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20-05-2012 | Genetics | Article

Researchers discover promising treatment for Fanconi anemia


Free abstract

MedWire News: Treatment with a combination of antioxidants significantly improves genetic stability in lymphocytes from patients with Fanconi anemia, in vitro study data show.

Filipa Ponte (University of Porto, Portugal) and colleagues say their findings suggest that the two antioxidants ‑ α-lipoic acid (α-LA) and N-acetylcysteine (NAC) ‑ could make an "effective antioxidant prophylactic cocktail" to prevent or delay bone marrow failure and early cancer development, characteristically seen in patients with Fanconi anemia.

The researchers explain that Fanconi anemia is a rare genetic disorder that renders patients hypersensitive to oxidative damage, and to the effects of chromosome-damaging alkylating agents, particularly diepoxybutane (DEB).

Mitochondrial dysfunction, which ultimately leads to oxidative modifications of DNA, proteins, and lipids, has been implicated in the pathology of the disease.

In the present study, Ponte and team examined the effects of α-LA, a mitochondrial protective agent, and NAC, a direct antioxidant and a known precursor for glutathione synthesis, on spontaneous and DEB-induced chromosome instability (CI) in lymphocyte cultures from 15 patients with Fanconi anemia.

The lymphocyte cultures were treated with 20 µM alpha-LA, 500 µM NAC, α-LA plus NAC at the same concentrations, or no antioxidant (control) for 48 hours and then assessed for chromosome breakage.

As reported in the Orphanet Journal of Rare Diseases, all of the treated lymphocyte cultures showed a significant reduction in the number of spontaneous breaks per cell, compared with cultures without antioxidant treatment. Overall, the percentage reduction in chromosome breakage relative to the control group was 35% in cultures treated with α-LA, 40% with NAC, and 58% α-LA plus NAC. All reductions were statistically significant.

In a subgroup of mosaics or post-transplant chimera patients (ie, those with a higher frequency of normal cells), the number of chromosome breaks per cell decreased by approximately 80% with α-LA plus NAC treatment, to a level similar to that observed in normal cells.

The researchers also evaluated the effect of the treatments on DEB-induced CI. As observed with spontaneous CI, all three treatments significantly reduced the number of chromosome breaks per cell by between 28% and 60% compared with no treatment.

Ponte and co-authors say that their findings "might open a novel strategy to deal with FA disease."

"The choice of these antioxidants, apart from their pharmacodynamics, takes into account that both α-LA and NAC have been already approved for safe human use [for other conditions] with minimal or no adverse effect, showing an excellent safety profile," the researchers note.

They conclude that a clinical trial investigating whether administration of these drugs can prevent the development of leukemia, in an initial phase, and solid tumors in an advanced form of the disease is now warranted.

By Laura Cowen

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