Antitumour Activity of Metal Complexes

The early miscellaneous studies have been summarized [2, 3] and cover a wide range of structural types. Systematic studies have included amines, cyclopentadienyls and macrocycles, although much of the recent data has been accumulated for amines, because of the structural similarities to the platinum complexes. As of early 1987 no nonplatinum metal complexes are undergoing full clinical trials, but there are promising leads from animal studies. This chapter, rather than presenting an exhaustive account of all complexes studied, will attempt to demonstrate the great diversity of metal complexes that have been shown to have antitumour activity in standard screens. Some systems have been examined in detail and these will be summarized. Perhaps of more importance than the diversity of structural types is the range of mechanisms by which these complexes are believed to act. 

Individual tumour screens may be susceptible or even resistant to a particular structural type, and the activity of initially promising complexes should be confirmed for a range of systems, as indicated in the case of cisplatin. The reasons for this spread of activities is not at all clear. Further, many complexes only show maximal TIC values (activity) at maximum tolerated or toxic doses. Much research centers on increasing that difference and, in view of the desirability of expanding our understanding of the biological effects of transition metal complexes, these results are, of course, valid but can also be misleading if compared with the clinically used cisplatin. Claims to equivalent activity to cisplatin are 

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However, it is inactive in many other tumour systems including L1210 leukaemia (NCI data). Pt(0) like Au(I) is a 5d metal ion. If the antitumour activity of the Au(I) phosphine complexes is attributable to the presence of the phosphine ligands, then the kinetic lability of the complexes is likely to be crucial, so that the ligand can be released at the target site. 

The main focus of attention in this article has been the c otoxicity and antitumour activity of phosphines and metal phosphine complexes. Activity is likely to stem from the strong reducing properties of phosphines. In natural biological systems phosphorus is present only as P(V) phosphate chemistry. Reduced phosphorus is rarely (if ever) detected. 

Biologically active platinum complexes have now been under investigation for nearly two decades. The large data base on structure-activity relationships has revealed a number of principles as well as raised new questions. Mechanistically, the aquation of the compounds and their ability to cause intrastrand cross-links in defined regions of DNA appear to be the chemical events most closely associated with antitumour activity. The reaction kinetics of the compounds in aqueous systems which may be influenced by chelate effects, steric hindrance of bulky ligands or metal oxidation state have been studied for... 

Cleare and Hoeschele [15] first suggested that there is a "window of reactivity" for metal complexes to display antitumour activity. Reaction times of 2-3 hours appear to be important. Thus Pd(II) complexes are too reactive, but Ru(II) complexes have suitable substitution rates and some of these complexes have been shown to display interesting antitumour activity. 

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