Amifostine prior to lethal irradiation prevents allogeneic bone marrow engraftment in mice

Thompson, John S.; Asmis, Reto; Chu, Yanxia; Glass, Judith; Nelson, Bela G; Brown, Stephen

doi:10.1038/sj.bmt.1705995

Cited by 5 publications

(7 citation statements)

References 33 publications

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“…To examine the hypothesis that, in primary cells PTDC acts as a pro-oxidant and may increase IR-induced cytotoxicity, NMSC were treated with PDTC for 2 h followed by 8 or 10 Gy IR and then incubated for an additional 2 h before analysis of viability and cytotoxicity. As expected from our previous studies [7,11], IR-alone at 8.0 Gy (P \ 0.05) and 10.0 Gy (P \ 0.001) significantly decreased survival as compared to non-IR treated cultures (Fig. 1a, b).…”

Section: Pdtc Enhances Ir-induced Cytotoxicity In Nmsc In a Dose-depesupporting

confidence: 78%

“…Not only did it not reduce IR-induced NMSC cytotoxicity but actually enhanced it. We have previously shown that equal molar concentrations of PDTC or amifostine administered 30 min before transplantation of allogeneic B6 cells into BALB/c mice led to sharply different results [7]. Whereas amifostine protected the host immune system and hematopoietic tissues allowing the mice to live, PDTC led to death shortly after transplantation.…”

Section: Discussionmentioning

confidence: 98%

“…Based on these results and the in vivo radiation induced LD 50 of 7.01 Gy and LD 100 of 8.5 Gy established in our laboratory for 8-10 week old BALB/c mice (23) and our reported results with lymphoid cells [7,21], 8.5 Gy IR was chosen for all subsequent experiments unless stated otherwise.…”

Section: Pdtc Enhances Ir-induced Cytotoxicity In Nmsc In a Dose-depementioning

confidence: 99%

“…However, there are very few agents that have proven clinically effective in reducing normal tissue injury induced by IR and cytoreductive chemotherapy. Of these, the aminothiol pro-drug amifostine is a free radical scavenger and is clinically effective in reducing ionizing radiation (IR) and chemotherapy-induced injury to normal tissues without apparently compromising their anti-tumor properties [2,[5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Pyrrolidine dithiocarbamate (PDTC) blocks apoptosis and promotes ionizing radiation-induced necrosis of freshly-isolated normal mouse spleen cells

et al. 2010

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Ionizing radiation (IR) is a pro-oxidant that kills cells by both apoptotic and necrotic mechanisms. Pyrrolidine dithiocarbamate (PDTC) is a thiol-containing compound that may act either as a pro- or anti-oxidant depending on the experimental conditions. This study was designed to determine whether PDTC would reduce or enhance IR-induced cell death of freshly-isolated normal mouse B6/129 spleen cells (NMSC). We determined the effect of increasing doses of IR, PDTC alone and PDTC followed by IR on the viability of NMSC. Annexin V and propidium iodide (Annexin V/PI) staining demonstrated a dose and time-dependent relationship in which PDTC enhanced the percentage of IR-induced apoptotic/necrotic NMSC. Trypan blue dye inclusion confirmed that a loss of membrane integrity was occurring 1 h after incubation with PDTC plus IR. Reduction in the glutathione (GSH)/glutathione disulfide (GSSG) ratio and GSH demonstrated that both IR (8.5 Gy) and PDTC acted as pro-oxidants, but their mechanisms of action differed: In contrast to IR, which promoted p53 activation and caspase 3/7-mediated apoptosis, PDTC inhibited IR-induced p53 and caspase 3/7 activity. However, PDTC increased H(2)O(2) formation and necrosis, resulting in an overall increase in IR-induced cell death. Catalase prevented the PDTC-induced increase in IR cytotoxicity implicating the generation of H(2)O(2) as a major factor in this mechanism. These results demonstrate that in NMSC PDTC acts as pro-oxidant and enhances IR-induced cell cytotoxicity by increasing H(2)O(2)formation and thiol oxidation. As such, they strongly suggest that the use of PDTC as an adjunct to reduce radiation toxicity should be avoided.

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Section: Pdtc Enhances Ir-induced Cytotoxicity In Nmsc In a Dose-depesupporting

confidence: 78%

Section: Discussionmentioning

confidence: 98%

Section: Pdtc Enhances Ir-induced Cytotoxicity In Nmsc In a Dose-depementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pyrrolidine dithiocarbamate (PDTC) blocks apoptosis and promotes ionizing radiation-induced necrosis of freshly-isolated normal mouse spleen cells

et al. 2010

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“…The peroxidase substrate Amplex Red is used to detect H 2 O 2 that has been extracellularly generated, as well as any that is produced inside the cell and has diffused out (Hole et al, 2010;Skinner et al, 2008;Thompson et al, 2008;Vlaski et al, 2014). Amplex Red can be oxidized to the fluorescent product resorufin by H 2 O 2 or other electron oxidants (e.g.…”

Section: Detection Of H 2 O 2 : Amplex Redmentioning

confidence: 99%

Reliability of ROS and RNS detection in hematopoietic stem cells − potential issues with probes and target cell population

Vlaski‐Lafarge

Ivanović

2015

Journal of Cell Science

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Many studies have provided evidence for the crucial role of the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the regulation of differentiation and/or self-renewal, and the balance between quiescence and proliferation of hematopoietic stem cells (HSCs). Several metabolic regulators have been implicated in the maintenance of HSC redox homeostasis; however, the mechanisms that are regulated by ROS and RNS, as well as their downstream signaling are still elusive. This is partially owing to a lack of suitable methods that allow unequivocal and specific detection of ROS and RNS. In this Opinion, we first discuss the limitations of the commonly used techniques for detection of ROS and RNS, and the problem of heterogeneity of the cell population used in redox studies, which, together, can result in inaccurate conclusions regarding the redox biology of HSCs. We then propose approaches that are based on single-cell analysis followed by a functional test to examine ROS and RNS levels specifically in HSCs, as well as methods that might be used in vivo to overcome these drawbacks, and provide a better understanding of ROS and RNS function in stem cells.

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Potential interactions of prescription and over‐the‐counter medications having antioxidant capabilities with radiation and chemotherapy

Lemmo¹

2014

Intl Journal of Cancer

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Oncology patients undergoing radiation treatment and chemotherapy routinely use prescription and/or over‐the counter medications either as part of pre‐existing comorbid conditions or in the context of conventional treatment management. A growing amount of data suggest that commonly used pharmaceuticals possess antioxidant properties, which may also partially explain some of their therapeutic efficacy. Clinical research is continuing on how such agents interact during chemotherapy and radiation when oxidative mechanisms of action are involved. Historically, such discussions centered on the category of dietary supplements, natural health products, fruits and vegetables, along with established protectant medications. Evidence confirms that some pharmaceutical agents exhibit antioxidant properties similar to dietary supplements, protectants, and may hence hinder the efficacy of chemotherapy and radiation treatment. Awareness by both healthcare providers and patients in this area is often lacking. After reviewing some of the more common and well‐established pharmaceuticals, which include those prescribed during cancer treatment, caution needs to be advised especially in regards to the use of corticosteroids, as long‐term randomized outcome studies ensuring safety in this area are still outstanding.

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Amifostine prior to lethal irradiation prevents allogeneic bone marrow engraftment in mice

Cited by 5 publications

References 33 publications

Pyrrolidine dithiocarbamate (PDTC) blocks apoptosis and promotes ionizing radiation-induced necrosis of freshly-isolated normal mouse spleen cells

Pyrrolidine dithiocarbamate (PDTC) blocks apoptosis and promotes ionizing radiation-induced necrosis of freshly-isolated normal mouse spleen cells

Reliability of ROS and RNS detection in hematopoietic stem cells − potential issues with probes and target cell population

Potential interactions of prescription and over‐the‐counter medications having antioxidant capabilities with radiation and chemotherapy

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