Antitumor activity of a new platinum(II) complex with low nephrotoxicity and genotoxicity.
Cisplatin is an important antineoplastic agent, but dose-limiting nephrotoxicity and the occurrence of cellular resistance prevent its potential efficacy. Moreover, cisplatin is known to be carcinogenic and genotoxic in mammalian cells and this feature is of a special interest due to the risk of inducing secondary malignancies. There is a great interest in developing new platinum agents that have broad spectrum of antitumor activity and reduced toxicity. We have recently synthesized a novel platinum(II) coordination complex containing a pyridine nucleus and a dithiocarbamate moiety as ligands, [Pt(ESDT)(Py)Cl], in order to obtain an agent with more favorable therapeutic indices than cisplatin. In this study, the new platinum(II) complex was tested for its cytotoxicity, by MTT assay, on various human cancer cell lines also including different cisplatin-resistant cells endowed with different mechanisms of resistance. On human peripheral blood lymphocytes we evaluated the genotoxic potential of [Pt(ESDT)(Py)Cl] via micronuclei and SCE detection. We also performed in vivo experiments with the purpose of investigating the antitumor and nephrotoxic effects of the new platinum(II) complex. The antitumor activity was studied in ascitic or solid Ehrlich carcinoma bearing mice while nephrotoxicity was monitored in male Wistar rats by means of histopathological findings of renal specimens and of biochemical investigation on urinary parameters (GS and NAG activities and of TUP excretion) of urine samples. The results reported here indicate that [Pt(ESDT)(Py)Cl] showed a remarkable in vitro antitumor activity (with IC50 values about twofold as low as those of cisplatin), moreover, it markedly circumvented the acquired cisplatin resistance in selected human cancer cells. The analysis of the cytogenetic damage in normal cells clearly attested that the new dithiocarbamate complex, tested at equitoxic concentrations, is less genotoxic than cisplatin. Chemotherapy in Ehrlich carcinoma bearing mice with [Pt(ESDT)(Py)Cl] was significantly better tolerated than that with cisplatin. Against the ascitic tumor, [Pt(ESDT)(Py)Cl], showed an activity noticeably higher than that of cisplatin in increasing the life span of treated animals (% T/C = 190 and 129, respectively). In solid-tumor-bearing mice, [Pt(ESDT)(Py)Cl] induced a tumor size reduction very close to that observed with the reference compound. Finally, our findings obtained from the nephrotoxicity studies demonstrated [Pt(ESDT)(Py)Cl] was not nephrotoxic, contrary to cisplatin which caused a notorious acute proximal tubular damage. In summary, [Pt(ESDT)(Py)Cl] may be considered as a new platinum(II) complex with remarkable antitumor activity and low nephrotoxicity and genotoxicity compared with cisplatin.
Marzano
Cristina
C
Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, 35131, Italy. cristina.marzano@unipd.it
Bettio
Frazia
F
Baccichetti
Francarosa
F
Trevisan
Andrea
A
Giovagnini
Lorena
L
Fregona
Dolores
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012854:Sister Chromatid Exchange / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D004247:DNA; D002945:Cisplatin