Platinum complexes toxic activity

Metal Complexes - The Fourth International Symposium on Platinum Coordination Complexes in Cancer Chemotherapy covered various aspects of the synthesis, biochemistry, pharmacology, toxicology and clinical evaluation of platinum containing drugs. A study correlating the structure of platinum complexes with activity, toxicity, and lability has appeared. 

The recent clinical success of platinum anticancer drugs has illustrated that metal complexes can be designed to have a specificity of biological activity. For example, not all platinum complexes are active anticancer agents. Some platinum complexes are inert and relatively non-toxic, some attack DNA, some do not. In general, the nature of the metal ion itself, its oxidation state, and the types and number of bound ligands can all play critical roles in the biological activity [4, 5]. 

Pt(TV) Prodrugs. Platinum(IV) complexes have been widely studied as potential prodrugs that avoid the limitations of the cisplatin class of anticancer drugs. Indeed, the Pt(IV) compound satraplatin [Pt(cha)Cl2(OAc)2(NH3)] (cha, cyclohexylamine) is currently in clinical trials for treatment of hormone-refractory prostate cancer (Fig. 1) (22). Satraplatin is the first orally bioavailable platinum derivative under active clinical investigation and is particularly attractive because of the convenience of administration, milder toxicity profile, and lack of cross-resistance with cisplatin. These results are promising and support the idea that platinum(IV) complexes offer the opportunity to overcome some of the problems associated with cisplatin and its analogs. 

Most platinum compounds exist as coordination complexes the tetravalent compounds typically are more toxic than the hexavalent ones [10]. Certain neutral platinum complexes exhibit antitumor activity and therefore are used in chemotherapy drugs such as cisplatin. Speeiation is required to distinguish platinum chemotherapy drugs from their metabolites in patients blood and serum samples. 

In the search for a more snccessful drag, numerous alternative concepts in the design of new platinum drags emerged. Requirements that have inflnenced the search for new complexes inclnde rednction in toxicity, increased spectrum of activity, circumventing resistance, and oral activity to facihtate ontpatient treatment. The remainder of this section will give an overview of the various approaches used, classical and novel. Platinum complexes with appended functionalities will be discussed in more detail. 

Calvert H, Judson I, van der Vijgh WJ. Platinum complexes in cancer medicine Pharmacokinetics and pharmacodynamics in relation to toxicity and therapeutic activity. Cancer Surv 1993 17 189-217. 

Platinum compounds without antitumor activity (17) such as t2 ons-DDP and [Pt(dien)Cl]Cl (Figure 1) covalently bind to DNA in vivo. Several studies have compared the biological effects which result when equal amounts of these three platinum compounds are fixed on DNA (typically r j 10" -10"6), Cis-DDP is 5-10 times more toxic toward E, ooli ( ) and mammalian cells (j, U.) than t2 ans-DDP, The relative toxicity is correlated with the ability of these two isomers to inhibit DNA replication (, i3, J 4). The ois isomer is repaired more efficiently by E, ooli W and is at least 750 times more mutagenic in mammalian cells (11) than the trans isomer. The compound [Pt(dien)Cl]Cl binds covalently to the DNA of E, ooli and seems not to be repaired nevertheless this compound does not inhibit DNA synthesis or kill the bacteria ( ), Repair of platinum compounds by E, ooli may be under the control of the SOS system c s-DDP induces 5-10 times more recA protein in treated E. Coli than an equal amount of trans-DPP or [Pt(dien)Cl]Cl fixed on the DNA (18), It seems that different modes of fixation on DNA are responsible for the different mutagenicity, toxicity and DNA repair of these platinum complexes. These results suggest that the antitumor activity of platinum(II) compounds may also depend on the formation of particular platinum-DNA lesions. 

DDP. It would be fortuitous indeed if the first platinum complex reported proved to be the most effective compound of its type. Furthermore, although DDP is one of the most effective antitumor drugs available, its use is accompanied by severe nausea and a range of toxic effects ( ). These factors, combined with the rather limited range of clinical activity for DDP, have led to the search for new antitumor platinum compounds having either increased efficacy or decreased toxicity, or both. 

We should note the fact that in the bacterial systems, the substitutionally inert complexes which are mutagenic and active in the repair assay all have effects similar to those of the platinum complexes known to be anti-tumor drugs. Since repair effects are closely correlated with activity of the platinum compounds (17), then the anti-tumor activity could be related to the substitutional inertness of our complexes. We have noted that many of the complexes we have studied are far less bacteriocidal than the platinum compounds, and yet comparable in repair activity. This suggests that further study of substitutionally inert metal complexes may yield anti-tumor drugs which are as effective as the platinum compounds, and yet lack their undesirable toxic side effects. 

It should increase delivery of the bioactive moiety and decrease toxicity. In aqueous solutions, cisplatin hydrolyzes with a reaction half-life of nine hours at room temperature or 2.4 hours at 37 °C. Cisplatin hydrolyzes in the body forming a wide variety of platinum-containing agents, none of which is as active as cisplatin itself and most of which exhibit increased toxicity to the body. Formation of these hydrolysis products increases the amount of platinum complex that must be added to effect desired tumor reduction. Consequently, this increases the amount of platinum complexes that must be processed by the body. The polymeric structure should also shield the platinum moiety from unwanted hydrolysis increasing the concentration of platinum in the beneficial form that is retained in the body thus permitting lower effective doses of the drug to be used. The nature of the more hydrophobic polymer chain should also act to protect the platinum moiety from ready attack by water. 

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