Cisplatin rescue

So, in principle, we have to consider three types of species, all competing for cisplatin, namely, the rescue agents, the peptides and proteins, and the DNA. Although, at present, much highly relevant information is available about Pt-DNA binding, information of other aspects of in vivo platinum chemistry has become recently available [18-20], A review devoted towards the interaction of (new, active, and some relevant inactive) platinum compounds (in model fluids in vitro and in vivo) with cellular components (DNA peptides) and additives (rescue agents) is highly relevant and timely, and the most important results available will be discussed below. 

After administration, the drug circulates in the blood, primarily as the chloride (for cisplatin), or as another rather inert form (such as the biscar-boxylate in carboplatin). In the blood, also reactions with proteins and rescue agents can take place. Upon passing through cell walls (either actively or passively), intracellular reactions with peptides and proteins may take place, presumably followed by transfer to nucleic acids. Given the strong (kinetic) preference of Pt compounds to react with class-B donor atoms (such as those from thiolates and thioethers), binding to nucleic-acid bases (a thermodynamic end product) must at least occur partially via labile intermediates. 

T) Do direct chemical interactions occur between rescue agents and platinum compounds (such as the drugs cisplatin and carboplatin transpla-tin), and between the relevant model compounds (such as Ptn(dien), or perhaps the kinetically faster reacting Pd11 compounds) Which interaction products are formed in vivo (structure, kinetics) This topic has been largely neglected in the literature. 

Reedijk, J. Teuben, J. M. "Platinum-Sulphur Interaction Involved in Antitumor Drugs, Rescue Agents and Biomolecules." In Cisplatin, Lippert, B (ed.) Wiley-VCH Weinheim, 1999. 

Cisplatin exhibits intense emetic reactions, ototoxicity, and severe cumulative renal toxicity. Some success with rescue techniques, using compounds with high heavy metal affinity such as diethyldithiocarbamate, have been reported. 

J. Reedijk and J. M. Teuben, Platinum - Sulfur Interactions Involved in Antitumor Drugs, Rescue Agents, and Biomolecules, in 30 Years of Cisplatin, Chemistry and Biochemistry of a Leading Anticancer Drug , ed. B. Lippert, Wiley VCH, Weinheim, 1999, p. 339. 

Dedon, P. C., R. Qazi, and R. F. Borch. 1986. Potential mechanisms of cisplatin toxicity of diethyldithiocarbamate rescue. Chem. Abstr. CA 705(19) 164609t. 

The picture is not totally clear but it seems possible that the previous use of cisplatin causes kidney damage that may not necessarily be detectable with the usual creatinine clearance tests, llie effect is to cause a marked reduction in the clearance of the methotrexate. The serum methotrexate levels of such patients should be closely monitored so that any delay in its clearance is detected early and folinic acid rescue therapy can be given. This appears to prevent serious toxicity. " ... 

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