correlation was also found with the Cox proportional-hazards regression model, which showed that the risk of an adverse event increased in proportion to increasing levels of MRP expression; there was a relative hazard of 8.4 (95 percent confidence interval, 1.8 to 38.0) associated with each unit increase in the PCR ratio for this gene.
We also analyzed MRP gene expression in subgroups of patients who were expected on the basis of previously established criteria to have good outcomes. Among patients without N-myc amplification, high levels of MRP expression were associated with significantly reduced rates of event-free survival (relative hazard, 8.9; 95 percent confidence interval, 1.8 to 44.1) (Figure 3AFigure 3
Relation between MRP Gene Expression and Outcome in Patients without N-myc Amplification and Those with Localized Disease.). Among patients with localized neuroblastoma (Evans stages I, II, and III and Pediatric Oncology Group stages A, B, and C), high levels of MRP expression were again associated with significantly reduced event-free survival (relative hazard, 6.1; 95 percent confidence interval, 1.6 to 23.1) (Figure 3B). These effects were similar in the analysis of overall survival in the two subgroups (relative hazard for patients without N-myc amplification, 10.6; 95 percent confidence interval, 1.2 to 95.1; for patients with localized disease, 5.2; 95 percent confidence interval, 1.0 to 26.9).Discussion
We found that expression of the multidrug-resistance gene MRP at high levels in primary neuroblastoma tumors predicts reduced event-free survival and shorter overall survival in children with this neoplasm. The association between high levels of MRP expression and poor outcome was evident both in the overall population of patients and in clinically relevant subgroups. Among the prognostic indicators analyzed, MRP gene expression was the most closely associated with outcome. The effect of overexpression of MRP appeared to be independent of tumor stage, TRK expression, and amplification of the N-myc gene. MRP expression thus differs from other molecular indicators of outcome in patients with neuroblastoma, such as TRK expression and deletions of chromosome 1p, which have no prognostic value after adjustment in multivariate analysis for the effect of N-myc amplification.37,38 This linkage of prognosis to the MRP gene has implications for our understanding of the biology of neuroblastoma and for improving the treatment of patients with this condition.
Amplification of the N-myc oncogene is also a predictor of poor outcome in such patients,3,40 but the molecular basis of the association is unknown. The N-myc oncoprotein appears to act as a transcriptional regulator and has been thought perhaps to govern the transcription of critical genes conferring multidrug resistance.41 Our multivariate analysis, which revealed that N-myc amplification had no prognostic value when MRP expression was included as a prognostic factor, raises the possibility that the N-myc protein regulates expression of the MRP gene. This effect could modulate the response of neuroblastoma cells to cytotoxic drugs. We previously demonstrated a significant correlation between the expression of the N-myc oncogene and that of the MRP gene in neuroblastomas and showed that these genes undergo coordinate down-regulation in neuroblastoma cell lines after treatment with retinoic acid.16 The promoter sequence of the MRP gene42 contains three E-box motifs,43 which are the consensus DNA-binding sequences of the myc family of oncoproteins. However, we do not know whether N-myc uses these motifs to influence MRP gene expression.
Although both the MRP and the MDR1 genes encode membrane glycoproteins that can function as transporters of multiple drugs, the prognostic value of the two genes differed in this study. Evidence about the contribution of MDR1 to clinical multidrug resistance in patients with neuroblastoma is contradictory.5-10 Moreover, several chemotherapeutic agents used to treat neuroblastoma, such as cisplatin and cyclophosphamide, are not substrates for P-glycoprotein.4 The difference we found in prognostic value between the MRP and MDR1 genes may be explained by the putative physiologic role of MRP as an efflux pump for glutathione S-conjugates.44-46 MRP has not been shown to mediate resistance to cisplatin or cyclophosphamide, but these drugs do undergo glutathione conjugation.47,48 It is possible that in their conjugated forms, these drugs could be exported from cells by MRP.
A prerequisite for future assessment of the expression of MRP is a reproducible standard against which tumor specimens can be compared. The level of MRP expression in the SK-N-SH cell line we used fell just below the cutoff value for the uppermost quartile of the PCR ratios for MRP. This value (0.56) discriminated patients with good outcome from those with poor outcome. Future studies may define the relation between intermediate levels of MRP expression and clinical outcome, but in evaluating the high MRP values that are associated with a poor prognosis, the SK-N-SH cell line may be a useful standard.
A clinical implication of our findings is that compounds capable of inhibiting the action of MRP 49-51 may prove therapeutically useful. Our results in a relatively small number of patients with advanced disease need to be confirmed in large prospective studies before any modification of current treatment protocols is considered. It would be feasible to conduct such studies with snap-frozen tumor tissue obtained at diagnosis.
It is plausible that MRP influences the outcome in patients with neuroblastoma by directly affecting the response of the tumor to chemotherapy. In a case of aggressive neuroblastoma in which tumor specimens were available both at diagnosis and after treatment, we found that MRP expression increased after treatment with cytotoxic drugs (unpublished data). It is also possible that MRP influences the aggressiveness of neuroblastoma, its metastatic potential, or both. But regardless of how MRP overexpression relates mechanistically to poor outcome, our results suggest that the evaluation of this gene can help in assessing the prognosis of patients with neuroblastoma. Further studies of MRP could add to our understanding of the pathogenesis of resistance to chemotherapy in this malignant disease.
Supported by grants (to Dr. Norris, Dr. M. Haber, and Dr. Marshall) from the National Health and Medical Research Council (Australia) and the New South Wales State Cancer Council (Australia), by a grant from the Leo and Jenny Leukaemia and Cancer Foundation of Australia (to Dr. Marshall), and by the Children's Leukaemia and Cancer Foundation (Australia). Ms. Bordow is the recipient of an Australian Postgraduate Research Award.
We are indebted to the Neuroblastoma Biology Subcommittee of the Pediatric Oncology Group for reviewing and approving this research project and providing samples of neuroblastoma tumors; to Drs. Vivienne Tobias, Ian Kern, and Bruce Currie for assistance in obtaining the tumors from Prince of Wales Children's Hospital; and to Professor Wayne Hall and Mr. Neil Donnelly, of the National Drug and Alcohol Research Centre, Prince of Wales Hospital, Sydney, Australia, for helpful discussions and assistance with the statistical analysis.
Source Information
From the Children's Leukaemia and Cancer Research Centre, University of New South Wales and Prince of Wales Children's Hospital, Sydney, Australia (M.D.N., S.B.B., G.M.M., M.H.); the Department of Gastroenterology, Prince of Wales Hospital, Sydney, Australia (P.S.H.); and the Department of Pediatrics, Northwestern University Medical School and Children's Memorial Hospital, Chicago (S.L.C.).
Address reprint requests to Dr. Michelle Haber at the Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, High St., Randwick, NSW 2031, Australia.
- References
References
1
Crist WM ,Kun LE . Common solid tumors of childhood. N Engl J Med 1991;324:461-471
Full Text | Web of Science | Medline2
Brodeur GM, Castleberry RP. Neuroblastoma. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. 2nd ed. Philadelphia: J.B. Lippincott, 1993:739-67.
3
Brodeur GM ,Azar C ,Brother M , et al. Neuroblastoma: effect of genetic factors on prognosis and treatment. Cancer 1992;70:Suppl:1685-1694
CrossRef | Web of Science | Medline4
Roninson IB, ed. Molecular and cellular biology of multidrug resistance in tumor cells. New York: Plenum Press, 1991.
5
Chan HSL ,Haddad G ,Thorner PS , et al. P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N Engl J Med 1991;325:1608-1614
Full Text | Web of Science | Medline6
Corrias MV ,Cornaglia-Ferraris P ,Di Martino D , et al. Expression of multiple drug resistance gene, MDR1, and N-myc oncogene in an Italian population of human neuroblastoma patients. Anticancer Res 1990;10:897-902
Web of Science | Medline7
Bourhis J ,Benard J ,Hartmann O ,Boccon-Gibod L ,Lemerle J ,Riou G . Correlation of MDR1 gene expression with chemotherapy in neuroblastoma. J Natl Cancer Inst 1989;81:1401-1405
CrossRef | Web of Science | Medline8
Goldstein LJ ,Fojo AT ,Ueda K , et al. Expression of the multidrug resistance, MDR1, gene in neuroblastoma. J Clin Oncol 1990;8:128-136
Web of Science | Medline9
Favrot M ,Combaret V ,Goillot E , et al. Expression of P-glycoprotein restricted to normal cells in neuroblastoma biopsies. Br J Cancer 1991;64:233-238
CrossRef | Web of Science | Medline10
Nakagawara A ,Kadomatsu K ,Sato S , et al. Inverse correlation between expression of multidrug resistance gene and N-myc oncogene in human neuroblastomas. Cancer Res 1990;50:3043-3047
Web of Science | Medline11
Cole SPC ,Bhardwaj G ,Gerlach JH , et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992;258:1650-1654
CrossRef | Web of Science | Medline12
Grant CE ,Valdimarsson G ,Hipfner DR ,Almquist KC ,Cole SPC ,Deeley RG . Overexpression of multidrug resistance-associated protein (MRP) increases resistance to natural product drugs. Cancer Res 1994;54:357-361
Web of Science | Medline13
Kruh GD ,Chan A ,Myers K ,Gaughan K ,Miki T ,Aaronson SA . Expression complementary DNA library transfer establishes mrp as a multidrug resistance gene. Cancer Res 1994;54:1649-1652
Web of Science | Medline14
Slovak ML ,Ho JP ,Bhardwaj G ,Kurz EU ,Deeley RG ,Cole SPC . Localization of a novel multidrug resistance-associated gene in the HT1080/DR4 and H69AR human tumor cell lines. Cancer Res 1993;53:3221-3225
Web of Science | Medline15
Zaman GJR ,Flens MJ ,van Leusden MR , et al. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc Natl Acad Sci U S A 1994;91:8822-8826
CrossRef | Web of Science | Medline16
Bordow SB ,Haber M ,Madafiglio J ,Cheung B ,Marshall GM ,Norris MD . Expression of the multidrug resistance-associated protein (MRP) gene correlates with amplification and overexpression of the N-myc oncogene in childhood neuroblastoma. Cancer Res 1994;54:5036-5040
Web of Science | Medline17
Brodeur GM ,Seeger RC ,Barrett A , et al. International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 1988;6:1874-1881
Web of Science | Medline18
Nitschke R ,Smith EI ,Shochat S , et al. Localized neuroblastoma treated by surgery: a Pediatric Oncology Group study. J Clin Oncol 1988;6:1271-1279
Web of Science | Medline19
Evans AE ,D'Angio GJ ,Randolph J . A proposed staging for children with neuroblastoma: children's cancer study group A. Cancer 1971;27:374-378
CrossRef | Web of Science | Medline20
Seeger RC ,Brodeur GM ,Sather H , et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 1985;313:1111-1116
Full Text | Web of Science | Medline21
Telford DJ ,Kavallaris M ,White L ,Norris MD ,Brian MJ ,Stewart BW . Association of N-myc amplification with neuroblastoma: the Australian and New Zealand experience. J Paediatr Child Health 1992;28:58-63
CrossRef | Web of Science | Medline22
Shimada H ,Chatten J ,Newton WA Jr , et al. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst 1984;73:405-416
Web of Science | Medline23
Bernard JL ,Philip T ,Zucker JM , et al. Sequential cisplatin/VM-26 and vincristine/cyclophosphamide/doxorubicin in metastatic neuroblastoma: an effective alternating non-cross-resistant regimen? J Clin Oncol 1987;5:1952-1959
Web of Science | Medline24
McCowage GB ,Vowels MR ,Shaw PJ ,Lockwood L ,Mameghan H . Autologous bone marrow transplantation for advanced neuroblastoma using teniposide, doxorubicin, melphalan, cisplatin and total body irradiation. J Clin Oncol 1995;13:2789-2795
Web of Science | Medline25
Joshi VV ,Cantor AB ,Brodeur GM , et al. Correlation between morphologic and other prognostic markers of neuroblastoma: a study of histologic grade, DNA index, N-myc gene copy number, and lactic dehydrogenase in patients in the Pediatric Oncology Group. Cancer 1993;71:3173-3181
CrossRef | Web of Science | Medline26
Castleberry RP ,Kun LE ,Shuster JJ , et al. Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma. J Clin Oncol 1991;9:789-795
Web of Science | Medline27
Nitschke R ,Smith EI ,Altshuler G , et al. Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 1991;9:1181-1188
Web of Science | Medline28
Bowman LC ,Castleberry RP ,Altshuler G , et al. Therapy based on DNA index (DI) for infants with unresectable and disseminated neuroblastoma (NB): preliminary results of the Pediatric Oncology Group “Better Risk“ Study. Med Pediatr Oncol 1990;18:364-364 abstract.29
Castleberry RP ,Cantor AB ,Green AA , et al. Phase II investigational window using carboplatin, iproplatin, ifosfamide, and epirubicin in children with untreated disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 1994;12:1616-1620
Web of Science | Medline30
Strother D ,Shuster JJ ,McWilliams N , et al. Results of Pediatric Oncology Group protocol 8104 for infants with stages D and DS neuroblastoma. J Pediatr Hematol Oncol 1995;17:254-259
CrossRef | Web of Science | Medline31
Noonan KE ,Beck C ,Holzmayer TA , et al. Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci U S A 1990;87:7160-7164
CrossRef | Web of Science | Medline32
Holzmayer TA ,Hilsenbeck S ,Von Hoff DD ,Roninson IB . Clinical correlates of MDR1 (P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas. J Natl Cancer Inst 1992;84:1486-1491
CrossRef | Web of Science | Medline33
Haber M, Madafiglio J, Bordow SB, et al. Expression of retinoic acid-responsive genes in primary neuroblastomas. In: Evans AE, Biedler JL, Brodeur GM, D'Angio GJ, Nakagawara A, eds. Advances in neuroblastoma research 4: proceedings of the Sixth Symposium on Advances in Neuroblastoma Research held in Philadelphia, Pennsylvania, May 13–15, 1993. Vol. 385 of Progress in clinical and biological research. New York: Wiley-Liss, 1994:245-51.
34
Marshall GM ,Cheung B ,Stacey KP , et al. Increased retinoic acid receptor gamma expression suppresses the malignant phenotype and alters the differentiation potential of human neuroblastoma cells. Oncogene 1995;11:485-491
Web of Science | Medline35
Chomczynski P ,Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156-159
CrossRef | Web of Science | Medline36
Gilbert J ,Norris MD ,Haber M ,Kavallaris M ,Marshall GM ,Stewart BW . Determination of N-myc gene amplification in neuroblastoma by differential polymerase chain reaction. Mol Cell Probes 1993;7:227-234
CrossRef | Web of Science | Medline37
Nakagawara A ,Arima-Nakagawara M ,Scavarda NJ ,Azar CG ,Cantor AB ,Brodeur GM . Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 1993;328:847-854
Full Text | Web of Science | Medline38
Christiansen H ,Sahin K ,Berthold F ,Hero B ,Terpe H-J ,Lampert F . Comparison of DNA aneuploidy, chromosome 1 abnormalities, MYCN amplification and CD44 expression as prognostic factors in neuroblastoma. Eur J Cancer 1995;31:541-544
CrossRef | Web of Science39
Look AT ,Hayes FA ,Shuster JJ , et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 1991;9:581-591
Web of Science | Medline40
Schwab M . Molecular cytogenetics of human neuroblastoma. Biochim Biophys Acta 1992;1114:43-50
Web of Science | Medline41
Bénard J, Bourhis J, de Vathaire F, et al. Prognostic value of MDR1 gene expression in neuroblastoma: results of a multivariate analysis. In: Evans AE, Biedler JL, Brodeur GM, D'Angio GJ, Nakagawara A, eds. Advances in neuroblastoma research 4: proceedings of the Sixth Symposium on Advances in Neuroblastoma Research, held in Philadelphia, Pennsylvania, May 13–15, 1993. Vol. 385 of Progress in clinical and biological research. New York: Wiley-Liss, 1994:111-6.
42
Zhu Q ,Center MS . Cloning and sequence analysis of the promoter region of the MRP gene of HL60 cells isolated for resistance to adriamycin. Cancer Res 1994;54:4488-4492
Web of Science | Medline43
Blackwell TK ,Huang J ,Ma A , et al. Binding of myc proteins to canonical and noncanonical DNA sequences. Mol Cell Biol 1993;13:5216-5224
Web of Science | Medline44
Jedlitschky G ,Leier I ,Buchholz U ,Center M ,Keppler D . ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res 1994;54:4833-4836
Web of Science | Medline45
Muller M ,Meijer C ,Zaman GJR , et al. Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc Natl Acad Sci U S A 1994;91:13033-13037
CrossRef | Web of Science | Medline46
Leier I ,Jedlitschky G ,Buchholz U ,Cole SPC ,Deeley RG ,Keppler D . The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J Biol Chem 1994;269:27807-27810
Web of Science | Medline47
Tew KD . Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 1994;54:4313-4320
Web of Science | Medline48
Ishikawa T ,Ali-Osman F . Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells: molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem 1993;268:20116-20125
Web of Science | Medline49
Gekeler V ,Boer R ,Ise W ,Sanders KH ,Schachtele C ,Beck J . The specific bisindolylmaleimide PKC-inhibitor GF 109203X efficiently modulates MRP-associated multiple drug resistance. Biochem Biophys Res Commun 1995;206:119-126
CrossRef | Web of Science | Medline50
Gekeler V ,Ise W ,Sanders KH ,Ulrich W-R ,Beck J . The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance. Biochem Biophys Res Commun 1995;208:345-352
CrossRef | Web of Science | Medline51
Versantvoort CHM ,Broxterman HJ ,Lankelma J ,Feller N ,Pinedo HM . Competitive inhibition by genistein and ATP dependence of daunorubicin transport in intact MRP overexpressing human small cell lung cancer cells. Biochem Pharmacol 1994;48:1129-1136
CrossRef | Web of Science | Medline
- Citing Articles (81)
Citing Articles
1
Andrew M. Davidoff. (2012) Neuroblastoma. Seminars in Pediatric Surgery 21:1, 2-14
CrossRef2
S. Cho, M. Lu, X. He, P.-L. R. Ee, U. Bhat, E. Schneider, L. Miele, W. T. Beck. (2011) Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells. Proceedings of the National Academy of Sciences
CrossRef3
Donald S. Backos, Christopher C. Franklin, Philip Reigan. (2011) The role of glutathione in brain tumor drug resistance. Biochemical Pharmacology
CrossRef4
Patrick du Souich, Caroline Fradette. (2011) The effect and clinical consequences of hypoxia on cytochrome P450, membrane carrier proteins activity and expression. Expert Opinion on Drug Metabolism & Toxicology 7:9, 1083-1100
CrossRef5
G. M. Brodeur. (2011) Knowing Your ABCCs: Novel Functions of ABCC Transporters. JNCI Journal of the National Cancer Institute 103:16, 1207-1208
CrossRef6
M. J. Henderson, M. Haber, A. Porro, M. A. Munoz, N. Iraci, C. Xue, J. Murray, C. L. Flemming, J. Smith, J. I. Fletcher, S. Gherardi, C.-K. Kwek, A. J. Russell, E. Valli, W. B. London, A. B. Buxton, L. J. Ashton, A. C. Sartorelli, S. L. Cohn, M. Schwab, G. M. Marshall, G. Perini, M. D. Norris. (2011) ABCC Multidrug Transporters in Childhood Neuroblastoma: Clinical and Biological Effects Independent of Cytotoxic Drug Efflux. JNCI Journal of the National Cancer Institute 103:16, 1236-1251
CrossRef7
Wayne L. Furman, Lisa M. McGregor, M. Beth McCarville, Mihaela Onciu, Andrew M. Davidoff, Sandy Kovach, Dana Hawkins, Valerie McPherson, Peter J. Houghton, Catherine A. Billups, Jianrong Wu, Clinton F. Stewart, Victor M. Santana. (2011) A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma. Investigational New Drugs
CrossRef8
J. Gong, R. Jaiswal, J.-M. Mathys, V. Combes, G.E.R. Grau, M. Bebawy. (2011) Microparticles and their emerging role in cancer multidrug resistance. Cancer Treatment Reviews
CrossRef9
Mario Pérez-Sayáns, José Manuel Somoza-Martín, Francisco Barros-Angueira, Pilar Gayoso Diz, José Manuel Gándara Rey, Abel García-García. (2010) Multidrug resistance in oral squamous cell carcinoma: The role of vacuolar ATPases. Cancer Letters 295:2, 135-143
CrossRef10
Marie Stiborová, Jitka Poljaková, Tomáš Eckschlager, Rene Kizek, Eva Frei. (2010) DNA and histone deacetylases as targets for neuroblastoma treatment. Interdisciplinary Toxicology 3:2, 47-52
CrossRef11
Julie R. Park, Angelika Eggert, Huib Caron. (2010) Neuroblastoma: Biology, Prognosis, and Treatment. Hematology/Oncology Clinics of North America 24:1, 65-86
CrossRef12
Dieter Fuchs, Alejandro Rodriguez, Sara Eriksson, Rolf Christofferson, Christian Sundberg, Faranak Azarbayjani. (2010) Metronomic administration of the drug GMX1777, a cellular NAD synthesis inhibitor, results in neuroblastoma regression and vessel maturation without inducing drug resistance. International Journal of CancerNA-NA
CrossRef13
T. Van Maerken, L. Ferdinande, J. Taildeman, I. Lambertz, N. Yigit, L. Vercruysse, A. Rihani, M. Michaelis, J. Cinatl, C. A. Cuvelier, J.-C. Marine, A. De Paepe, M. Bracke, F. Speleman, J. Vandesompele. (2009) Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53. JNCI Journal of the National Cancer Institute 101:22, 1562-1574
CrossRef14
Takaharu Oue, Akihiro Yoneda, Shuichiro Uehara, Hiroaki Yamanaka, Masahiro Fukuzawa. (2009) Increased expression of multidrug resistance–associated genes after chemotherapy in pediatric solid malignancies. Journal of Pediatric Surgery 44:2, 377-380
CrossRef15
Evelyn Sieczkowski, Claudia Lehner, Peter F. Ambros, Martin Hohenegger. (2009) Double impact on p-glycoprotein by statins enhances doxorubicin cytotoxicity in human neuroblastoma cells. International Journal of CancerNA-NA
CrossRef16
Michelle L. Holland, John D. Allen, Jonathon C. Arnold. (2008) Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). European Journal of Pharmacology 591:1-3, 128-131
CrossRef17
Julie R. Park, Angelika Eggert, Huib Caron. (2008) Neuroblastoma: Biology, Prognosis, and Treatment. Pediatric Clinics of North America 55:1, 97-120
CrossRef18
S K Radhakrishnan, M Halasi, U G Bhat, R T Kurmasheva, P J Houghton, A L Gartel. (2008) Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells. Oncogene 27:5, 694-699
CrossRef19
Paul R. Ginkel, William Yang, Marcus M. Marcet, Clement C. Chow, Amol D. Kulkarni, Soesiawati Darjatmoko, Mary J. Lindstrom, Janice Lokken, Saswati Bhattacharya, Daniel M. Albert. (2007) 1 α-Hydroxyvitamin D2 inhibits growth of human neuroblastoma. Journal of Neuro-Oncology 85:3, 255-262
CrossRef20
Titilope A. Ishola, Dai H. Chung. (2007) Neuroblastoma. Surgical Oncology 16:3, 149-156
CrossRef21
Andy J. Cheng, Ngan Ching Cheng, Jette Ford, Janice Smith, Jayne E. Murray, Claudia Flemming, Maria Lastowska, Michael S. Jackson, Christopher S. Hackett, William A. Weiss, Glenn M. Marshall, Ursula R. Kees, Murray D. Norris, Michelle Haber. (2007) Cell lines from MYCN transgenic murine tumours reflect the molecular and biological characteristics of human neuroblastoma. European Journal of Cancer 43:9, 1467-1475
CrossRef22
Patricia de Cremoux, Nathalie Jourdan-Da-Silva, Jérôme Couturier, Carine Tran-Perennou, Gudrun Schleiermacher, Pascale Fehlbaum, François Doz, Véronique Mosseri, Olivier Delattre, Jerzy Klijanienko, Philippe Vielh, Jean Michon. (2007) Role of chemotherapy resistance genes in outcome of neuroblastoma. Pediatric Blood & Cancer 48:3, 311-317
CrossRef23
Éva Bakos, László Homolya. (2007) Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1). Pflügers Archiv - European Journal of Physiology 453:5, 621-641
CrossRef24
S. Asgharzadeh, R. Pique-Regi, R. Sposto, H. Wang, Y. Yang, H. Shimada, K. Matthay, J. Buckley, A. Ortega, R. C. Seeger. (2006) Prognostic Significance of Gene Expression Profiles of Metastatic Neuroblastomas Lacking MYCN Gene Amplification. JNCI Journal of the National Cancer Institute 98:17, 1193-1203
CrossRef25
Gentao Liu, Keith L Black, John S Yu. (2006) Sensitization of malignant glioma to chemotherapy through dendritic cell vaccination. Expert Review of Vaccines 5:2, 233-247
CrossRef26
Sunghoon Kim, Dai H. Chung. (2006) Pediatric Solid Malignancies: Neuroblastoma and Wilms' Tumor. Surgical Clinics of North America 86:2, 469-487
CrossRef27
Chie Shinoda, Muneharu Maruyama, Takashi Fujishita, Junichi Dohkan, Hirofumi Oda, Kouichirou Shinoda, Toru Yamada, Koutarou Miyabayashi, Ryuji Hayashi, Yukio Kawagishi, Tadashi Fujita, Shoko Matsui, Eiji Sugiyama, Atsushi Muraguchi, Masashi Kobayashi. (2005) Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway. International Journal of Cancer 117:1, 21-31
CrossRef28
Marina Pajic, Murray D. Norris, S.L. Cohn, Michelle Haber. (2005) The role of the multidrug resistance-associated protein 1 gene in neuroblastoma biology and clinical outcome. Cancer Letters 228:1-2, 241-246
CrossRef29
T Liu, A Bohlken, S Kuljaca, M Lee, T Nguyen, S Smith, B Cheung, M D Norris, M Haber, A J Holloway, D D L Bowtell, G M Marshall. (2005) The retinoid anticancer signal: mechanisms of target gene regulation. British Journal of Cancer 93:3, 310-318
CrossRef30
Jon Pritchard, Simon J. Cotterill, Shirley M. Germond, John Imeson, Jan de Kraker, David R. Jones. (2005) High dose melphalan in the treatment of advanced neuroblastoma: Results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatric Blood & Cancer 44:4, 348-357
CrossRef31
Sanjeev A. Vasudevan, Jed G. Nuchtern. (2005) Gene Profiling of High Risk Neuroblastoma. World Journal of Surgery 29:3, 317-324
CrossRef32
John M Maris. (2005) The biologic basis for neuroblastoma heterogeneity and risk stratification. Current Opinion in Pediatrics 17:1, 7-13
CrossRef33
L Calvet, A Santos, A Valent, M-J Terrier-Lacombe, P Opolon, J-L Merlin, G Aubert, J Morizet, J H M Schellens, J Bénard, G Vassal. (2004) No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan. British Journal of Cancer
CrossRef34
G. LUO, L. P. SAMARANAYAKE, B. P. K. CHEUNG, G. TANG. (2004) Reverse transcriptase polymerase chain reaction (RT-PCR) detection of HLP gene expression in Candida glabrata and its possible role in in vitro haemolysin production. APMIS 112:4-5, 283-290
CrossRef35
M.C Smith, M Maggi, C Orlando. (2004) Somatostatin receptors in non-endocrine tumours. Digestive and Liver Disease 36, S78-S85
CrossRef36
Keith L Lee, Jian F Ma, Linda D Shortliffe. (2003) Neuroblastoma: Management, recurrence, and follow-up. Urologic Clinics of North America 30:4, 881-890
CrossRef37
C. A. Burkhart. (2003) Effects of MYCN Antisense Oligonucleotide Administration on Tumorigenesis in a Murine Model of Neuroblastoma. CancerSpectrum Knowledge Environment 95:18, 1394-1403
CrossRef38
E.J Estlin, G.J Veal. (2003) Clinical and cellular pharmacology in relation to solid tumours of childhood. Cancer Treatment Reviews 29:4, 253-273
CrossRef39
Michael D. Hogarty. (2003) The requirement for evasion of programmed cell death in neuroblastomas with MYCN amplification. Cancer Letters 197:1-2, 173-179
CrossRef40
Etienne Blanc, David Goldschneider, Eric Ferrandis, Michel Barrois, Gwenaëlle Le Roux, Stéphane Leonce, Sétha Douc-Rasy, Jean Bénard, Gilda Raguénez. (2003) MYCN Enhances P-gp/MDR1 Gene Expression in the Human Metastatic Neuroblastoma IGR-N-91 Model. The American Journal of Pathology 163:1, 321-331
CrossRef41
Rouslan Kotchetkov, Jaroslav Cinatl, Roman Blaheta, Jens-Uwe Vogel, Jana Karaskova, Jeremy Squire, Pablo Hern
iz Driever, Thomas Klingebiel, Jindrich Cinatl. (2003) Development of resistance to vincristine and doxorubicin in neuroblastoma alters malignant properties and induces additional karyotype changes: A preclinical model. International Journal of Cancer 104:1, 36-43
CrossRef42
Markus Bredel, Josef Zentner. (2002) Brain-tumour drug resistance: the bare essentials. The Lancet Oncology 3:7, 397-406
CrossRef43
J-H Choi, H-Y Lim, H J Joo, H S Kim, J W Yi, H C Kim, Y K Cho, M W Kim, K B Lee. (2002) Expression of multidrug resistance-associated protein1,P-glycoprotein, and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection. British Journal of Cancer 86:10, 1578-1585
CrossRef44
Bryone J. Kuss, Margherita Corbo, Wen Min Lau, Dean A. Fennell, Nicholas M. Dean, Finbarr E. Cotter. (2002) In vitro andin vivo downregulation of MRP1 by antisense oligonucleotides: A potential role in neuroblastoma therapy. International Journal of Cancer 98:1, 128-133
CrossRef45
Susan P.C. Cole, Roger G. Deeley. 2002. Multidrug Resistance II: MRP and Related Proteins. , 255-267.
CrossRef46
Y Cho. (2001) Expression of multidrug resistance-related genes in oral squamous cell carcinomas. Oral Oncology 37:8, 652-659
CrossRef47
Jörg Dötsch, Reinald Repp, Wolfgang Rascher, Holger Christiansen. (2001) Diagnostic and scientific applications of TaqMan real-time PCR in neuroblastomas. Expert Review of Molecular Diagnostics 1:2, 233-238
CrossRef48
Markus Bredel. (2001) Anticancer drug resistance in primary human brain tumors. Brain Research Reviews 35:2, 161-204
CrossRef49
M.D. Norris, J. Gilbert, S.A. Smith, G.M. Marshall, H. Salwen, Susan L. Cohn, M. Haber. (2001) Expression of the putative tumour suppressor gene,p73, in neuroblastoma and other childhood tumours. Medical and Pediatric Oncology 36:1, 48-51
CrossRef50
M.D. Norris, J. Madafiglio, J. Gilbert, G.M. Marshall, M. Haber. (2001) Reversal of multidrug resistance-associated protein-mediated drug resistance in cultured human neuroblastoma cells by the quinolone antibiotic difloxacin. Medical and Pediatric Oncology 36:1, 177-180
CrossRef51
Xao X. Tang, Huaqing Zhao, Marjorie E. Robinson, Avital Cnaan, Wendy London, Susan L. Cohn, Nai-Kong V. Cheung, Garrett M. Brodeur, Audrey E. Evans, Naohiko Ikegaki. (2000) Prognostic significance ofEPHB6, EFNB2, andEFNB3 expressions in neuroblastoma. Medical and Pediatric Oncology 35:6, 656-658
CrossRef52
Hiroaki Goto, Nino Keshelava, Katherine K. Matthay, John N. Lukens, Robert B. Gerbing, Daniel O. Stram, Robert C. Seeger, C. Patrick Reynolds. (2000) Multidrug resistance-associated protein 1 (MRP1) expression in neuroblastoma cell lines and primary tumors. Medical and Pediatric Oncology 35:6, 619-622
CrossRef53
M.D. Norris, C.A. Burkhart, G.M. Marshall, W.A. Weiss, M. Haber. (2000) Expression of N-myc andMRP genes and their relationship to N-myc gene dosage and tumor formation in a murine neuroblastoma model. Medical and Pediatric Oncology 35:6, 585-589
CrossRef54
Gen-fa Shan, Hong Zhong, Fu-xian Zhang, Guo-qing Li, Guilin Long, He-ding Gu, Xiao-min Qi. (2000) Expression and prognostic significance of multidrug resistance associated protein (MRP) gene in non-small cell lung cancer by in site hybridization. Chinese Journal of Cancer Research 12:3, 216-219
CrossRef55
Frederick Alexander. (2000) NEUROBLASTOMA. Urologic Clinics of North America 27:3, 383-392
CrossRef56
Robert J. Arceci. (2000) Can multidrug resistance mechanisms be modified?. British Journal of Haematology 110:2, 285-291
CrossRef57
Frank Berthold, Barbara Hero. (2000) Neuroblastoma. Drugs 59:6, 1261-1277
CrossRef58
Carlos S. Alvarado, Wendy B. London, A. Thomas Look, Garrett M. Brodeur, Dale H Altmiller, Paul S. Thorner, Vijay V. Joshi, Susan T. Rowe, Michael B. Nash, E. Ide Smith, Robert P. Castleberry, Susan L. Cohn. (2000) Natural History and Biology of Stage A Neuroblastoma: A Pediatric Oncology Group Study. Journal of Pediatric Hematology/Oncology 22:3, 197-205
CrossRef59
David R Hipfner, Roger G Deeley, Susan P.C Cole. (1999) Structural, mechanistic and clinical aspects of MRP1. Biochimica et Biophysica Acta (BBA) - Biomembranes 1461:2, 359-376
CrossRef60
Qingcheng Mao, Elaine M. Leslie, Roger G. Deeley, Susan P.C. Cole. (1999) ATPase activity of purified and reconstituted multidrug resistance protein MRP1 from drug-selected H69AR cells. Biochimica et Biophysica Acta (BBA) - Biomembranes 1461:1, 69-82
CrossRef61
Jayne Gilbert, Michelle Haber, Sharon B. Bordow, Glenn M. Marshall, Murray D. Norris. (1999) Use of Tumor-Specific Gene Expression for the Differential Diagnosis of Neuroblastoma from Other Pediatric Small Round-Cell Malignancies. The American Journal of Pathology 155:1, 17-21
CrossRef62
T Yanagisawa, A Newman, H Coley, J Renshaw, C R Pinkerton, K Pritchard-Jones. (1999) BIRICODAR (VX-710; Incel™): an effective chemosensitizer in neuroblastoma. British Journal of Cancer 80:8, 1190-1196
CrossRef63
Gerald M. Haase, Carlos Perez, James B. Atkinson. (1999) Current aspects of biology, risk assessment, and treatment of neuroblastoma. Seminars in Surgical Oncology 16:2, 91-104
CrossRef64
Tadashi Matsunaga, Hiroshi Shirasawa, Tomoro Hishiki, Hideki Enomoto, Katsunori Kouchi, Yasuhiro Ohtsuka, Jun Iwai, Hideo Yoshida, Masahiro Tanabe, Susumu Kobayashi, Takehide Asano, Takao Etoh, Yoshisuke Nishi, Naomi Ohnuma. (1998) Expression of MRP and cMOAT in Childhood Neuroblastomas and Malignant Liver Tumors and Its Relevance to Clinical Behavior. Cancer Science 89:12, 1276-1283
CrossRef65
Sanjay Shah, Y. Ravindranath. (1998) Neuroblastoma. The Indian Journal of Pediatrics 65:5, 691-705
CrossRef66
Yvan Canitrot, Francis Bichat, Susan P.C Cole, Roger G Deeley, James H Gerlach, Gérard Bastian, Francisco Arvelo, Marie-France Poupon. (1998) Multidrug resistance genes (MRP) and MDR1 expression in small cell lung cancer xenografts: relationship with response to chemotherapy. Cancer Letters 130:1-2, 133-141
CrossRef67
Yuji Takebayashi, Shin-ichi Akiyama, Shoji Natsugoe, Shuichi Hokita, Kiyoshi Niwa, Masaki Kitazono, Tomoyuki Sumizawa, Ayako Tani, Tatsuhiko Furukawa, Takashi Aikou. (1998) The expression of multidrug resistance protein in human gastrointestinal tract carcinomas. Cancer 82:4, 661-666
CrossRef68
M HABER, S BORDOW, P HABER, G MARSHALL, B STEWART, M NORRIS. (1997) The prognostic value of MDR1 gene expression in primary untreated neuroblastoma. European Journal of Cancer 33:12, 2031-2036
CrossRef69
N KESHELAVA, R SEEGER, C REYNOLDS. (1997) Drug resistance in human neuroblastoma cell lines correlates with clinical therapy. European Journal of Cancer 33:12, 2002-2006
CrossRef70
Caroline E. Grant, Ebba U. Kurz, Susan P.C. Cole, Roger G. Deeley. (1997) Analysis of the Intron–Exon Organization of the Human Multidrug-Resistance Protein Gene (MRP) and Alternative Splicing of Its mRNA. Genomics 45:2, 368-378
CrossRef71
VIJAY V. JOSHI, GREGORY J. TSONGALIS. (1997) Correlation between Morphologic and Nonmorphologic Prognostic Markers of Neuroblastoma. Annals of the New York Academy of Sciences 824:1 Challenges an, 71-83
CrossRef72
Esther Berry, David A. Aitken, Jennifer A. Crossley, James N. Macri, J. Michael Connor. (1997) Screening for Down's syndrome: changes in marker levels and detection rates between first and second trimesters. BJOG: An International Journal of Obstetrics and Gynaecology 104:7, 811-817
CrossRef73
Masayuki Nakagawa, Akio Emoto, Nobuyoshi Nasu, Toshikatsu Hanada, Michihiko Kuwano, Susan P. C. Cole, Yoshio Nomura. (1997) Clinical Significance of Multi-Drug Resistance Associated Protein and P-Glycoprotein in Patients with Bladder Cancer. The Journal of Urology1260-1264
CrossRef74
Masayuki Nakagawa, Akio Emoto, Nobuyoshi Nasu, Toshikatsu Hanada, Michihiko Kuwano, Susan P.C. Cole, Yoshio Nomura. (1997) Clinical Significance of Multi-Drug Resistance Associated Protein and P-Glycoprotein in Patients with Bladder Cancer. The Journal of Urology 157:4, 1260-1265
CrossRef75
Roman Perez-Soler, Nouri Neamati, Yiyu Zou, Erasmus Schneider, L. Austin Doyle, Michael Andreeff, Waldemar Priebe, Yi-He Ling. (1997) Annamycin circumvents resistance mediated by the multidrug resistance-associated protein (MRP) in breast MCF-7 and small-cell lung UMCC-1 cancer cell lines selected for resistance to etoposide. International Journal of Cancer 71:1, 35-41
CrossRef76
T. Licht, F. Herrmann, M. M. Gottesman, I. Pastan. (1997) In Vivo Drug‐Selectable Genes: A New Concept in Gene Therapy. Stem Cells 15:2, 104-111
CrossRef77
Garrett M. Brodeur, John M. Maris, Darrell J. Yamashiro, Michael D. Hogarty, Peter S. White. (1997) Biology and Genetics of Human Neuroblastomas. Journal of Pediatric Hematology/Oncology 19:2, 93-101
CrossRef78
Hiroyuki Kubo, Tomoyuki Sumizawa, Keisuke Koga, Kenryu Nishiyama, Yuji Takebayashi, Yutaka Chuman, Tatsuhiko Furukawa, Shin-ichi Akiyama, Yoshitada Ohi. (1996) Expression of the multidrug resistance-associated protein (MRP) gene in urothelial carcinomas. International Journal of Cancer 69:6, 488-494
CrossRef79
Irene Bosch, James Croop. (1996) P-glycoprotein multidrug resistance and cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1288:2, F37-F54
CrossRef80
D Loe. (1996) Biology of the multidrug resistance-associated protein, MRP. European Journal of Cancer 32:6, 945-957
CrossRef81
John F. Kuttesch. (1996) Multidrug resistance in pediatric oncology. Investigational New Drugs 14:1, 55-67
CrossRef
