Cisplatin, cis-[Pt(NH3)2Cl2], was the first inorganic compound applied in clinics to treat a broad range of malignancies. It is able to bind DNA on the N7 positions of adjacent G/A residues, resulting in the cross-link lesions believed to be responsible for observed antitumor activity. Sometimes N7-metalated purines seem to be characterized by a relevant antitumor activity. This has led us to hypothesize a parallel mechanism of action of platinum drugs, based on free platinated purines, formed after drug administration and incorporated into DNA by DNA polymerases. In order to evaluate this possibility, as a key step to develop new drugs, we performed experiments focused on platinated nucleobases, i.e. [Pt(dien)(N7-G)] and cis-[Pt(NH3)2(py)(N7-G)], dien = diethylenetriamine, py = pyridine, G = 5’-dGTP, cell and mitochondrial uptake and processing. For the first time cell uptake and mobility mechanisms, related to plasmatic cell and/or mitochondrial membrane crossing, has been studied. The results of the present study suggest that nucleotide carriers can be actively implicated in the specific uptake of free cytoplasmic platinum bonded nucleotides. Moreover the possible insertion of metalated nucleobases into nuclear and/or mitochondrial new synthesized DNA/RNA, operated by DNA/RNA polymerases, has been evaluated.
Cell uptake and processing of platinated nucleotides
BENEDETTI, MICHELE;ANTONUCCI, DANIELA;Paola Lunetti;Chiara R. Girelli;MIGONI, DANILO;VERRI, Tiziano;CAPOBIANCO, Loredana;FANIZZI, Francesco Paolo
2013-01-01
Abstract
Cisplatin, cis-[Pt(NH3)2Cl2], was the first inorganic compound applied in clinics to treat a broad range of malignancies. It is able to bind DNA on the N7 positions of adjacent G/A residues, resulting in the cross-link lesions believed to be responsible for observed antitumor activity. Sometimes N7-metalated purines seem to be characterized by a relevant antitumor activity. This has led us to hypothesize a parallel mechanism of action of platinum drugs, based on free platinated purines, formed after drug administration and incorporated into DNA by DNA polymerases. In order to evaluate this possibility, as a key step to develop new drugs, we performed experiments focused on platinated nucleobases, i.e. [Pt(dien)(N7-G)] and cis-[Pt(NH3)2(py)(N7-G)], dien = diethylenetriamine, py = pyridine, G = 5’-dGTP, cell and mitochondrial uptake and processing. For the first time cell uptake and mobility mechanisms, related to plasmatic cell and/or mitochondrial membrane crossing, has been studied. The results of the present study suggest that nucleotide carriers can be actively implicated in the specific uptake of free cytoplasmic platinum bonded nucleotides. Moreover the possible insertion of metalated nucleobases into nuclear and/or mitochondrial new synthesized DNA/RNA, operated by DNA/RNA polymerases, has been evaluated.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
