Platinum complexes cisplatin mechanism

Carboplatin is a platinum complex in which platinum is incorporated into a more complex molecule. Its mechanism of action and spectrum of anti-tumor activity are similar to those of cisplatin. However carboplatin is better tolerated that cisplatin. 

Since the discovery of the antitumor activity of m-PtCNFhuC (cisplatin, cd-DDP) by Rosenberg et al. [1], the interactions of cisplatin with nucleotides and nucleobases have attracted attention towards gaining an understanding of the mechanism of the antitumor activity of cisplatin at a molecular level. In the course of such studies, dark-blue platinum complexes called platinum blues were obtained when hydrolysis products of cis-... 

Although the platinum-amino-acid complexes do not show much promise as cytotoxic agents, these results demonstrated the utility of in vitro screening methods to survey the DNA-binding properties of platinum compounds in a combinatorial manner. Assuming that HMG-domain proteins are involved in the cisplatin mechanism of action, then screening based on the Pt-... 

Kalayda GV, Jansen BAJ, Molenaar C, Wielaard P, Tanke HJ, Reedijk J. Dinuclear platinum complexes with N,N -bis (aminoalkyl)-l,4-diaminoanthraquinones as linking ligands. Part II. Cellular processing in A2780 cisplatin-resistant human ovarian carcinoma cells new insights into the mechanism of resistance. J. Biol. Inorg. Chem. 2004 9 414-422. 

The diminution of antitumour activity by sulfur nucleophiles may be due to the sequestration of active metabolites or to interaction with Pt— DNA adducts. Some agents such as DDTC do not affect the antitumour activity of cisplatin [28], whereas other agents such as TU do so. Thiourea can remove Pt—DNA crosslinks and inhibits the cytotoxicity [29]. Indeed, thiourea has been of great utility in allowing examination of the mechanism of formation of Pt—DNA adducts (see Chapter 4.5). Depletion of intracellular glutathione (GSH) content, on the other hand, results in enhanced platinum cytotoxicity [30], and GSH can also quench Pt monoadducts [31]. Thus, all sulfur nucleophiles do not behave in the same manner with platinum complexes and the fundamental aspects of these interactions and their relationships to platinum complex metabolism are now being explored (Chapter 3.7). Some aspects of the biochemical mechanisms relating to these points are summarized in recent volumes [27,91]. 

The mechanism of platinum nephrotoxicity may be similar to that of mercury and may involve depletion of SH groups of the renal tubules and in this case the sulfur agents would act in competition with the renal SH groups [32]. The ATPase enzyme is critical for kidney function (see Chapter 12.1) and this has also been proposed as the site of action [33, 34], although it has been pointed out that the inhibiting concentrations are high and unlikely to be achieved in vivo [35]. Other urinary enzymes have also been examined for inhibition by platinum complexes [28, 36]. In general, the mechanisms of action related to the toxic manifestations of cisplatin are unclear, especially when compared to the details of the proposed Pt—DNA reaction (Chapter 4). 

Consideration of membrane as a target for chemotherapeutic drugs has been reviewed and relevant studies with cisplatin summarized [79]. The amino acid uptake mechanism in LI 210 cells is affected by cisplatin [80] and platinum complexes inhibit plasma membrane phosphatase activity in ascites cells [81]. Microtubule protein polymerization is also affected adversely [82]. Effects on mitochondrial functions and properties have been examined [83—86], along with studies on inhibition of sulfhydryl-containing enzymes [87—90]. 

Over the last few years, significant advances in the depth of understanding of the conformational features of the polynucleotide—platinum complex interaction have come from both solution (CD, NMR) and solid-state (X-Ray) studies on oligonucleotide fragments, particularly dinucleotide complexes. Excellent summaries of the status of model studies and their relationship to the molecular mechanism of cisplatin can be found in references [82 and 141]. These complement the earlier reviews [83, 84]. The features outlined do in fact confirm some of those expected from model studies, although there has not been an extensive comparison with the trans-isomcr. 

The interactions of platinum complexes with DNA, oligonucleotide sequences and constituent bases give a detailed description of the binding and contribute to the understanding of the molecular mechanism of action of cisplatin. 

While transplatin is not an active anticancer drug some trans platinum complexes, however, are highly cytotoxic. In the search for active trans platinum compounds several complexes with triphenylphosphine or dimethylphenylphos-phine ligands have been studied (Fig. 13.5), and found to be active on various cancer cell lines, with no cross resistance to cisplatin observed [22]. Apoptotic cell death with no G1 and G2/M accumulation in the cell cycle, typical for the cisplatin, was observed indicating a non-classical mechanism of action. 

Loh S Y, Mistry P, Kelland LR, Abel G, Harrap KR. Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line circumvention studies using novel platinum (II) and (IV) ammine/amine complexes. BrJ Cancer 1992 66 1109-1115. 

Cisplatin (dx-Diamminedichloroplatinum) is a divalent water-soluble platinum containing complex. It reacts directly with DNA, resulting in both intra-and inter-strand cross-links. It also causes DNA breaks and it inhibits DNA replication and RNA transcription. A mechanism for the occurrence of resistance appears to be an increased of the levels of DNA-excision repair enzymes. Cisplatin is used in combination therapies with other anticancer drugs in the treatment of testicular and ovarian cancers and it has also shown high activity against cancers of the bladder, head, neck and endometrium. It is administered intravenously by rapid injection or by continuous infusion. It is for more that 90% bound to... 

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