Platinum cisplatin properties

Hambley and co-workers have reported the synthesis, DNA cross-linking, and in vitro anticancer properties of a platinum(II) complex that was designed to bind the macromolecule in an interstrand rather than intrastrand manner,162 the latter being the dominant mode of DNA-binding by platinum anticancer drugs such as cisplatin. The complex [PtCl2(hpip)] ((46) ... 

In laboratory animals, parenteral administration of organic and inorganic selenium (210 to 12,000 ig/kg) has been shown to protect against cisplatin-induced nephrotoxicity. Protection occurs without apparent inhibition of the antineoplastic activity of cisplatin, although this may be attributed to the fact that selenium administration allows for higher doses of cisplatin to be used. Additionally, selenium administration reduces cisplatin-induced myelosuppression. This raises a concern similar to that with administering cisplatin with thiol compounds, i.e., that the reduction of myelosuppression may indicate that selenium can also interfere with the antitumor activity of cisplatin. Selenium, with chemical properties similar to those of sulfur, can bind with platinum and... 

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. 

Reactions of cisplatin and its hydrolytes with longer-chain amino acids +NH3(CH2)nC02 are less relevant to the biological properties of platinum because these compounds are less abundant in vivo. The six- and seven-membered chelate rings formed with /3-alanine (n = 2) and y-aminobutyric acid (n = 3) are progressively less stable kinetically and thermodynamically than the five-membered A/, 0-chelate ring formed with glycine [3]. 

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-... 

To develop platinum drugs with improved properties compared to cisplatin, a plethora of cisplatin analogs have been designed with appended additional ftmctionalities. The rationale is that these incorporated moieties could lead to a host of favorable pharmacokinetic properties, such as targeting to cancer cells, improved transport into the cell, and increased affinity for DNA. Furthermore, to overcome the problem of resistance, pendant DNA interacting moieties have been... 

After the serendipitous discovery of the antitumor properties of cisplatin (m-diaminedichloro-platinum), much effort has been devoted to finding other anticancer metal agents, and several Sn, Ti, Zr, and Hf /3-diketonates have been proven to possess interesting biological activity. For example, budotitane ((EtO)2Ti(bzac)2) was the first non-Pt metal complex to reach clinical trials as a potential anticancer agent.11-15... 

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