Cisplatin, anticancer activity

A comparison of the thermodynamical hydration surfaces of platinum and palladium complexes will be done showing that the SAR (structure and activity relationship) is not valid in relation to the cisplatin anticancer activity. 

The first report on the anticancer properties of ruthenium was published in 1976 when the Ru(III) compound /ac-[RuC13(NH3)3] (Fig. 11) was found to induce filamentous growth of Escherichia coli at concentrations comparable to those at which cisplatin generates similar effects (49). This Ru(III) complex and related compounds such as cis-[RuCl2(NH3)4]Cl illustrated the potential anticancer activity of ruthenium complexes, but insolubility prevented further pharmacological use. Since these initial studies, other Ru(III) complexes have been studied for potential anticancer activity, and two compounds, NAMI-A (50) and KP1019 (51), are currently undergoing clinical trials. Remarkably,... 

The DKPs cyclo(His-Ala) and cyclo(His-Gly) proved to have promising anticancer activity comparable with that observed for cisplatin. Cyclo(His-Ala) in particular demonstrated an ability to inhibit tumor growth in HT-29, HeLa, and MCF-7 cancer cell lines. Cyclo(His-Gly) however, only had a marked effect on MCF-7 carcinoma cells at a concentration of 100 pmol 1. Both DKPs at a concentration of 0.5 mmolwere effective against two of the three Gram-positive bacteria, that is, Bacillus and S. aureus. Cycfo(His-Gfy) was more effective against Klebsiella pneumoniae than cyclo(His-Ala). Cyclo(His-Afa) and cycfo(His-Gfy) inhibited the growth of C. albicans by 66.3 and 47%, respectively. 

Platinum complexes are actually a major constituent in the treatment of testicular, ovarian, bladder, colon and non-small cellular lung cancer. The anticancer activity of cisplatin (cis-diammine-dichloro-platinum (II)) was discovered in 1969.164 Two additional compounds,... 

The chemotherapeutic agent d.v-diammincdichloroplatinum(II), cis-DDP, or cisplatin, can form covalent adducts with many cellular macromolecules, but there is convincing evidence that its cytotoxic properties are a consequence of bifunctional-DNA adduct formation [ 1 ] [2]. Platinum binds to the N(7) position of purine nucleotides, resulting predominantly in 1,2-d(GpG) and l,2-d(ApG) intrastrand cross-links, but also in l,3-d(GpNpG) intrastrand, interstrand and protein-DNA cross-links [3][4], The 1,2-intrastrand cross-links, which comprise 90% of the DNA adducts, are not formed by the clinically inactive trans-DDP because of geometric constraints, and attention has therefore focused on these adducts as the active lesions in the anticancer activity of the drug. 

Cellular sensitivity to different platinum compounds and the recognition of the platinum DNA adducts by mismatch repair protein complexes appear to be linked [103]. It may also be significant that hMSH2 is expressed to higher levels in testicular and ovarian tissue than in other organs such as heart, liver and colon [109], Whether or not mismatch repair plays a general role in the anticancer activity of cisplatin still remains debatable, however. Mismatch repair proteins bind to cisplatin-DNA adducts in vitro with weak specificity [109][113]. Although specificity is enhanced when aplat-inum lesion is combined with a mutation [113], it is still less than the affinity of these proteins for the unplatinated mutation [63] [108]. 

Reactions between cisplatin and serum albumin are thought to be the main route for platinum binding in human blood plasma. Several clinical and experimental observations have suggested that albumin-bound platinum may be anticancer active [47] [48]. Additionally, albumin binding may reduce some of the side-effects of cisplatin treatment, especially its nephrotoxicity [49]. The reaction of cisplatin with intact and chemically modified recombinant human albumin (rHA), and with HSA (human serum al-... 

Cisplatin is a neutral square planar coordination complex with two chloride and ammonium ligands in the cis-configuration. The compounds with trans-configuration are mostly devoid of activity. Pt exists in two main oxidation states, namely Pt [Pt(II) and Pt4+ Pt(IV)]. In the latter, two of the ligands are located axially directly above and below the square plane, which results in an octahedral configuration. Although many of the Pt(IV) derivatives exhibit anticancer activity, only the Pt(II) complexes with cis-configuration have become widely applied in the clinical practice [2]. 

Oe Cisplatin. Cisplatin [civ-diammincdichloroplatinum(II)] is a clinically used chemotherapeutic agent in the treatment of a variety of human cancers. The anticancer activity of cisplatin is believed to result from cytotoxicity induced by cisplatin DNA adducts. Not surprisingly, cisplatin itself is a mutagen and carcinogen. G - T and A —> T transversions appear to be the main mutations induced by cisplatin. 

Dinuclear complexes formed with polyamines have attracted attention since polyamines are known to interact with the DNA backbone. Dinuclear cationic trans complexes that use the natmally available polyamines spermine (19) and spermidine (20) as linkers have been shown to be very active and to circumvent cisplatin resistance in L1210 mmine leukemia cells in vitro. The internal charge, from an incorporated amine (19) and (20) or a platinum atom (18), featmed in the diamine linker, seems to contribute significantly to the anticancer activity of the complexes. 

Cisplatin has become one of the most widely used chemotherapy drugs. The mechanism of action relies on the ability of the drug to modify the DNA structure in cancer cells, hence causing their apoptosis. However, it presents severe toxicity and its anticancer activity is limited to a small group of tumor cell types. In further development, several... 

The structure of a protein believed to be involved in anticancer activity when combined with a cisplatin-modified DNA complex shows a larger kink (61°) in the DNA and intercalation of a phenylalanine ring from the protein into the resulting notch (where the phenylalanine ring is stacked between two base layers). Binding such as this might prevent removal of the cisplatin and other repair reactions of the DNA. 

Cisplatin (cis-dichlorodiammineplatinum cisDDP) belongs to one of the most frequently explored platinum compounds since Rosenberg s discovery of its anticancer activities.1 It was found that cisplatin makes a bridge connection between two (usually) adjacent guanine bases in DNA predominately forming 1,2-intrastrand GpG complexes (about 65% of the occurrences). Some other intrastrand coordinations occur less frequently, namely with the l,2-d(ApG) and the l,3-d(GpXpG) base sequences. However, coordination to the l,2-d(ApA) or the l,2-d(GpA) fragment was observed only very rarely. 

In the other cases, there is not only qualitative but also quantitative agreement for all of the considered reactions. Regarding the markedly different biochemical roles of Pt- and Pd-based compounds, the very high degree of similarity between the calculated hydration surfaces of the Pd and Pt compounds does not correspond with the QSAR principle. The differences are considerably smaller compared to those we have recently noticed between Zn2+ and Mg2+ cations.100,109 This clearly demonstrates that an understanding of the anticancer activity of the cisplatin complex is related not only to the thermodynamical description, but also some additional factors have to be included. This will be discussed in the next section. 

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