Amifostine (WR-2721) selective protection against melphalan genotoxicity.

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Buschini A, Anceschi E, Carlo-Stella C, Regazzi E, Rizzoli V, Poli P, Rossi C

Amifostine (WR-2721) selective protection against melphalan genotoxicity.

Leukemia. 2000 Sep;14(9):1642-51.

PubMed ID

10995012 [ View in PubMed

]

Abstract

Amifostine (WR-2721) is an aminothiol compound dephosphorylated at the tissue site by alkaline phosphatase to the active metabolite, which is able to inactivate electrophilic substances and scavenge free radicals. Amifostine effects against melphalan-induced DNA strand breaks were studied in normal human white blood cells (WBC) and K562 leukemic cells using the single cell gel electrophoresis (SCGE) or Comet assay, a reported method for measuring DNA damage in individual cells. Prior to treatment (1 h, 37 degrees C) with increasing doses of melphalan, with or without S9, the cells were treated (15 min, 37 degrees C) with a control medium or amifostine (3 mg/ml). Treatment of normal and leukemic cells with melphalan induced a dose-dependent 'comet formation'. Melphalan-induced DNA damage follows a normal distribution in WBC. On the other hand, in K562, a significant proportion of undamaged cells remains even with doses at which mean DNA damage is serious. Pretreatment with WR-2721 protects WBC, but not K562, against the genotoxic effect of melphalan. Amifostine might even strengthen the action of the antiblastic drug against K562 cells. S9 addition appears to enhance melphalan effectiveness. SCGE appears as a suitable primary screening method for in vitro and in vivo studies on drug-DNA interactions and their modulations by endogenous/exogenous factors.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Amifostine	Alkaline phosphatase, germ cell type	Protein	Humans	Yes	Inducer	Details