1.Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells.
Hofer M1, Falk M1, Komůrková D1, Falková I1,2, Bačíková A1, Klejdus B, Pagáčová E1, Štefančíková L1, Weiterová L1, Angelis KJ3, Kozubek S1, Dušek L4, Galbavý Š2. J Med Chem. 2016 Apr 14;59(7):3003-17. doi: 10.1021/acs.jmedchem.5b01628. Epub 2016 Apr 1.
Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on γH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in γ-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography-mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration.
2.Amifostine Treatment Mitigates the Damaging Effects of Radiation on Distraction Osteogenesis in the Murine Mandible.
Monson LA1, Nelson NS, Donneys A, Farberg AS, Tchanque-Fossuo CN, Deshpande SS, Buchman SR. Ann Plast Surg. 2016 Apr 11. [Epub ahead of print]
According to the American Society of Clinical Oncology, in 2012, more than 53,000 new cases of head and neck cancers (HNCs) were reported in the United States alone and nearly 12,000 deaths occurred relating to HNC. Although radiotherapy (XRT) has increased survival, the adverse effects can be unrelenting and their management is rarely remedial. Current treatment dictates surgical mandibular reconstruction using free tissue transfer. These complex operations entail extended hospitalizations and attendant complications often lead to delays in initiation of adjuvant therapy, jeopardizing prognosis as well as quality of life. The creation of new bone by distraction osteogenesis (DO) generates a replacement of deficient tissue from local substrate and could have immense potential therapeutic ramifications. Radiotherapy drastically impairs bone healing, precluding its use as a reconstructive method for HNC. We posit that the deleterious effects of XRT on bone formation could be pharmacologically mitigated.
3.Improvement of the in vitro safety profile and cytoprotective efficacy of amifostine against chemotherapy by PEGylation strategy.
Yang X1, Ding Y2, Ji T2, Zhao X2, Wang H2, Zhao X2, Zhao R2, Wei J3, Qi S4, Nie G5. Biochem Pharmacol. 2016 May 15;108:11-21. doi: 10.1016/j.bcp.2016.02.014. Epub 2016 Mar 2.
Amifostine, an organic thiophosphate prodrug, has been clinically utilized for selective protection of normal tissues with high expression of alkaline phosphatase from oxidative damage elicited by chemotherapy or radiotherapy. However, the patients receiving amifostine suffer from severe dose-dependent adverse effects. Strategies for improvement of the protective efficacy and toxicity profile of amifostine are urgently required. Here we constructed a PEGylated amifostine (PEG-amifostine) through conjugation of amifostine to the 4-arm PEG (5000Da) by a mild one-step reaction. The relatively large PEG-amifostine molecules clustered into spherical nanoparticles, resulting in distinct hydrolysis properties, cell uptake profile and antioxidative activity compared with the free small molecules. PEGylation prolonged the hydrolysis time of amifostine, providing sustained transformation to its functional metabolites. PEG-amifostine could be internalized into cells and translocated to acidic organelles in a time-dependent manner.
4.The effect of amifostine on lung ischaemia-reperfusion injury in rats.
Bougioukas I1, Didilis V2, Emigholz J3, Waldmann-Beushausen R3, Stojanovic T3, Mühlfeld C4, Schoendube FA3, Danner BC3. Interact Cardiovasc Thorac Surg. 2016 Apr 27. pii: ivw105. [Epub ahead of print]
OBJECTIVES: Lung ischaemia-reperfusion injury (LIRI) frequently occurs after lung transplantation or cardiac surgery with cardiopulmonary bypass, thus increasing postoperative morbidity and mortality. As LIRI is associated with the release of reactive oxygen species and a subsequent inflammatory reaction, we tested whether amifostine, a thiol and free radical scavenger, has a beneficial effect on LIRI.