Naddtc

The affinity of sulfur for platinum complexes has led to investigations of numerous sulfur nucleophiles as inhibitors of cis-Pt nephrotoxicity, including Naddtc, STS, WR-2721, mesna, methionine, thiourea, cysteine, IV-acetylcysteine, penicillamine, and GSH. Of these, Naddtc, STS, and WR-2721 are undergoing preclinical and/or clinical evaluation (Fig. 8). Some of the more promising compounds will be discussed here. 

Naddtc has proved to be a very effective inhibitor of nephrotoxicity [it is also effective against bone marrow toxicity (117-119)] and should be administered 1-4 hours after cis-Pt, without interfering with the anti-... 

Fig. 9. Inhibition of fumarase by cis-Pt (A) and regeneration to) by Naddtc (a), STS (b), and thiourea (c). The values for Naddtc and STS remained constant for 24 hours, but those for thiourea increased to 80%.

Half-Lives and Products of Exchange Reactions between Naddtc, Thiourea, or STS and Platinated Sulfur Compounds"... 

Naddtc does not react with all the platinated proteins, as was observed by Hegedus et al. (133). Therefore, the nephrotoxicity of cis-Pt is likely to be the result of inactivation of certain enzymes through binding at cysteines and/or methionines and Naddtc can reduce the nephrotoxicity only by reversing the Pt—S bonds of the methionine type. 

Thiourea probably acts in a manner comparable to that of Naddtc and should also be administered after cis-Pt treatment (78). Like Naddtc, thiourea is able to remove platinum from platinated enzymes, such as leucine aminopeptidase (76, 128), y-glutamyltranspeptidase (76,128), and fumarase (129) (Fig. 9), and from Pt-methionine model adducts (Table III) (131). However, thiourea appears to be less useful as an inhibitor of nephrotoxicity it also reacts quite rapidly with platinum-DNA cross-links (56). 

Numerous studies have shown that protein-bound cis-Pt cannot be released by STS (76, 128, 129, 143) (Fig. 9), although STS is able to break the Pt—S bond of the methionine type in the model system (Table III) (131). Therefore, this model system, does not mimic enzymes in every detail for the reaction with STS. This difference might originate from the 2 charge of STS compared to the 1 charge in Naddtc (129), keeping STS more separated from the active site. 

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. 

The high affinity of many platinum compounds for sulfur and the availability of many sulfur-containing biomolecules have raised the question whether Pt-sulfur biomolecule interactions could serve as a drug reservoir for platination at DNA, necessary for the antitumor activity of cis-Pt. Two reaction paths are possible, i.e., spontaneous release of plantinum from the sulfur, or nucleophilic displacement of platinum from sulfur by guanine (N7), for example. At the moment, there is no real evidence for the existence of such reactivation mechanisms. In fact, it has been reported that Pt-protein interactions in the plasma (albumin) are not reversible under normal conditions (161, 165). Further, a mixture of cis-Pt-methionine products does not show antitumor properties (166), indicating no induced platination of DNA. More research is required to investigate the existence of a reactivation mechanism. However, it is predicted that if such a reactivation phenomenon is operational, the most likely candidate is the labile Pt-methionine bond, as has been shown by its rapid reaction with Naddtc, STS, and thiourea (vide supra) (131). 

Fig. 16. Formation scheme of the complexes of SAH and their interconversions as a function of pH as well as decomposition reactions with Naddtc. Values for are also...

The development of permanent nephrotoxicity. Nephrotoxicity cannot be cured by Naddtc and thiourea when administered more than 4 hours after cis-Pt treatment. A possible mechanism for the development of permanent nephrotoxicity might be that the platinum migrates from a methionine to a cysteine within a protein, resulting in irreversible binding. 

Nephrotoxicity has also been reviewed recently (200-202), whereas Borch and Markman (203) have published an interesting paper on the modulation of cts-Pt toxicity, by using a combination of Naddtc and hypertonic saline, for example. 

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. 

The mixture was extracted with 3 mL of benzene for 2 h in a mechanical shaker after addition of 2 g of NaCl and 3 mL of NaDDTC. After centrifugation of the mixture, 1 mL of benzene was transferred to a glass-stoppered vial and butylated with 0.2 mL of n-BuMgCl. 

There are some serious drawbacks to the use of cis-platin in anticancer therapy. Severe toxicity problems occur, such as failure of the kidneys and bone marrow (nephrotoxicity and hematoxicity), nausea, intractable vomiting (emesis), peripheral neuropathy, deafness (ototoxicity), and seizures. These toxic side effects of cisplatin limit the dose that can be administered to patients typical doses are 100 mg day for up to five consecutive days. The nephrotoxicity can be reduced by hydration and diuresis. 5-HT3-receptor blockers control nausea and emesis. Much effort has been devoted to the development of chemopro-tective agents, which alleviate the side effects on normal tissues without compromising antitumor activity - mainly sulfur-containing agents such as sodium dithiocarbamate (Naddtc), 2-mercaptoethanesulphonate (mesna), and amifos-tine (WR-2721). Amifostine has recently been approved for coadministration with cisplatin, which reduces nephro- and neurotoxicity. ... 

To verify the between-bottle homogeneity, the artificial rainwater samples (100 mL) were diluted with 900 mL of Milli-Q deionised water prior to analysis. NaCl (20 g), 5 mL of 0.25 mol L NaDDTC and 5 mL hexane were added to the diluted sample and the solution was shaken mechanically for 30 min. The organic fraction was transferred... 

NaDDTC complexation, hexane extraction, Grignard derivatization (pentylation), CGC separation and MS detection... 

First method 50 mL H2O, 5 mL phthalate buffer at pH 4 and 5 mL NaDDTC (2%) were added to 2 mL of sample, followed by an extraction into MIBK. The detection was by ETAAS. Calibration was carried out using a commercial solution of Cr checked by an independent method. 

Spectrophotometric determination using NaDDTC General remarks... 

At a pH between 4 and 11, copper (II) ions react with sodium diethyl dithio-carbamate (NaDDTC) to form a brownish-yellow complex... 

Dissolve 1 g of reagent-purity NaDDTC (C2H5>2N CS2Na 3 H2O in water, filter, and make up to 100 ml. The solution keeps for 1 month in a dark glass bottle. 

Energy dispersive X-ray fluorescence (EDXRF) technique has been employed by Joshi et al. (2006) to determine the concentrations of different elements in water samples collected from different locations of famous Nainital Lake including tap water and spring water sample from Nainital (Uttaranchal). Lake Nainital is a constant source of drinking water for local people as well as tourists. A chelating agent (NaDDTC) was used for the preconcentration of the trace elements. Seventeen elements were detected. The concentrations of Na, Si, K, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Ag, Pb, and Bi were found to be within BIS/WHO limits. 

Precipitation Collection on NADDTC, APDC activated coal DBDTC... 

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