Amifostine (WR-2721) selective protection against melphalan genotoxicity

Buschini, Annamaria; Anceschi, Elena; Carlo‐Stella, Carmelo; Regazzi, Ester; Rizzoli, Vittorio; Poli, Paola; Rossi, Carlo

doi:10.1038/sj.leu.2401877

Cited by 21 publications

(13 citation statements)

References 59 publications

(67 reference statements)

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“…The observed CR conversion rate is not inconsistent with in vitro observations, suggesting that amifostine may lead to sensitisation of malignant cells, resulting in an enhanced likelihood of genotoxicity following subsequent exposure to melphalan. 34 Overall, as expected, the impact of attaining CR was highly significant with a median PFS for patients in CR post-ASCT of 30 months, but only 17 months for the remainder (P ¼ 0.003).…”

Section: Discussionsupporting

confidence: 70%

“…It may be that reductions in supportive care may only be demonstrable when amifostine is used in combination with regimens associated with more prolonged and/or severe gastrointestinal toxicity, for example, melphalan 220 mg/m 2 or multi-agent high-dose chemotherapeutic regimens such as HD-VIC 9,20 Work undertaken combining amifostine pre-and posttreatment with carboplatin in patients with various cancers has demonstrated a reduction in dose-limiting thrombocytopenia despite enhanced drug delivery 31,32 Likewise, the severity and duration of neutropenia secondary to cyclophosphamide can be ameliorated by amifostine. 17 These effects would appear to be due principally to the ability of amifostine to protect haemopoietic progenitors from a range of chemotherapeutic agents, as shown by in vitro clonogenic assays 17,33,34 and further supported by engraftment data from a randomised trial of in vitro amifostine in the context of 4-HC purged bone marrow prior to transplantation. 35 This being the case, it is not surprising that we saw no differences in engraftment times or subsequent blood product support required when using myeloablative doses of melphalan as haemopoietic reconstitution was derived in both trial arms from reinfused progenitors that had not been exposed to conditioning chemotherapy.…”

Section: Discussionmentioning

confidence: 97%

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Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation

Spencer

Horvath

Gibson

et al. 2005

Bone Marrow Transplant

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Summary:In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n ¼ 43) or not receive (n ¼ 47) amifostine 910 mg/m 2 prior to melphalan 200 mg/m 2 . Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P ¼ 0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P ¼ 0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P ¼ 0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to highdose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis. Bone Marrow Transplantation (2005) 35, 971-977.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 97%

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation

Spencer

Horvath

Gibson

et al. 2005

Bone Marrow Transplant

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“…2-[(Aminopropyl)amino] ethanethiol (WR-1065) has been reported to protect against the bleomycininduced cytotoxicity in V79 cells (Nagy and Grdina, 1986). Amifostine, an aminothiol, has also been reported to protect against the melphalan-induced genotoxicity (Buschini et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Naringin, a grapefruit flavanone, protects V79 cells against the bleomycin‐induced genotoxicity and decline in survival

Jagetia

Jha

2006

J of Applied Toxicology

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The effect of naringin, a grapefruit flavonone was studied on bleomycin-induced genomic damage and alteration in the survival of cultured V79 cells. Exposure of V79 cells to bleomycin induced a concentration dependent elevation in the frequency of binucleate cells bearing micronuclei (MNBNC) and a maximum number of MNBNCs were observed in the cells treated with 50 microg ml(-1) bleomycin, the highest concentration evaluated. This genotoxic effect of bleomycin was reflected in the cell survival, where a concentration dependent decline was observed in the cells treated with different concentrations of bleomycin. Treatment of cells with 1 mm naringin before exposure to different concentrations of bleomycin arrested the bleomycin-induced decline in the cell survival accompanied by a significant reduction in the frequency of micronuclei when compared with bleomycin treatment alone. The cell survival and micronuclei induction were found to be inversely correlated. The repair kinetics of DNA damage induced by bleomycin was evaluated by exposing the cells to 10 microg ml(-1) bleomycin using single cell gel electrophoresis. Treatment of V79 cells with bleomycin resulted in a continuous increase in DNA damage up to 6 h post-bleomycin treatment as evident by migration of more DNA into the tails (% tail DNA) of the comets and a subsequent increase in olive tail moment (OTM), an index of DNA damage. Treatment of V79 cells with 1 mm naringin reduced bleomycin-induced DNA damage and accelerated DNA repair as indicated by a reduction in % tail DNA and OTM with increasing assessment time. A maximum reduction in the DNA damage was observed at 6 h post-bleomycin treatment, where it was 5 times lower than bleomycin alone. Our study, which was conducted on the basis of antioxidant, free radical scavenging and metal chelating properties of naringin demonstrates that naringin reduced the genotoxic effects of bleomycin and consequently increased the cell survival and therefore may act as a chemoprotective agent in clinical situations.

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“…In contrast with these results, Kataoka et al [1996] reported that WR-2721 reduced cyclophosphamide-induced hypox-anthine-guanine phosphoribosyl transferase mutation frequency in mice splenocytes. Buschini et al [2000] also found that WR-2721 protected normal human white blood cells against the in vitro genotoxic effect of melphalan.…”

Section: Differential Cytoprotection Of Amifostinementioning

confidence: 88%

Differential antigenotoxic and cytoprotective effect of amifostine in idarubicin‐treated mice

Nebel

Larripa

González-Cid

2002

Environ and Mol Mutagen

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In this study we evaluated the antigenotoxic and cytoprotective capabilities of WR-2721 [S-2-(3-aminopropylamino)-ethylphosphorothioic acid (amifostine)] in different normal tissues of BALB/c mice treated with idarubicin [4-demethoxydaunorubicin (IDA)]. The aminothiol WR-2721 is a pro-drug that requires dephosphorylation to its active metabolite WR-1065, to produce selectively cytoprotective activity in normal tissues exposed to radio- and chemotherapeutic agents, without protecting malignant tissues. IDA is an effective chemotherapeutic agent against hematological diseases, but produces a broad spectrum of toxicity in nontumoral cells. Animals were injected intravenously with WR-2721 (250 mg/kg) or IDA (6 mg/kg) and WR-2721/IDA. Micronuclei frequency in bone marrow was measured 24 and 48 hr after initiation of the treatments. The IDA-treated group showed increased levels of micronuclei. However, the WR-2721- and WR-2721/IDA-treated groups did not show differences from the controls. Genetic damage was evaluated by alkaline single-cell gel electrophoresis at 24-hr posttreatments. Important DNA damage was observed in liver, spleen, and peripheral blood cells of mice treated with IDA. The presence of WR-2721 diminished that damaging effect only in liver cells. The apoptotic index was measured in liver and spleen tissues by the TUNEL assay 14 and 24 hr after treatment. In liver we observed an increased percentage of apoptotic cells at 24 hr for the IDA-treated group, whereas the WR-2721 and WR-2721/IDA groups remained at low levels. Splenic cells treated with IDA and WR-2721/IDA showed increased DNA fragmentation levels at any time. In conclusion, WR-2721 has a tissue-specific antigenotoxic and cytoprotective effect in IDA-treated mice using these experimental conditions.

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Amifostine (WR-2721) selective protection against melphalan genotoxicity

Cited by 21 publications

References 59 publications

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation

Naringin, a grapefruit flavanone, protects V79 cells against the bleomycin‐induced genotoxicity and decline in survival

Differential antigenotoxic and cytoprotective effect of amifostine in idarubicin‐treated mice

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