Synthesis and biologic studies of iodinated (I-125/I-127) ethidium

An iodinated (I-125/I-127) ethidium derivative (3,8-diamino-5-[6'-(p-iodobe nzoylamino)-4'-azahexyl]-6-phenylphenanthridinium chloride hydrochloride) w as synthesized and characterized. The labeling yield of the I-125-labeled d erivative was 75% for carrier-free I-125, with a radiochemical purity of 95 %. The incubation of iodoethidium with calf thymus DNA resulted in a substa ntial enhancement of fluorescence yield, indicating the intercalation of th is compound into DNA. In the presence of iodoethidium, the nuclei of methan ol-treated mammalian cells fluoresced, while those of viable cells did not (since the plasma membrane is impermeable to iodoethidium). When viable cel ls were incubated with the reduced form of the derivative, I-125/I-127-dihy droethidium traversed the plasma membrane, was oxidized in the cytoplasm, a nd intercalated into nuclear DNA. Finally, we tested the hypothesis that la rger malignant solid tumors, containing a relatively greater percentage of degenerating permeable cells, can be targeted with I-125-ethidium. In-vivo studies demonstrated a small but positive correlation (R=0.72) between tumo r volume and the uptake of the derivative. Because of the ubiquitous presen ce of abnormal permeable cells and necrosis in tumors, our results support the belief that radiolabeled DNA-intercalating or DNA-binding molecules may be of diagnostic and therapeutic value for a variety of solid tumors in hu mans. (C) 2001 Elsevier Science Inc. All rights reserved.