Antitumor drugs platinum compounds

Natile, G. Coluccia, M. Trans-platinum Compounds in Cancer Therapy A Largely Unexplored Strategy for Identifying Novel Antitumor Platinum Drugs In Metallopharmaceuticals l DNA Interactions, Clarke, M. J. Sadler, P. I, Eds. Springer-Verlag Berlin, 1999 Vol. 1, pp 73-98. 

Antitumor drugs cisplatin as, history, 37 175-179 platinum compounds future studies, 37 206-208 resistance to, 37 192-193 second-generation, 37 178 Antiviral agents, 36 37-38 AOR, see Aldehyde oxidoreductase Aphanothece sacrum, ferredoxins, amino acid sequence, 38 225-227 Apo-calcylin, 46 455 Apo-caldodulin, 46 449-450 Apoenzyme, 22 424 Apoferritin biosynthesis, 36 457 cystalline iron core, 36 423 Fe(III)distribution, 36 458-459 Fe(II) sequestration, 36 463-464 ferroxidase centers, 36 457-458 iron core reconstruction in shell, 36 457 mineralization, 36 25 Mdssbauer spectra, 36 459-460 optical absorbance spectra, 36 418-419 subunit conformation and quaternary structure, 36 470-471... 

Over the past 20 years, cis-diamminedichloroplatinum(II), known for more than 145 years, has emerged as the classic compound in the context of antitumor drug therapy. Because it is generally accepted that binding of the compound to DNA is a major requirement for its biological activity, scientists have focused their attention especially on platinum-DNA interactions. In the present review, the latest results... 

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). 

Platinum-based compounds are commonly used as cancer treatment agents. Pharmacokinetic studies of these antitumor drugs require ultratrace analysis. Electrothermal vaporization ICP-MS provides low detection limits for small samples [256]. High-performance liquid chromatography with ICP-MS detection allows speciation of platinum compounds in tissues [256]. LA-ICP-MS can be used to study the distribution of platinum in tissues and tumors [256]. Natural levels of Pt are below typical quadrupole ICP-MS detection limits [257]. 

Most platinum compounds exist as coordination complexes the tetravalent compounds typically are more toxic than the hexavalent ones [10]. Certain neutral platinum complexes exhibit antitumor activity and therefore are used in chemotherapy drugs such as cisplatin. Speeiation is required to distinguish platinum chemotherapy drugs from their metabolites in patients blood and serum samples. 

At the preclinical level, oral antitumor activity has been observed with two other classes of platinum compound, the PtIV monocarboxylate, C(5)-OHP-C1, and the first Ptn complex to exhibit oral activity, the sterically hindered AMD473. Now licenced to Zeneca, AMD473 exhibited promising circumvention of acquired cisplatin resistance against both in vitro and in vivo preclinical models. Together with the drug s favourable pharmacokinetic and toxicology profile in rodents (myelosuppression was dose-limit-... 

The success of cisplatin and carboplatin in treating cancer, combined with the intrinsic and acquired resistance of many tumors to traditional platinum chemotherapy, has generated considerable interest in developing next-generation platinum drugs. Since the discovery of the antitumor activity of cisplatin, researchers have reported the synthesis, characterization, and antitumor activity of thousands of platinum compounds [1] [2]. The previous two chapters in this section describe the promising activity of novel multi-nuclear Ptn and orally active PtIV complexes [3] [4],... 

In vitro methods are not widely used to predict the antitumor activity of platinum compounds. Until it is determined what factors render a specific platinum-DNA adduct cytotoxic, the in vitro screens for platinum drugs will be limited. Because a good platinum drug must form DNA adducts, preliminary screening methods have been employed which measure DNA binding alone as a measure of potential antitumor activity. In one such study [13], the DNA binding of palladium and platinum complexes having inter-... 

The aim of the present contribution is to critically review computational work related to platinum antitumor drugs, published prior to 1998. After a section devoted to molecular-orbital calculations on platinum antitumor complexes and related compounds, we address force-field calculations on platinum adducts with DNA constituents that have been used (mainly in combination with NMR spectroscopy) to evaluate the structure of the adduct. A brief outlook concludes this chapter. 

DDP. It would be fortuitous indeed if the first platinum complex reported proved to be the most effective compound of its type. Furthermore, although DDP is one of the most effective antitumor drugs available, its use is accompanied by severe nausea and a range of toxic effects ( ). These factors, combined with the rather limited range of clinical activity for DDP, have led to the search for new antitumor platinum compounds having either increased efficacy or decreased toxicity, or both. 

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