Chelation treatment in a novel sub-toxic multi-metal model in rats

Chronic, sub-toxic, multi-metal accumulation stemming from environmental exposure in daily life is a common phenomenon in modern humans and has been linked to numerous diseases. Toxic metals found in leukemia patients have recently been linked to chemoresistance and poor survival. To reverse chemoresistance, depletion of metal ions by chelators has been suggested as a possible adjuvant to chemotherapy. However, existing animal models for metal accumulation are largely unsuitable for this type of cancer research. We developed a novel accelerated model for chronic, sub-toxic, multi-metal accumulation in rats, in which a mixture of 11 metals was administered orally, followed by an equilibration period of at least five weeks to allow the metal ions to settle into their target organs in a chronic-like distribution, without overt toxicity. The model was characterized in terms of metal ion levels in urine, feces, serum, and organs. We surveyed seven chelators with different properties, seeking a compound that would specifically remove highly toxic metals, while exerting a minimal effect on essential elements. Our studies pointed to Monoisoamyl-dimercaptosuccinic acid (MiADMSA), an exploratory chelator with promising properties, as the most suitable for this purpose. Different treatment regimens, aimed at optimizing the clinical application of the chelator, were explored and characterized. Repeated monthly cycles of 5 treatments per cycle led to efficient removal of inorganic arsenic, cadmium, vanadium, and cobalt from rat organs. Our study shows that MiADMSA is a promising chelator that may be efficient in treating chronic metal accumulation, and potentially as an adjuvant to chemotherapy.