Cisplatin selective toxicity

The compounds were first tested against two panels of human tumour cell lines. The primary cell panel consisted of cells from tumours representative of different tissue types and with different chemosensitivities to cisplatin . Differential cytotoxicity, as opposed to non-selective toxicity, was used as an indicator of potential antitumour activity of test compounds . The second panel was disease-oriented and consisted of cell lines established from human ovarian tumours. This panel included two pairs of cisplatin-sensitive and cisplatin-resistant hnes, with defined mechanisms of resistance (CHl/CHl-R, A2780/A2780-R), and also two inherently resistant cell hnes (HX62 and SK-OV-3). This panel has been used to identify agents with the abihty to circumvent cisplatin resistance . ... 

In this latter respect the overall role of repair processes is receiving increasing attention [29, 71]. The physical binding of any drug to DNA is eventually translated into cell death by an inability to replicate, which also results from an inabihty of the cell to repair that lesion. The nature of that specific lesion for cisplatin and the explanation of why tumour cells are less capable of its repair (since the complex must be somewhat selectively toxic to tumour cells) lie, then, at the heart of the understanding of the mechanism of action. 

Novel mechanisms of interest include sensitizing hypoxic tumor cell lines to enhance radiotoxicity. Tirapazamine is a hypoxia-selective compound 1-2-fold greater in magnitude in comparison to mitomycin C or porfiromycin (84). Its mechanism of action results in a one-electron reduction inducing DNA double-strand breaks and cell death under hypoxic conditions. The free radical is oxidized back to the parent compound under aerobic conditions. When combined with the platinum compounds, the cytotoxic effects may be equivalent to that seen with five times the dose of cisplatin without the toxicities that would be encountered if actually administered (85). 

Despite knowing the structures of all of the DNA lesions, it remains to be determined if any one lesion is more or less toxic to the cells. As discussed above, it was originally thought that DNA interstrand cross-links were the critical lesion. Once it was realized that these lesions are very rare, opinions shifted to suggest that DNA intrastrand cross-links are more cytotoxic. Unfortunately, there is no specific data that implicates either type of lesion in cytotoxicity. For some drugs like nitrosoureas, DNA repair pathways that remove only selected lesions (i.e., 0(6)-methylguanine DNA methyltransferase) have helped to define the role of a particular lesion [24], No separate pathway has been found for repair of a specific cisplatin adduct, so this approach has not been informative. A number of experiments have been performed in which specific adducts on defined DNA sequence, have been transfected into cells. This approach has shown that an adduct inhibits replication or transcription, but this does not directly address the question of mechanism of cytotoxicity. 

Although the PI3-K/Akt pathway is a promoter of cell proliferation and cell survival, under defined conditions, the PI3-K/Akt pathway is also involved in promoting cell death. The activation of PI3-K/Akt has been observed in some experimental systems on induction of apoptosis by selected stimuli like CD95, cisplatin, arsenite, TNF, serum withdrawal, hypoxia (Aki et al. 2001, 2003 Bar et al. 2005 Lee et al. 2005 Lu et al. 2006 Nimbalkar et al. 2003 Ono et al. 2004 Shack et al. 2003). Recent data also indicate that apoptin, a viral protein that selectively kills cancer cells, requires for its toxicity both PI3-K/Akt activation and the phosphorylation by CDK2 (Maddika et al. 2008a). 

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