Cell proliferation is related to in vitro drug resistance in childhood acute leukaemia

Kaaijk, Patricia; Kaspers, Gertjan J. L.; Wering, E. R. Van; Broekema, G J; Loonen, A. H.; Hählen, K.; Schmiegelow, Kjeld; Janka-Schaub, G. E.; Henze, Günter; Creutzig, Ursula; Veerman, A. J. P.

doi:10.1038/sj.bjc.6600787

Cited by 34 publications

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“…This is in accordance with the general notion of a correlation between high proliferation and increased anticancer drug sensitivity (Valeriote and van Putten, 1975;Kaaijk et al, 2003). Some limitations of the study should be discussed.…”

Section: Discussionsupporting

confidence: 89%

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

et al. 2005

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Acquired drug resistance is a major problem in cancer treatment. To explore the genes involved in chemosensitivity and resistance, 10 human tumour cell lines, including parental cells and resistant subtypes selected for resistance against doxorubicin, melphalan, teniposide and vincristine, were profiled for mRNA expression of 7400 genes using cDNA microarray technology. The drug activity of 66 cancer agents was evaluated on the cell lines, and correlations between drug activity and gene expression were calculated and ranked. Hierarchical clustering of drugs based on their drug -gene correlations yielded clusters of drugs with similar mechanism of action. Genes correlated with drug sensitivity and resistance were imported into the PathwayAssist software to identify putative molecular pathways involved. A substantial number of both proapoptotic and antiapoptotic genes such as signal transducer and activator of transcription 1, mitogen-activated protein kinase 1 and focal adhesion kinase were found to be associated to drug resistance, whereas genes linked to cell cycle control and proliferation, such as cell division cycle 25A and signal transducer of activator of transcription 5A, were associated to general drug sensitivity. The results indicate that combined information from drug activity and gene expression in a resistance-based cell line panel may provide new knowledge of the genes involved in anticancer drug resistance and become a useful tool in drug development.

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Section: Discussionsupporting

confidence: 89%

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

et al. 2005

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“…Interestingly, it has been noted earlier that the proportion of cycling cells is increased in relapsed versus initial ALL (28). Our data now reveal that this mainly applies to very early relapse, whereas late relapse displays an even lower fraction of cycling cells in the bone marrow than samples at first presentation (median, 3.9% S phase cells at late relapse versus 6.9% at first presentation in the study of Kaaijk et al;ref.…”

Section: Discussionsupporting

confidence: 46%

“…At ALL relapse, however, we consider leukemic blasts that have escaped frontline treatment and progressed in malignancy reflected by higher rates of poor or nonresponse to treatment in particular in very early relapsed patients (4). Accordingly, higher proportions of cycling cells did not correlate with in vitro chemosensitivity at ALL relapse (28). At relapse, leukemic blasts may have gained signaling pathways that enable a more aggressive growth of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…28 and references therein). However, in in vitro experiments, an increased proliferation rate was associated with good response to treatment (28).…”

Section: Discussionmentioning

confidence: 99%

“…28 and references therein). However, in in vitro experiments, an increased proliferation rate was associated with good response to treatment (28). In initial ALL, a higher fraction of proliferating cells seems to result in a higher efficacy of chemotherapeutic drugs targeting the cell division cycle.…”

Section: Discussionmentioning

confidence: 99%

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Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Kirschner-Schwabe

Lottaz

Tödling

et al. 2006

Clinical Cancer Research

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Purpose: In childhood acute lymphoblastic leukemia (ALL), f25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood. Experimental Design: Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Mu« nster study group. Results: We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern.We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G 2 -M phase cells and this correlated well with the expression level of cell cycle genes. Conclusions: Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes.The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis.Acute lymphoblastic leukemia (ALL) is the most common malignant disease in children (1). Although event-free survival rates range between 70% and 75%, relapse of ALL remains the fourth most frequent diagnosis in childhood cancer affecting 25% of ALL patients (2). At relapse, overall cure rates of f40% remain unsatisfactory and survival rates are particularly poor in certain subgroups (3). Treatment of relapse usually implies intensified polychemotherapy containing high-dose elements. Although in most children, second remissions can be induced high-risk patients require further treatment intensification by stem cell transplantation. Stem cell transplantation provides a better relapse-free survival rate than chemotherapy alone but is also associated with higher treatment-related morbidity and mortality rates (2). Thus, alternative treatment strategies are needed to improve the treatment and outcome of patients with relapsed ALL.In the treatment of ALL relapse, intensity of chemotherapy and stem cell transplantation are indicated by well-established prognostic factors (summarized in ref.2), with the most evident being the time to relapse. Early recurrence of disease with respect to frontline therapy affects f60% of patients and is associated with a high rate of nonresponse to treatment, shorter duration of second ...

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Development of multidrug resistance due to multiple factors including P‐glycoprotein overexpression under K‐selection after MYC and HRAS oncogene activation

Nakamura

Satō

Motokura

2006

Intl Journal of Cancer

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Multistep tumorigenesis is a form of microevolution consisting of mutation and selection. To clarify the role of selection modalities in tumor development, we examined two alternative evolutionary conditions, r-selection in sparse culture, which allows cells to proliferate rapidly, and K-selection in confluent culture, in which overcrowding constrains cell proliferation. Using MYC-and EJ-RAS-transformed rat embryo fibroblasts, we found that K-selected cells acquired and stably maintained multidrug resistance (MDR) to DOX, VCR, MTX and Ara-C. Then, we examined the involvement of a number of factors potentially causal of the development of MDR, that is, ploidy, Tp53 mutation, doubling time and the expression levels of genes related to drug resistance. Although ploidy status and Tp53 mutations did not correlate with MDR, we found that Abcb1/Mdr1, encoding P-glycoprotein (Pgp), was significantly upregulated after K-selection. Cyclosporin A, a competitive inhibitor of Pgp, increased the intracellular accumulation of DOX and reduced the resistance to it. Indeed, the population of Pgp-transfected cells significantly expanded under K-, but not under r-selection. In addition to Pgp upregulation, altered expression of other genes such as Cda/cytidine deaminase and Slc29a1/equilibrative nucleoside transporter 1 and prolonged doubling times were associated with MDR. This system reproduces events associated with MDR in vivo and would be useful for analysis of MDR development. ' 2005 Wiley-Liss, Inc.Key words: natural selection; drug resistance; multistep tumorigenesis; clonal evolution While the original Darwinian theory of natural selection explains the evolution of species during millions of years, the theory has also been applied to explain the development of cancer, which occurs over a period of years, which is often called microevolution. Foulds proposed a theory of multistep tumorigenesis according to which a cancer originates from one single cell, from which a tumor develops in a stepwise fashion through qualitatively different stages. 1 Nowell further proposed that multistep tumorigenesis consists of mutation and selection, resulting in successive clonal evolution. 2 In recent years, numerous molecular events associated with the multistep tumorigenesis have been identified. 3 Although the functional involvement of these molecular events in tumorigenesis has been extensively investigated, what types of selection modalities contribute to cancer development is still not well understood.A rodent cell culture system was shown to recapitulate a variety of events frequently encountered in human tumors, such as the emergence of polyploid cells and genetic aberrations such as TP53 gene mutations. 4 We have been investigating the roles of different selection processes using such a culture system of rat embryo fibroblasts (REFs) transformed with MYC and activated HRAS (EJ-RAS) oncogenes. 5 Using this culture system, we previously applied two selection modalities, r-and K-selection, which were originally defined by MacArthur an...

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Cell proliferation is related to in vitro drug resistance in childhood acute leukaemia

Cited by 34 publications

References 37 publications

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Development of multidrug resistance due to multiple factors including P‐glycoprotein overexpression under K‐selection after MYC and HRAS oncogene activation

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