Chemical reactions occurring between metal-containing antineoplastic drugs and biological molecules

Abstract

The introduction into human chemotherapy of a platinum-containing drug for the treatment of human neoplasia in the early 1970s represented the first time that metallic complexes had been widely utilized in this capacity. The outstanding success of this agent --cisplatin--has prompted a far-reaching search for analogs of cisplatin with a greater therapeutic efficacy or chemicals containing other metals with similar--or dissimilar but equally effective--physicochemical properties. Dozens of metallic or metalloid elements have been screened for antineoplastic activity in animal screening systems. Thus early transition metals (titanium, vanadium, molybdenum), group IB metals (copper, silver, gold), group IIIA metals (gallium, indium, aluminum), other group VIII metals (palladium) as well as miscellaneous other metals (rhuthenium, rhodium, nickel) have all been tested either in vitro or in vivo for their antitumor activity. Relatively few of the thousands of chemical compounds that have been tested in animals have had sufficient properties to warrant consideration for clinial trials. Unfortunately little success was seen with most of the clinical trials when they were conducted and in spite of numerous examples of metal-containing drugs exhibiting antitumor activity, either in vitro or in animal test systems, none except for several analogs of cisplatin were found to have composite characteristics suitable for clinical trials. There were two major exceptions to this lack of success. One was a drug containing gallium that had a long history of clinical use to study bone diseases, and the other was a novel organic chemical structure discovered in the early 1980s and containing germanium. Most recently the antiarthritic gold complexes have been screened for antitumor activity and some were found to be consistently positive, although no clinical trials have yet been proposed for these agents. The extent of testing of metal-containing compounds was recently highlighted by Dr. Barnett Rosenberg during his remarks following presentation to him of the Galileo Galilei medal of the University of Padua (Italy) at the 5th International Symposium of Metal-Containing Anticancer Drugs. Dr. Rosenberg called attention to the fact that a total of 56 metal or metalloid elements have been tested for in vivo antitumor activity in animals (Sadler, 1982b). Some elements have had only a few compounds tested for in vivo antitumor activity in animals (Y = 10, Ho = Tm = Lu = 11) while others have had greater than a thousand compounds tested (Sn = 1400, As = 1200, Pt = Cu = 1100). As of 1980, 988 metal-containing chemicals containing 35 different metals had sufficient in vitro anticancer activity to be considered positive in the National Cancer Institute (USA) antitumor drug screen (Sadler, 1982b), but as mentioned above, only a handful of these compounds have been tested for clinical activity or toxicity. Once reproducible antitumor activity has been documented and clinical efficacy has been established, the mechanism of action of drugs is then pursued. This review will examine one aspect of that mechanism of action--the reactivity with biological molecules that takes place with several metals found in antineoplastic drugs--notably platinum, gold, gallium and the metallocene dihalides. Because of its more widespread use and more extensive