A randomized study comparing interferon (IFNα) plus low-dose cytarabine and interferon plus hydroxyurea (HU) in early chronic-phase chronic myeloid leukemia (CML)

Kühr, Thomas; Burgstaller, Sonja; Apfelbeck, Ute; Linkesch, Werner; Seewann, H. L.; Fridrik, Michael A.; Michlmayr, G.; Krieger, O.; Lutz, D.; Lin, Werner; Pont, Jörg; Köck, L.; Abbrederis, K; Baldinger, C.; Buder, R; Geissler, Dietmar; Hausmaninger, H.; Lang, Alois; Zabernigg, August; Duba, Christoph; Hilbe, Wolfgang; Eisterer, Wolfgang; Fiegl, Michael; Greil, Richard; Gastl, Guenther; Thaler, Josef

doi:10.1016/s0145-2126(02)00223-0

Cited by 22 publications

(10 citation statements)

References 12 publications

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“…HU has been used for over 40 years as an antitumor/cytostatic drug and is a frequently used medication for cytoreduction (18). For example, patients treated for chronic myelogenous leukemia can be treated with an oral HU regimen resulting in average plasma concentrations in the 100 to 200 M range (45), which is similar to concentrations employed in our experiments (100 to 150 M). Although when used as a single agent HU treatment has not been associated with increased cancer risk (96), patients treated with chemotherapeutic regimens that include VP16 are at increased risk of treatment-related acute myeloid leukemia (67).…”

supporting

confidence: 69%

p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress

Marusyk

Wheeler

Mathews

et al. 2007

Molecular and Cellular Biology

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Previous studies have shown that exposure of cells to high levels of replicational stress leads to permanent proliferation arrest that does not require p53. We have examined cellular responses to therapeutically relevant low levels of replicational stress that allow limited proliferation. Chronic exposure to low concentrations of hydroxyurea, aphidicolin, or etoposide induced irreversible cell cycle arrest after several population doublings. Inhibition of p53 activity antagonized this arrest and enhanced the long-term proliferation of p53 mutant cells. p21 CIP1 was found to be a critical p53 target for arrest induced by hydroxyurea or aphidicolin, but not etoposide, as judged by the ability of p21 CIP1 suppression to mimic the effects of p53 disruption. Suppression of Rad51 expression, required for homologous recombination repair, blocked the ability of mutant p53 to antagonize arrest induced by etoposide, but not aphidicolin. Thus, the ability of mutant p53 to prevent arrest induced by replicational stress per se is primarily dependent on preventing p21 CIP1 up-regulation. However, when replication stress is associated with DNA strand breaks (such as with etoposide), up-regulation of homologous recombination repair in response to p53 disruption becomes important. Since replicational stress leads to clonal selection of cells with p53 mutations, our results highlight the potential importance of chronic replicational stress in promoting cancer development.

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supporting

confidence: 69%

p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress

Marusyk

Wheeler

Mathews

et al. 2007

Molecular and Cellular Biology

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“…Common plasma levels of HU range 100–200 μM [261]. It is used for the treatment of sickle cell disease, essential thrombocytosis [262], myeloproliferative disorders and psoriasis [260] and is commonly indicated as a cytoreductive treatment in polycythemia vera [263] and others.…”

Section: Compoundsmentioning

confidence: 99%

“…Lower concentrations are used for RS induction [254], induction of senescence [74], apoptosis [257], and repair pathways induction [217]. HU reaches plasma concentrations around 0.1 mM; this should be bear in mind when interpreting the data for clinical relevance [261]. The MRN (Mre11-Rad50-Nbs1) complex members Mre11 (Meiotic recombination 11) and Nbs1 (Nijmegean breakage syndrome 1) are required for efficient recovery of replication after treatment with replication stalling agents such as hydroxyurea [12].…”

Section: Compoundsmentioning

confidence: 99%

Common Chemical Inductors of Replication Stress: Focus on Cell‐Based Studies

et al. 2017

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DNA replication is a highly demanding process regarding the energy and material supply and must be precisely regulated, involving multiple cellular feedbacks. The slowing down or stalling of DNA synthesis and/or replication forks is referred to as replication stress (RS). Owing to the complexity and requirements of replication, a plethora of factors may interfere and challenge the genome stability, cell survival or affect the whole organism. This review outlines chemical compounds that are known inducers of RS and commonly used in laboratory research. These compounds act on replication by direct interaction with DNA causing DNA crosslinks and bulky lesions (cisplatin), chemical interference with the metabolism of deoxyribonucleotide triphosphates (hydroxyurea), direct inhibition of the activity of replicative DNA polymerases (aphidicolin) and interference with enzymes dealing with topological DNA stress (camptothecin, etoposide). As a variety of mechanisms can induce RS, the responses of mammalian cells also vary. Here, we review the activity and mechanism of action of these compounds based on recent knowledge, accompanied by examples of induced phenotypes, cellular readouts and commonly used doses.

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“…3 Before the introduction of imatinib, IFN-␣-based regimens were preferred for upfront treatment of patients not eligible for allogeneic stem cell transplantation. [4][5][6][7] In vitro, IFN-␣ has a synergistic effect in combination with imatinib. 8 IFN-␣ is, however, barely detectable in the serum 24 hours after its administration, thus warranting frequent administration (daily to 2 or 3 times weekly) for sustained efficacy.…”

Section: Introductionmentioning

confidence: 99%

Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

Simonsson

Gedde‐Dahl

Markevärn

et al. 2011

Blood

172

121

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Biologic and clinical observations suggest that combining imatinib with IFN-␣ may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN␣2b (Peg-IFN-␣2b) 50 g weekly and imatinib 400 mg daily (n ‫؍‬ 56) or to receive imatinib 400 mg daily monotherapy (n ‫؍‬ 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-␣2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-␣2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P ‫؍‬ .002). The MMR rate increased with the duration of Peg-IFN␣2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-␣2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-␣2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent. (Blood. 2011;118(12):3228-3235)

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A randomized study comparing interferon (IFNα) plus low-dose cytarabine and interferon plus hydroxyurea (HU) in early chronic-phase chronic myeloid leukemia (CML)

Cited by 22 publications

References 12 publications

p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress

p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress

Common Chemical Inductors of Replication Stress: Focus on Cell‐Based Studies

Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

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