Properties of Cisplatin

In aqueous solution cisplatin is knovm to undergo spontaneous hydrolysis, (e.g., see Refs. 7,11,52,53). The reaction produces species such as monoaquo platinum and diaqua platinum complexes arising from nucleophilic substitution in water. 

In addition to the aqua species noted above, other aqueous species can exist, including hydroxy complexes such as 5 and 6. The actual form of the hydroxyl species is pH-dependent. At a pH of 7.4, 85% of the monohy-drated complex will exist in the less reactive dihydroxy form (6). Lowering the pH to 6.0 results in the most common form (80%) being the monohydrate species (5). 

The relatively high chloride concentration (about 100 mM) in blood minimizes hydrolysis and the formation of aquated species. Once inside the cell, where the chloride ion concentration is much lower (4 mM), hydrolysis readily occurs, giving a munber of aquated species including the diaqua complex. At 37°C the half-life for the completion of the formation of the diaqua complex is 1.7 h with an activation energy of about 20 kcal/mol (80 kJ/mol). 3 

While the active form within the cell is believed to be the monohydrated structure (7), the preferred extracellular species contains two cw-oriented leaving groups that are normally chloride ligands. As noted before, due to the high chloride ion concentration in blood, these leaving groups will remain in position causing the 

As noted above, cw-DDP enters cells by diffusion where it is converted to an active form. This is due to the lower intracellular chloride concentration, which promotes ligand exchange of chloride for water and thus formation of the active aquated complex. Thus, the platinum-containing complex should be neutral to enter the cell and labile chloride groups need to be present to form the active species widiin the cell. The antineoplastic activity of cw-DDP appears to be related to its interaction with DNA nucleotides, as a monoaquo species. The monohydrated complex reacts with the DNA nucleotide, forming intra/interstrand crosslinks. Of the four nucleic acid bases, cw-DDP has been shown to preferentially associate with guanine. The most common are intrastrand crosslinks between adjacent guanines.  

The first platinum drugs entered human clinical trials in 1971—1972. The trials culMnated in 1978 in the United States with approval for use of cisplatin in the treatment of testicular and ovarian cancers, and later to bladder cancer. Using the definition of chemotherapeutic sensitivity as in Table 2JII [8], a summary of the present clinical utility is given in Table 2.IV. 

The early results have been reviewed up to 1981 [9], and more recent results on clinical utility and toxic manifestations have also been well summarized [10]. The complex, although active in many tumours, is regularly curative in only one, testicular. The results, however, have been dramatic and, for instance, of approximately 300 patients in one long-term study 70% are considered as being probably cured [llj. Ovarian cancer is sensitive, and other positive changes may be classed as responsive and resistant. 

A major obstacle to more widespread use of cisplatin is the persistence 

Chemotherapy Sensitivity CeUKiU (logio) Response Rate Complete Remissions Duration Response Cures (%) 

Various e.g. Non-small-cell lung Osteogenic sarcoma Hodgkins lymphoma 

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The mutagenic properties of cisplatin (resulting in both frame-shift and base-substitution mutations) are also pointing towards a (major) interaction with DNA48). 

The mutagenic properties of cisplatin have been demonstrated in a variety of prokaryotic and eukaryotic systems. In this paragraph we will focus on data concerning the molecular bases of this mutagenicity, the pattern of mutations induced with regard to the lesions produced, and the biological consequences for the cell. 

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... 

This chapter describes the clinical properties of cisplatin, and of its analogues that have undergone extensive clinical trials (particularly carboplatin), platinum chemistry relating to mechanism of action, the mechanisms of tumour resistance to cisplatin and their circumvention. 

Cisplatin was introduced into clinical practice in 1971 (only some five years after the initial discovery of its cell-killing properties), and the less toxic analogue, carboplatin, in 1981. To date, carboplatin is the only platinum analogue to have received worldwide registration. Comparative clinical properties of cisplatin and carboplatin are summarised in Table 1. 

Table 1 Comparative clinical properties of cisplatin and carboplatin...

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) ... 

The first report on the anticancer properties of ruthenium was published in 1976 when the Ru(III) compound /ac-[RuC13(NH3)3] (Fig. 11) was found to induce filamentous growth of Escherichia coli at concentrations comparable to those at which cisplatin generates similar effects (49). This Ru(III) complex and related compounds such as cis-[RuCl2(NH3)4]Cl illustrated the potential anticancer activity of ruthenium complexes, but insolubility prevented further pharmacological use. Since these initial studies, other Ru(III) complexes have been studied for potential anticancer activity, and two compounds, NAMI-A (50) and KP1019 (51), are currently undergoing clinical trials. Remarkably,... 

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... 

Upon binding of cisplatin to DNA in vitro (either ss or ds) one may monitor the differences in spectroscopic properties. A very sensitive technique has been shown to be circular dichroism spectroscopy70,103 In fact, early observations103,104) already dealt with the enhancement of the ellipticity at 275 nm, indicating the occurrence of intrastrand cross linking. Gur results on the decanucleotide (see above) show the same CD effects (Fig. 18) after platination, suggesting similar distortions in the decamer and in DNA. 

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