Inorganic Chemistry in Biology and Medicine - American Chemical

8 Introduction to Metal Complexes and the Treatment of Cancers BARNETT ROSENBERG

Downloaded by UNIV ILLINOIS URBANA on June 27, 2013 | http://pubs.acs.org Publication Date: December 22, 1980 | doi: 10.1021/bk-1980-0140.ch008

Department of Biophysics, Michigan State University, East Lansing, MI 48824

It is somewhat surprising that the classic warhorse of metal coordination chemistry, Peryone's Chloride, a simple, inorganic platinum complex has proven to be one of the most potent of anticancer drugs. This chemical-cis-dichlorodiammineplatinum (II) (cisplatin) has now been approved in most countries of the world for the treatment of advanced, metastatic, testicular and ovarian cancers. It is now considered, when used in appropriate combination chemotherapy, to be curative for these cancers. Many recent clinical advances suggest that it will also be of significant utility in the treatment of other solid cancers such as those of the bladder, prostate, lung, head and neck, certain cancers in children, and finally, in other genitourinary cancers. These clinical trials have been underway for eight years now and are still continuing in an effort to increase the efficacy and decrease the toxicity of cisplatin, as well as broadening the spectrum of responsive cancers. In the meantime, hundreds of other metal complexes have been shown to be active against various animal-tumor screens. These include predominantly analog structures of the parent drug, but also a scattering of complexes of metals other than platinum. Active pursuit of these areas may be highly rewarding. It is curious, however, that while the value of the cisplatin drug is well established, knowledge of it's relevant chemistry and mechanisms of action remains still in a fairly primitive state. For example, i f cisplatin is simply dissolved in water, the subsequent aquation reactions are numerous and complex. The diammine ligands are not likely to be exchanged under these conditions, but the chloride ligands are. These are sequentially exchanged for water or hydroxyl ligands. The extent of the exchanges is primarily controlled by the chloride concentration in the solution. However, further reactions of the aquated species are known to occur, forming a variety of oligomeric species, including a dimer, a cyclic trimer and a tetramer. The relative concentrations at equilibrium of a l l of these products is markedly dependent on pH and temperature. Thus the relatively 0-8412-05 88-4/80/47-140-143 $05.00/0 © 1980 American Chemical Society In Inorganic Chemistry in Biology and Medicine; Martell, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.


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innocuous a c t i o n of d i s s o l v i n g c i s p l a t i n i n water already i n t r o duces a l a r g e v a r i e t y of products. T h i s makes any simple i n t e r p r e t a t i o n of the b i o l o g i c a l r e a c t i o n s dubious at the very l e a s t . Neverthless, some guiding i n t e r p r e t a t i o n s f o r f u r t h e r e x p e r i mental work are necessary, even i f these be, admittedly, simple minded. We w i l l assume that upon i n j e c t i o n of the c i s p l a t i n i n t o the e x t r a c e l l u l a r f l u i d of an animal the high c h l o r i d e conc e n t r a t i o n (on the order of 100 m i l l i e q u i v a l e n t s per l i t e r ) l i m i t s any aquation r e a c t i o n , and the drug remains i n t a c t as i t courses through the body. A d d i t i o n a l r e a c t i o n s of c i s p l a t i n with molecules i n the blood w i l l have to be l e f t to the pharmacokineticists to s o r t out. There i s evidence to suggest that the i n t a c t drug p a s s i v e l y permeates c e l l membranes ( v i z , no a c t i v e c a r r i e r i s necessary). U s u a l l y , the i n t r a c e l l u l a r c h l o r i d e concentration i s lower than the e x t r a c e l l u l a r v a l u e . In some c e l l s of the body, such as muscle c e l l s , the c h l o r i d e concentration may be as low as 10 m i l l i e q u i v a l e n t s per l i t e r , while i n other c e l l s , such as the e p i t h e l i a l c e l l s l i n i n g the stomach and i n t e s t i n e s , the c h l o r i d e c o n c e n t r a t i o n i s a p p r o x i mately the same as i n the e x t r a c e l l u l a r f l u i d . In those c e l l s where the c h l o r i d e concentration i s low, the aquation r e a c t i o n w i l l occur to some degree. This i s the only step necessary to a c t i v a t e the drug. The aquated species are now able to r e a c t w i t h v a r i o u s i n t r a c e l l u l a r molecules, and i n p a r t i c u l a r , the n u c l e i c a c i d s . Evidence from both i n v i t r o and i n v i v o s t u d i e s s t r o n g l y imply that the primary t a r g e t molecule l e a d i n g to the s i g n i f i c a n t b i o l o g i c a c t i o n s i s the c e l l u l a r DNA. The r e a c t i o n s of the aquated c i s p l a t i n species with DNA again provides a p l e t h o r a of r e a c t i o n s i t e s , one or more of which may be the s i g n i f i c a n t l i g a n d exchange l e a d i n g to the anticancer a c t i v i t y . I t i s the task of those attempting to understand the mechanisms of drug a c t i o n to unravel the r e s u l t s of these d i f f e r e n t r e a c t i o n s . A higher order of complexity i s added to t h i s system i n that the d i f f e r e n t aquated species may each produce a d i f f e r e n t set of r e a c t i o n products with DNA. I t i s q u i t e c l e a r by now that drug a c t i o n of the d i c h l o r o diammineplatinum (II) i s s t e r e o s e l e c t i v e . For a n t i c a n c e r a c t i v i t y to occur the drug must be i n the c i s c o n f i g u r a t i o n . The trans isomer i s i n a c t i v e . This i s true f o r a l l the other analogs t e s t e d so f a r . We may t r y to use t h i s s t e r e o s e l e c t i v i t y as a t o o l to pry out the s i g n i f i c a n t l i g a n d exchanges. We f i r s t w i l l l i m i t our c o n s i d e r a t i o n s to those r e a c t i o n s of aquated c i s p l a t i n which the c i s isomer i s capable of but the trans isomer i s not. Of t h i s sub-class of r e a c t i o n s , one i s most i n t e r e s t i n g . This i s the formation of a c l o s e d r i n g chelate of c i s p l a t i n with the N-7 and 0-6 n u c l e o p h i l i c s i t e s of guanine. I t had been shown p r e v i o u s l y that the c i s p l a t i n reacted p r i m a r i l y with the GC r i c h regions of DNA. I t has a l s o been suggested that the t e r t i a r y s t r u c t u r e of DNA i s probably too p l a s t i c to e x h i b i t the necessary stereoselectivity. I t i s a l s o known that the c i s p l a t i n does not

In Inorganic Chemistry in Biology and Medicine; Martell, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.


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i n t e r c a l a t e . And i t i s b e l i e v e d that r e a c t i o n s with the phosphate-sugar chains are not r e l e v a n t . Both intra-and i n t e r s t r a n d c r o s s l i n k i n g s of DNA by the aquated c i s p l a t i n and i t ' s trans isomer are known to occur. Crossl i n k i n g has been t r a d i t i o n a l l y invoked to account f o r c y t o t o x icity. In t h i s case, however, evidence e x i s t s that equal numbers of trans complex c r o s s l i n k s as c i s complex c r o s s l i n k s cause the same degree of c y t o t o x i c i t y - b u t the trans i s not an a c t i v e a n t i c a n c e r agent. I emphasize the importance of s e p a r a t i n g c y t o t o x i c and a n t i c a n c e r e f f e c t s . A l l c e l l u l a r poisons are not a n t i c a n c e r agents. Somehow a degree of s e l e c t i v i t y i s necessary i n order to have l a r g e tumor masses disappear with l i t t l e or no t o x i c i t y to the normal c e l l s of the body. What i s l a c k i n g at the present time i s hard chemical e v i dence f o r the e x i s t e n c e of the N-7, 0-6 c h e l a t e complex with guanine. Reactions of aquated c i s p l a t i n with the v a r i o u s n u c l e o p h i l i c s i t e s of guanine produces a m u l t i p l i c i t y of r e a c t i o n products. These are the k i n e t i c a l l y allowed s p e c i e s . They form w i t h i n 48 hours of r e a c t i o n time. With longer i n c u b a t i o n times, however, the number of r e a c t i o n products decreases. Those r e maining are l i k e l y to represent the more thermodynamically s t a b l e products. These are a l s o the ones that u s u a l l y end up i n the c r y s t a l l o g r a p h e r s hands. I t must be p o i n t e d out, however, that the s i g n i f i c a n t l e s i o n need e x i s t f o r no more than one to two days w i t h i n the c e l l (one r e p l i c a t i o n of the DNA), and t h e r e f o r e , t h i s l e s i o n may w e l l be one of the l e s s thermodynamically s t a b l e products. Therefore, i n the court of l a s t r e s o r t , c r y s t a l l o g r a p h y , we s t i l l may not o b t a i n a f i n a l judgement. One of the aspects of the c h e l a t e complex that makes i t p a r t i c u l a r l y a t t r a c t i v e t o me i s the involvement of the 0-6 s i t e of guanine. There i s an i n t r i g u i n g s t o r y developing i n the f i e l d of c a r c i n o g e n e s i s by a l k y l a t i n g agents, which now i m p l i c a t e s the a l k y l a t i o n at the 0-6 s i t e as p o s s i b i b l y the most r e l e v a n t i n causing mutations i n somatic c e l l s . T h i s i s considered to be a necessary, but not s u f f i c i e n t step, i n the t r a n s f o r m a t i o n of the c e l l i n t o a cancer c e l l . S u f f i c i e n c y occurs when the l e s i o n i s not r e p a i r e d p r i o r to DNA r e p l i c a t i o n and leads to a m i s p a i r i n g w i t h thymine i n s t e a d of the c o r r e c t p a i r i n g with c y t o s i n e . This then leads on f u r t h e r r e p l i c a t i o n to the replacement of the o r i g i n a l GC p a i r by an AT p a i r - a base s u b s t i t u t i o n mutation. Whether such mutations need to occur i n p a r t i c u l a r regions of the DNA i s not yet c l e a r . The hypothesis of the 0-6 guanine involvement does provide an e x t r a bonus i n that a mechanism of a c t i o n can be p o s t u l a t e d , and t e s t e d , which allows an e x p l a n a t i o n of the s e l e c t i v e d e s t r u c t i o n of cancer c e l l s . I f the cancer c e l l becomes so because of i t s i n a b i l i t y to r e p a i r the 0-6 guanine l e s i o n caused by a c a r cinogen then i t may a l s o be unable to r e p a i r the c i s p l a t i n i n duced damage. But the normal c e l l s have i n t a c t r e p a i r mechanisms and can r e p a i r the damage p r i o r to DNA r e p l i c a t i o n and


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thus s u r v i v e . Tests of t h i s mechanism of s e l e c t i v i t y are i n progress. The d i s c o v e r y of a new c l a s s of a n t i c a n c e r drugs based on metal complexes a f f o r d s us a new opportunity to reexamine the problems of cancer chemotherapy. I t i s obvious that i n t e r a c t i o n s of metals with DNA i s l a r g e l y an undeveloped f i e l d of study, but i s too important to remain so.


RECEIVED April 7,1980.


Inorganic Chemistry in Biology and Medicine - American Chemical

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