Cytotoxicity of [ 125 I ] iodoHoechst 33342 : contribution of scavengeable e Ú ects

target of radiation action. The greatest toxicity is Purpose : The incubation of the DNA minor-groove binder observed when the I atom is incorporated within [I]iodoHoechst 33342 (IH) with plasmid DNA leads to the the DNA helix (i.e. 5-[I]iodo-2 3⁄4 -deoxyuridine, production of one double-strand break (dsb) per decay, both in IdUrd (Kassis et al. 1988)) , while its dislocation by the presence and absence of dimethylsulfoxide (DMSO). In a few nanometers from the DNA axis (e.g. Icontrast, when I is incorporated into mammalian cell DNA as an iodinated pyrimidine base, DMSO decreases the dsb yield labelled DNA intercalator (Kassis et al. 1989) ) leads and enhances survival. Because these variations in radioprotective to a substantial decrease in toxicity. e Ú ects may be due either to the location of I vis-à-vis the DNA Displacement of the I atom from the axis of the helix or to di Ú erences in DNA architecture, the toxicity of IH DNA helix can also be achieved by using iodinated and its modiŽ cation by DMSO were examined in mammalian cells. ligands; for example, Hoechst dyes that bind to the Methods: Uptake and retention of IH in V79 cells were DNA minor groove. Such radioiodinated Hoechst measured, and survival was determined after accumulation of molecules were Ž rst used by Martin and coI decays at 0.3ß C Ô 10% DMSO. workers (Martin and Holmes 1983, Murray and Results: A linear–quadratic survival curve was obtained both in Martin 1988a,b) who synthesized carrier-free the absence [D37= 114 Ô 36 decays/cell, a= (5.39 Ô 1.17) Ö 10Õ 3 cell/decay] and presence [D37= 211 Ô 65 decays/cell, a= [I]iodoHoechst 33258 by direct electrophilic re(1.27 Ô 0.52) Ö 10Õ 3 cell/decay] of DMSO. The dose modiŽ caaction of Hoechst 33258 with sodium [I]iodide. tion factor for the linear component of the survival curve was Harapanhalli et al. (1996) , however, found that this 4.25 Ô 1.97, indicating the predominance of indirect mechanisms. molecule is prone to excessive deiodination as a This value is similar to that obtained with DNA-incorporated I (4.05 Ô 1.72) and for the initial slope (a) of Cs c-rays consequence of the presence of the o-iodophenol (4.43 Ô 1.41). grouping. In view of this [I]iodoHoechst 33258 Conclusions : Cytotoxicity resulting from the decay of the Auger instability and the superior cellular uptake of Hoechst electron emitter I in the mammalian cell nucleus is caused 33342, they synthesized [I]iodoHoechst 33342 mainly by indirect mechanisms. (IH) (Ž gure 1B) by destannylation of the trimethylstannyl derivative of Hoechst 33342. This compound