Amifostine has the potential to induce haematologic responses and decelerate disease progression in individual patients with low- and intermediate-1-risk myelodysplastic syndromes

Schanz, Julie; Jung, Heike; Wörmann, Bernhard; Gaßmann, W.; Petersen, Thomas; Hinke, Axel; Haase, Detlef

doi:10.1016/j.leukres.2009.03.027

Cited by 9 publications

(4 citation statements)

References 23 publications

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“…149 Unlike the pro-oxidant approach, the effects of reducing ROS using antioxidant therapy has not been extensively investigated in leukemias, however, patients with lowto intermediate-risk MDS did appear to benefit from treatment with the aminothiol prodrug, amifostine. 150 Another study demonstrated a trend of longer clinical progression-free survival and overall survival in CML patients when they were treated with vitamin A in combination with standard chemotherapy, although this trend was not significant. 151 A recent review conducted by Block et al examined the effect of combined antioxidant/chemotherapy treatment in patients with a variety of cancers in 19 randomized clinical trials.…”

Section: Is There a Case For Targeting Ros In Myeloid Disease?mentioning

confidence: 99%

Do reactive oxygen species play a role in myeloid leukemias?

Hole

Darley

Tonks

2011

Blood

216

196

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Reactive oxygen species (ROS) are a heterogeneous group of molecules that are generated by mature myeloid cells during innate immune responses, and are also implicated in normal intracellular signaling. Excessive production of ROS (and/or a deficiency in antioxidant pathways) can lead to oxidative stress, a state that has been observed in several hematopoietic malignancies including acute and chronic myeloid leukemias (AML and CML). Currently it is unclear what the cause of oxidative stress might be and whether oxidative stress contributes to the development, progression, or maintenance of these diseases. This article reviews the current evidence suggesting a role for ROS both in normal hematopoiesis and in myeloid leukemogenesis, and discusses the usefulness of therapeutically targeting oxidative stress in myeloid malignancy. (Blood. 2011;117(22):5816-5826) IntroductionOver the past 15 years, there has been a growing appreciation that reactive oxygen species (ROS) production plays an important role in a variety of cellular processes, in addition to their antimicrobial role during phagocytosis by cells of the innate immune system. Specifically, ROS generated by the mitochondria or nicotinamide adenine dinucleotide phosphate (NADPH) oxidases have been shown to influence cell-cycle progression, cell motility, and growth factor signaling in a variety of normal cell types. 1 Many pathologic states are accompanied by excessive cellular ROS production and/or a deficiency in antioxidant defenses, leading to a state known as oxidative stress. 2 Evidence for chronic oxidative stress has been found in many cancers, both in solid tumors such as prostate carcinoma 3 and melanoma 4 and in several hematopoietic malignancies including acute lymphoblastic leukemia (ALL), 5 myelodysplastic syndrome (MDS), 6 and myeloid leukemias including chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). 7 The importance of the association between oxidative stress and malignancy is not currently clear; however, there is evidence that tumor-derived ROS may promote cell survival, 8-10 migration and metastasis, 11,12 proliferation, 13,14 and even drug-resistance, 15 depending on the origin of the cancer. These observations suggest that oxidative stress may subvert the normal roles of ROS so as to benefit the malignant clone.In the context of AML, a recent report indicates that relapse in this disease is associated with increased markers of oxidative stress within the leukemic blasts, suggesting that ROS production may be an important factor in AML progression. 16 Indeed, recent published data from our group suggest that constitutively active Ras (one of the most common abnormalities detected in AML) is capable of driving ROS production in CD34 ϩ human hematopoietic progenitor cells, and this significantly contributes to the mutant Ras phenotype. 17 Furthermore, ROS production appears to contribute to proliferation and migration of hematopoietic cells expressing a variety of oncogenic tyrosine kinases. 18 Thus, increased oxidative s...

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Section: Is There a Case For Targeting Ros In Myeloid Disease?mentioning

confidence: 99%

Do reactive oxygen species play a role in myeloid leukemias?

Hole

Darley

Tonks

2011

Blood

216

196

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“…Amifostine is converted to its active metabolite (WR-1065) after dephosphorylation by alkaline phosphatase, an enzyme presents at higher relative concentrations in normal cells, therefore higher levels of the active WR-1065 metabolite accumulate in non-neoplastic tissue [216, 217]. Amifostine protects primitive hematopoietic progenitors against chemotherapy cytotoxicity [184], suppresses apoptosis in AML/MDS patients [187] and has been used in the management of MDS [188]. In normal bone marrow progenitors, amifostine stimulates the growth of granulocyte, erythroid, macrophage, megakaryocyte colony-forming units and erythroid bursts and inhibits apoptosis in cytokine-deficient conditions [185].…”

Section: Redox Active Drugs Used For Differentiation/redox Therapymentioning

confidence: 99%

Oxidative stress, redox regulation and diseases of cellular differentiation

Zhang

Townsend

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

216

142

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Background Within cells, there is a narrow concentration threshold that governs whether reactive oxygen species (ROS) induce toxicity or act as second messengers. Scope of review We discuss current understanding of how ROS arise, facilitate cell signaling, cause toxicities and disease related to abnormal cell differentiation and those (primarily) sulfur based pathways that provide nucleophilicity to offset these effects. Primary conclusions Cellular redox homeostasis mediates a plethora of cellular pathways that determine life and death events. For example, ROS intersect with GSH based enzyme pathways to influence cell differentiation, a process integral to normal hematopoiesis, but also affecting a number of diverse cell differentiation related human diseases. Recent attempts to manage such pathologies have focused on intervening in some of these pathways, with the consequence that differentiation therapy targeting redox homeostasis has provided a platform for drug discovery and development. General Significance The balance between electrophilic oxidative stress and protective biomolecular nucleophiles predisposes the evolution of modern life forms. Imbalances of the two can produce aberrant redox homeostasis with resultant pathologies. Understanding the pathways involved provides opportunities to consider interventional strategies.

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“…They also found that the expression of PRX I and PRX II was upregulated, while that of Trx1 was downregulated upon CKI administration. Meanwhile, the hematological parameters of patients with low- to intermediate-risk MDS can be improved by amifostine [ 245 , 246 ]. Notably, antioxidants combined with specific chemotherapeutic agents result in positive benefits and improved patient survival.…”

Section: Is Targeting Ros For Mds Therapy Feasible?mentioning

confidence: 99%

Role of reactive oxygen species in myelodysplastic syndromes

Jing,

Zhou,

Zhang

et al. 2024

Cell Mol Biol Lett

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Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy. Graphical Abstract

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Amifostine has the potential to induce haematologic responses and decelerate disease progression in individual patients with low- and intermediate-1-risk myelodysplastic syndromes

Cited by 9 publications

References 23 publications

Do reactive oxygen species play a role in myeloid leukemias?

Do reactive oxygen species play a role in myeloid leukemias?

Oxidative stress, redox regulation and diseases of cellular differentiation

Role of reactive oxygen species in myelodysplastic syndromes

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