Copper Polycarboxylate Complexes

The sequestering agent 1,2-propylenediamine-N,N,N,N'-tetraacetic acid (PDTA) is a good example of a polycarboxylic ligand forming active metal complexes against several human tumour cells.17'59 61 It is well known that Cu(II) complexes with chelating ligands play an important role as models of the associative complexes involved in the substitution reactions at the copper site of SOD enzymes; indeed strongly donor ligands as PDTA should favour the formation of six-coordinate copper complexes' the coordination number of the associative complex.62 Based on these arguments, a recent communication deals with the synthesis of the solid compound [Cu(PDTA-H2)(H2O)2] ■ H2O (1), anti-cancer properties of which have been evaluated against the established ovarian tumour cell line TG (in vitro) and the solid tumour Sarcoma 180 (in vivo).63 Animals were BDF1 female mice with weights within a 3 g value range and a minimum weight of 17 g. The number of animals was six per test group. The therapeutic activity of the complex was obtained from the T/C percentage which is described as T/C (%) = (100) x mean lifespan of treated mice/mean lifespan of untreated mice. The inhibiting effects of complex 1 are shown in Figure 12.5 which presents the evolution with time of the total number of culture cells in the absence (control) or presence of the complex.

In this way, the growth kinetics of culture treated with doses of 1 mg/ml and 10 mg/ml of complex is significantly lower (p < 0.001) than that shown in

0 24 48 72 96 120

lime (hours)

Figure 12.5 Determination of the effects exerted by complex 1 on the growth kinetics of the TG human cancer cell line

0 24 48 72 96 120

lime (hours)

Figure 12.5 Determination of the effects exerted by complex 1 on the growth kinetics of the TG human cancer cell line

Chemotherapeutic Copper Compounds 8ft -

control 1 nfiMil NHg/ml

Dose

Figure 12.6 Variation of the duration of the cellular cycle of the TG ovarian cancer cell line with a dose of complex 1 (mg/ml, x-axis)

control cultures after 48 h of the treatment. Similar results are obtained 24 h after administration of the higher dose of the compound (100 mg/ml). As seen, the growth kinetics of the tumour cells decreases with increasing doses of compound 1; thus, the proliferation process is almost completely cancelled by this complex after 96 h of treatment even at the lower doses handled.

The effect produced by the copper complex on the vital cellular cycle was also studied. Figure 12.6 shows the duration of the cellular cycle corresponding to treated and control TG cell lines. At doses of 1 mg/mg, an important induced increasing of the TG cellular cycle is observed (30 h) if compared to that of the control cells (23 h). The length of the cycle of treated cells at a dose of 10 mg/mg was also significantly enhanced (62 h). However, a dose of 100 mg/ml was strongly cytotoxic and the death of the treated cells was observed. Thus, obtained results demonstrate that significant enhancement of the vital cellular cycle is reached at all doses lower than 100 mg/ml.

In conclusion, this chapter included representative complexes of copper formed with different groups of compounds that have been recently tested for their anti-cancer activity. Thus, it has been established that the copper ion chelation plays a definite role in the biological activity of most of the selected organic ligands, enhancing the cytotoxicity and the anti-tumour activity of the metal-free substances on several tumour cell lines, in vivo and in vitro. The tested complexes are strong inhibitors of the enzyme ribonucleotide reductase, an obligatory enzyme in the pathway of synthesis of precursors of DNA.

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