Molecular Pharmacology, Vol 11, 298-309, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

The Role of Metals in the Antitumor Action of 1,5-Bisthiosemicarbazones

¹ Departments of Oncology and Pharmacology, Wayne State University School of Medicine and Michigan Cancer Foundation, Detroit, Michigan 48201, and Medical Research Council of Ireland, Trinity College, Dublin, Ireland

A recent study of a new series of bisthiosemicarbazones showed that optimal inhibition of DNA synthesis in Leukemia 1210 cells was obtained with derivatives of 1,5-dicarbonyl compounds. In the present study these compounds were highly efficient scavengers of copper. Facilitation of uptake of Cu⁺⁺ via chelation was associated with drug toxicity. Studies using a ³⁵S-labeled drug, ⁶³Ni⁺⁺, and ⁶⁴Cu⁺⁺ showed that metal chelates readily penetrated L1210 cells, where the metal was tightly bound. The drug then diffused from the cells to shuttle more metal ions inward. Chelation strongly potentiated the lipophilicity of both drug and metal, as shown by water/octanol partition studies. Some drugs were such potent scavengers of copper that drug toxicity was only abolished by addition of EDTA to "copper-free" media. Of the drugs studied, most could chelate both nickel and copper, and a few, only copper. The capacity for inhibiting synthesis of DNA was correlated with copper chelation and facilitation of uptake of Cu⁺⁺. The bisthiosemicarbazones of 1,5-dicarbonyl compounds were more effective agents for promotion of Cu⁺⁺ uptake by L1210 cells than the analogous derivatives of -ketoaldehydes, which have been extensively studied.

Note:
ACKNOWLEDGMENTS The technical assistance of Gwynne Smith, Joanne Blahnik, and Melody Sands is appreciated. We thank Marie Gannon for carrying out organic syntheses.