Clinical implications of glucocorticoid receptor studies in childhood acute lymphoblastic leukemia

Mastrangelo, Renato; Malandrino, Renee; Riccardi, Riccardo; Longo, Paola; Ranelletti, F O; Iacobelli, Stéfano

doi:10.1182/blood.v56.6.1036.1036

Cited by 66 publications

(9 citation statements)

References 9 publications

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“…For a detailed summary of these studies, please refer to the review of Kaspers et al (1994a). Several authors studying the relationship between GR expression and clinical response to GCs or multiagent therapy found that a lower number of receptors per cell was associated with poor treatment response (Mastrangelo et al , 1980; Costlow et al , 1982; Pui et al , 1984; Quddus et al , 1985; Iacobelli et al , 1987), but this was not always confirmed (Homo et al , 1980). A large overlap between receptor expression in poor and good responders was observed (Quddus et al , 1985).…”

Section: The Glucocorticoid Receptormentioning

confidence: 99%

“…A large overlap between receptor expression in poor and good responders was observed (Quddus et al , 1985). In addition, the cut‐off values of GR expression used in the different studies to define groups with poor and good prognosis varied considerably [from 4000 receptors/cell by Mastrangelo et al (1980) to 16 000/cell by Costlow et al (1982)]. With improvements in treatment protocols, the prognostic value of GR levels disappeared (Pui et al , 1984).…”

Section: The Glucocorticoid Receptormentioning

confidence: 99%

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Glucocorticoid resistance in childhood leukaemia: mechanisms and modulation

2003

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Section: The Glucocorticoid Receptormentioning

confidence: 99%

Section: The Glucocorticoid Receptormentioning

confidence: 99%

Glucocorticoid resistance in childhood leukaemia: mechanisms and modulation

2003

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“…The finding that T-and B-ALL are relatively resistant to Pred correlates well with the fact that the number of glucocorticoid receptors are low in these phenotypes [17,18]. Low number of receptors usually implicate a Pred resistance but high numbers do not guarantee a response to this drug [19][20][21]. Therefore, studies to Pred resistance should incorporate a drug resistance assay, e.g., the MTT assay because this measures cell lysis which is the endpoint of all mechanisms of resistance instead of only the presence of receptors.…”

Section: Lmmunophenotype and Drug Resistancementioning

confidence: 95%

Clinical relevance of in vitro drug resistance testing in childhood acute lymphoblastic leukemia: The state of the art

Pieters

Kaspers

Klumper

et al. 1994

Med. Pediatr. Oncol.

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Nowadays about two-thirds of children with acute lymphoblastic leukemia (ALL) can be cured with chemotherapy, but one-third die from the disease. The clinical response of leukemic cells to chemotherapy is roughly due to two factors: the effective drug levels reaching the cells and the resistance of these cells to the drugs. The clinical value of cellular drug resistance in children with ALL is not known. We developed an in vitro assay to study drug resistance in these children. In this article, the main results obtained with this MTT assay on samples from 137 children with ALL are summarized: (1) patients whose cells are resistant to several drugs at initial diagnosis have a poor prognosis; (2) relapsed leukemias show a considerable drug resistance which might partly explain the poor prognosis. Relapsed cases differ in their type and degree of resistance; (3) the poor outcome of high risk groups as defined by age and immunophenotype can partly be explained by specific patterns of drug resistance; (4) P-glycoprotein-mediated multidrug resistance is not an important cause of resistance in childhood ALL; and (5) no relation exists between the activities of the purine enzymes HGPRT, 5'NT, ADA, and PNP and drug resistance in childhood ALL. The conclusion is that in vitro drug resistance data have clinical relevance and can be used to develop more effective and less toxic treatment strategies in childhood ALL.

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“…Small reductions in GR protein levels significantly affect GC response (Costlow et al, 1982;Gruber et al, 2009), thus the effect of GR expression levels on GC sensitivity has been extensively studied. While some studies report a correlation between quantitative expression of the GR and ligand binding on GC sensitivity (Mastrangelo et al, 1980;Marchetti et al, 1981;Pui et al, 1984;Tissing et al, 2005a), others do not confirm this association (Homo et al, 1980;Lauten et al, 2003a). However, it may be that a threshold GR level is needed for dexamethasone response and that higher levels confer no increased GC sensitivity.…”

Section: Mechanisms Of Dexamethasone Resistancementioning

confidence: 99%

Personalization of dexamethasone therapy in childhood acute lymphoblastic leukaemia

2016

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Dexamethasone is a key component in the treatment of childhood acute lymphoblastic leukaemia (ALL). Despite playing a key role in the improved survival of ALL over several decades, intensification of dexamethasone therapy has also contributed to the increased toxicity associated with treatment, which is now seen to be at unacceptable levels given the favourable disease prognosis. Therefore the focus for treatment is now shifting towards reducing toxicity whilst maintaining current survival rates. As approximately 50% of patients were successfully treated on less intensive protocols of the 1980s, it has been questioned whether therapy intensification is necessary in all patients. Furthermore, there remains a subset of children who are still not cured of their disease. New strategies are therefore needed to identify patients who could benefit from dose reduction or intensification. However, adjusting a potentially life threatening therapy is a challenging task, particularly given the heterogeneous nature of ALL. This review focuses on the potential for patient stratification based on our current knowledge of dexamethasone pharmacokinetics, pharmacogenetics and the action of dexamethasone at the cellular level. A carefully designed, combined approach is needed if we are to achieve the aim of improved personalization of dexamethasone therapy for future patients.

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Clinical implications of glucocorticoid receptor studies in childhood acute lymphoblastic leukemia

Cited by 66 publications

References 9 publications

Glucocorticoid resistance in childhood leukaemia: mechanisms and modulation

Glucocorticoid resistance in childhood leukaemia: mechanisms and modulation

Clinical relevance of in vitro drug resistance testing in childhood acute lymphoblastic leukemia: The state of the art

Personalization of dexamethasone therapy in childhood acute lymphoblastic leukaemia

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