Arden P. Zipp and Sybil G. Zipp State University College Cortland, New York 13045
Pt(NH3)2C12 and Cancer An old compound with a new use
Dichlorodiammineplatinum(I1) has been known for well over 100years ( I ) and was separated into cis and trans isomers before the turn of the century (2). It has heen used as a model compound for studies of square planar reactivity (3) as long as such studies have been carried out. Despite its lone historv. however, an asprrt of its behavior whirh u,ar dischered 1;). accident in 196%mav ultimatt~lvliwu the rreatest simiific:~nt,e for mankind. This ihance discovery occurred while Barnett Rosenberg and his coworkers were usine platinum electrodes to apply an electric field across a chambbr of growing E. c d r and d w r v e d that the bacteria failed to divide hut continued to grow, resulting in the formation of long, filamentous cells (4). From the point of this initial discovery, a great deal of time and additional work, which has been described briefly in this Journal (51, were necessary before the cause of the inhibition was finally identified as small (-10 ppm) concentrations of cis-dichlorodiammineplatinum(I1) (DDP) and cis-tetrachlorodiammineplatinum(1V)which had been formed electrolytically from the platinum electrodes and the NH&I buffer which was used in the study (6,7). The ability of these compounds to inhihit hscterial cell division prompted their trial as antitumor agents where they were found to be successful against both Sarcoma 180 and Leukemia L1210 test tumors in mice, with cis-Pt(NH&C12 having somewhat Indeed, DDP is greater activity than cis-Pt(NHs)&14 (8,9). active against an extremely wide range of tumors in animals (10) and in man (111, including several which are particularly resistant to treatment by other methods (e.g., testicular and ovarian carcinomas and certain head and neck cancers). The use of metal complexes as antitumor agents is not new and complexes of Cu, Ph, Cr, Mn, Fe, Co, Ni, Ru, Rh, and 0 s were studied as early as 1931, while more recent studies have added Mg, Zn, Hg, Pd, and Ir to this list. Although some of these compounds show promise against certain tumors (12), none has shown either the level or range of activity exhibited by platinum compounds. In view of the much greater antitumor activity of platinum compounds, i t is appropriate to discuss some aspects of the chemistry of this element. With an atomic number of 78, olatinum has a around state electron configuration of 5dq6sl.&d exhihits noknnl oxidauon states of t2 (Sd" and t4 (SdG). It has a lnreccrvstal field stabilization energy which leads to the formaiionbfcomp~exeswhich are diamagnetic and slow to undergo ligand exchange (13).For example, the rate constant for the substitution of H 2 0for C1in PtC142- is 3.9 X s-' while that for the corresponding PtCls2- is immeasurably slow unless catalyzed by traces of Pt(I1) (14). With hut a very few exceptions, platinum complexes exhibit square planar or octahedral geometries in the +2 and +4 oxidation states, respectively, both of which can exist in cis and trans forms when two of the ligands are unique. The early promise of platinum compounds as broad spectrum antitumor agents was marred by several features, some of which have also been found with other chemotherapy agents; abdominal discomfort (15), hearing loss (16), and kidney failure (17). of which the last is the most dangerous. Almost from the initial discovery of DDP's anticancer activity, attempts have been made to achieve its therapeutic benefits while lowering its toxicity. These efforts have consisted of altering treatment methods by administering large volumes of fluids andlor comhinations of other drugs with DDP in
addition to modifying the drug itself by varying the metal ion and its attached ligands.' The most successful techniques found thus far for dealing with the kidney toxicity of Pt(NH3)2CI2are the use of drug comhinations or laree volumes of fluids. For example, it was P discovered some time ago that the combination O ~ D Dwith an alkvlating aeent increased the number of "cures" against a standard t&
