Rescue agents

MH M20 M20.001 Glutamate carboxypeptidase Rescue agent during high-dose methotrexate therapy... 

The rescue agent sodium thiosulfate (STS) (Fig. 8), which as such is nontoxic (137), should be injected during the period 1 hour before and 0.5 hour after cis-Pt treatment (138). The optimal protocol in fact uses STS intravenously (i.v.) in conjunction with intraperitoneal (i.p.) cis-Pt (139-141). Concurrent injection of STS and cis-Pt, i.p. (138) or i.v. (142), partly reduces the antitumor activity, probably by inactivation of cis-Pt. A likely explanation for the nephrotoxicity protecting effect is that STS is concentrated extensively in the kidney (137), where it has been proved to react rapidly with cis-Pt (143). 

Thus, though Naddtc acts as a true rescue agent, i.e., by reversing Pt-biomolecule interactions, STS most likely acts by local inactivation of cis-Pt and its concentration in the kidney. This may also explain why STS is not effective when administered after cis-Pt treatment. 

Exchange reactions of rescue agents with platinated proteins, which are known to form Pt—S cysteine bonds, to test the hypothesis (131) that the Pt—S cysteine bond is inert this is important in the unraveling of the mechanism of the nephrotoxicity. 

Platinum-Sulfur Interactions Involved in Antitumor Drugs, Rescue Agents, and Biomolecules... 

In this chapter we will mainly focus on questions related to the S-donor ligands. So, how can platinum reach the DNA after administration of the drug, after or despite its reactions with rescue agents, its transport through the cell membrane, and its possible binding to proteins and peptides as an intermediate ... 

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. 

In spite of much effort that has been put into reducing the side-effects, toxicity remains a major limitation of the clinical use of platinum complexes in anticancer therapy [26][27] [29] [30] and several compounds termed rescue agents , or protective agents have been investigated for co-administration with platinum compounds in order modulate these side effects of platinum therapy. 

The activity of sulfur towards platinum complexes has led to investigation of so-called rescue agents to ameliorate the side effects of platinum therapy, without compromising its anti-tumor activity. These nucleophilic sulfur compounds include sodium thiosulfate (STS), sodium diethyldithio-carbamate (Naddtc), (S)- 2-[(3-aminopropyl)amino]ethyl phosphorothioic acid (WR-2721, Ethyol , amifostine), glutathione (GSH), methionine, thiourea, cysteine, -acetylcysteine, penicillamine, biotin, sulfathiazole, sodium 2-mercaptoethanesulfonate (mesna), and its dimer (di)mesna (BNP-7787). The protective effect of these compounds is either due to prevention, or reversal of Pt-S adducts in proteins. Some of the more promising of the above-mentioned compounds (see Fig. 1) will be discussed below. 

Research in the last decade has made clear that the toxic side effects of platinum compounds have an exciting molecular basis. It has stimulated the research activities dealing with Pt compounds and rescue agents (usually S-donor ligands) and especially the study of the reactions of these compounds in combination with other cellular components and their complicated cell-wall transport. 

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. 

Do such Pt-rescue-agent interactions (and the resulting products) interfere with the binding of the Pt compounds in cells (especially with nucleic acids and/or proteins) ... 

Can rescue agents and sulfur-containing peptides cause in vivo de-platination of DNA and proteins Do such interaction products still have antitumor activity on their own, and may this knowledge be used to the development of new drugs ... 

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

Montine TJ and Borch RF. Quiescent LLC-PK1 cells as a model for cis-diamminedichloroplatinum(ll) nephrotoxicity and modulation by thiol rescue agents. Cancer Res 48 6017-6024,1988. 

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. 

Patients who experience nausea and vomiting after radiation therapy should receive prochlorperazine, metoclopramide, or thiethylperazine as rescue agents, and then receive prophylactic treatment with a SSRl prior to subsequent radiation treatment. ... 

The efficacy of tacrolimus as a primary immunosuppressant for the prophylaxis of rejection and for rescue therapy following failure of conventional cyclosporin-based rejection prophylaxis has been demonstrated in numerous clinical studies in adults and pediatrics using various types of combination therapy since 1989. Tacrolimus is now well established not only as a primary immunosuppressant in organ transplantation but also an excellent rescue agent for patients experiencing posttransplant rejection while on cyclosporin-based regimens [44]. 

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