Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase π gene expression in primary and relapsed state adult and childhood leukaemias

Gekeler, Volker; Frese, Gerd; Noller, A.; Handgretinger, Rupert; Wilisch, A; Schmidt, Helmuth; Müller, C.; Dopfer, R.; Klingebiel, Thomas; Diddens, H.

doi:10.1038/bjc.1992.304

Cited by 88 publications

(42 citation statements)

References 39 publications

(42 reference statements)

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“…These results show that analysis of TOP2A gene at the RNA level is as sensitive as DNA analysis. However, as reported in previous studies, 43,45 we also found large interpatient variations in TOP2A gene expression levels, suggesting that in addition to a simple increase in TOP2A gene copy number, transcriptional and/or post-transcriptional regulation mechanisms might also be implicated in the increased expression of TOP2A gene in ALL cells.…”

Section: Discussionmentioning

confidence: 47%

“…This result confirms previous reports tending to show lower TOP2A gene expression levels in primary AML compared to human Tlymphoblastoid cell lines as controls. 43,46 In our cohort of ALL patients, we also identified a small population of children, around 20%, in which TOP2A gene is not amplified or overexpressed and which, remarkably, tends to correspond to most of the VHR patients exhibiting glucocorticoid resistance. This information, which can be rapidly and easily available at the day of diagnosis through the molecular analysis of TOP2A gene, represents a complementary and independent factor that can be useful for a better and faster characterization of VHR patients.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, expression levels were often indicated as percentages of the value found in a particular cell line chosen as a standard, hampering the exact quantification of gene expression level in blast cells. [43][44][45][46] In two other studies performed on clinical samples of untreated childhood ALL, topoisomerase II expression level was determined with rather low-sensitive techniques such as immunocytochemistry or dot-blot hybridization, although the results were substantiated in some cases by semi-quantitative RT-PCR assays. 47,48 Finally, none of these studies evaluated the precise status of topoisomerase genes at the DNA level.…”

Section: Discussionmentioning

confidence: 99%

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Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

et al. 2003

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Topoisomerase genes were analyzed at both DNA and RNA levels in 25 cases of newly diagnosed childhood acute lymphoblastic leukemia (ALL). The results of molecular analysis were compared to risk group classification of children in order to identify molecular characteristics associated with response to therapy. At diagnosis, allelic imbalance at topoisomerase IIa (TOP2A) gene locus was found in 75% of informative cases whereas topoisomerase I and IIb gene loci are altered in none or only one case, respectively. By semiquantitative Polymerase chain reaction, we found a 2.5 to 8-fold TOP2A gene amplification in 72% of the children, which was correlated to gene overexpression in every case. These results show that TOP2A gene amplification is a frequent event in ALL at diagnosis. Interestingly, we also identified a small population of children that do not present TOP2A gene amplification or gene overexpression and who are significantly associated with very high risk classified patients showing glucocorticoid resistance. In conclusion, characterization of TOP2A gene status in childhood ALL at diagnosis provides useful complementary information for risk assessment.

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

et al. 2003

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“…Because of its physiological function GST-i expression was found in all samples at a low level so that only patients with moderate or intensive staining were considered to be positive for GST-7c overexpression. Gekeler et al (1992) reported moderate GST levels in patients with the initial stage of ALL and with relapsed ALL at the mRNA levels when compared with the cell line CCRF-CEM.…”

Section: Discussionmentioning

confidence: 99%

P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia

Sauerbrey

Zintl²,

Volm³

1994

Br J Cancer

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Summary Blast cells obtained from 104 children with untreated acute lymphoblastic leukaemia were analysed for the expression of P-glycoprotein (P-170) and glutathione S-transferase (GST-it) using immunohistochemistry. Expression of P-170 was detected in 36 of 104 patients (35%) and increased GST-i was seen in 52 patients (50%). Coexpression of both resistance proteins was observed in 22 leukaemias (21 %), whereas no evidence of the resistance markers was found in 38 cases (37%). In patients with P-170-positive leukaemic cells, a significantly lower probability of remaining in first continuous complete remission (CCR) was observed when compared with patients with P-I 70-negative tumours (P < 0.05J. However, only a trend for a more frequent expression of P-170 was found in the leukaemic cells of patients who experienced relapses (P = 0.099). Overexpression of GST-i was correlated with a higher relapse rate (P = 0.001) and a lower probability of remaining in first CCR (P = 0.01). Expression of P-170 and GST-i was independent of sex, FAB type, immunological subtype and initial blast cell count. The multivariate analysis indicated that only the expression of P-170 is an unfavourable prognostic factor for children with acute lymphoblastic leukaemia in addition to the prognostic clinical factors.The results of chemotherapy on childhood acute lymphoblastic leukaemia (ALL) have been markedly improved during the past decade (Riehm et al., 1992). The remission rate of patients treated with chemotherapy is more than 95%, and the long-term disease-free survival rate about 75%. In spite of these excellent results, 25% of the patients will experience a relapse with a poor prognosis. The search for risk factors to define patients at high risk of relapse who need a different or more aggressive therapy is thus a current problem.

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“…Gekeler et al, 1992;Ishikawa et al, 1993;Beck et al, 1994;Kaufmann et al, 1994;Larsson et al, 1994;McKenna et al, 1994). However, recently more information has become available on Topo-II levels in solid tumours or in primary cultures of solid tumours (e.g.…”

Section: Discussionmentioning

confidence: 99%

DNA topoisomerase IIα and -β expression in human ovarian cancer

Withoff

Zee²,

Jong

et al. 1999

Br J Cancer

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To study DNA topoisomerase IIα (Topo-IIα) and -β expression and regulation in human ovarian cancer, 15 ovarian tumour samples were investigated. To compare different levels of expression, the samples were screened for topo IIα and -β mRNA with Northern blotting and a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay for Topo-IIα mRNA. Additionally, protein levels were determined with Western blotting and topoisomerase II activity levels with the decatenation assay. The results obtained were compared with each other and with the tumour volume index of the samples. In tumours with a tumour volume index ≥ 50%, the mRNA levels (as determined by Northern blotting) and protein levels for each isozyme were in accordance. Additionally, correlations were found between Topo-IIα RT-PCR data and Topo-IIα Northern blot results, and between Topo-IIα RT-PCR data and Topo-IIα protein levels. Interestingly, Topo-IIβ protein levels correlated better with Topo-II activity than Topo-IIα protein levels. In eight ovarian cystadenoma samples, no Topo-IIα protein could be found. In only three out of eight of these cystadenomas, Topo-IIβ protein could be detected. These findings suggest that Topo-IIα and Topo-IIβ protein levels are up-regulated in ovarian cancer and may indicate that Topo-IIβ is an interesting target for chemotherapy in ovarian tumours. © 1999 Cancer Research Campaign

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Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase π gene expression in primary and relapsed state adult and childhood leukaemias

Cited by 88 publications

References 39 publications

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia

DNA topoisomerase IIα and -β expression in human ovarian cancer

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