Synergistic effects of copper(II) complexes and cisplatin: an application of artificial neural networks and experimental design
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| Year of publication | 2012 |
| Type | Appeared in Conference without Proceedings |
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| Description | Cisplatin is highly effective in treating a variety of cancers [ 1] but both inherited and acquired tumoral cell resistance seriously limits its applications [2]. Anticancer drugs are widely used in suitable combinations in order to improve their action [3]. In the cell, associations of two or more drugs may exhibit synergistic, antagonistic or addictive effects. Synergistic, antagonistic or additive type of interaction occurs when the cytotoxicity of the drug combination is respectively greater, lower, or equal to the sum of the cytotoxicity of individual drugs. Complexes of copper(II) with 1,10-ortho-phenanthroline (phen) are also endowed with cytotoxic and antitumoral effects being capable of cleaving DNA and improving nuclease activity [4]. Recently, we prepared a series of new copper(II) complexes, containing two phen units and N,N’-substituted-imidazolidine-2-thione as auxiliary ligands [5]; these compounds are characterized by a high chemical stability coupled with a high cytotoxic activity against mouse neuroblastoma as well as human hematologic and solid tumor-derived cell lines [6]. In this work we propose a new approach to search for optimal combination of the two compounds for which maximum synergy is observed, by using Artificial Neural Networks (ANNs) and the Experimental Design (ED). The studied compounds are reported in Table 1. We prepared 40 mixtures of copper complex and cisplatin and measured the corresponding cytotoxicity against CCRF-CEM T-leukaemia cell lines. A neural network was used to model experiments and then to predict the cytotoxicity values on the whole working space. The values so obtained were corrected for the pure additive effect, putting in evidence the synergistic effect. In Figure 1a and 1b the calculated and corrected response surfaces for the C1-cisplatin system respectively, are shown. ED-ANN can be considered as a new, efficient and fast method to search for synergy of drug mixtures and/or even for new drugs. |
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