In vivo studies of a platinum(ii) metallointercalator

Fisher, Dianne M.; Fenton, Ronald R.; Aldrich‐Wright, Janice R.

doi:10.1039/b811723c

Cited by 40 publications

(38 citation statements)

References 25 publications

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“…Mechanisms involved in 56MESS nephrotoxicity were unknown but apoptosis activation may be caspase-independent [12]. However, the potential of metallointercalators as effective antitumor drug remains unaffected in regard of a recent study in which PHENSS was effective in decreasing tumour growth in female Specific Pathogen Free (SPF) Swiss nude mice bearing PC3 tumour xenograft without inducing toxic effect [18].…”

Section: Discussionmentioning

confidence: 98%

“…All metallointercalators were synthesized as previously reported [10][11][12][13][14]18] and generously supplied by Prof. Aldrich-Wright. Metallointercalators, cisplatin (SigmaAldrich, France), oxaliplatin (Sanofi-Aventis, France) and carboplatin (Teva, France) were diluted in sterile physiological serum (Aguettant Co., France).…”

Section: Drugsmentioning

confidence: 99%

“…I L behaves as a DNA anchor for the metal complex via π-π stacking interactions and directs A L orientation [9,15]. Compounds with substituted 1,10-phenanthroline (phen) as I L have already displayed in vitro cytotoxic activity against different cell lines resistant to cisplatin [10,12,13,16,17] and one has been investigated in vivo [18]. The resulting antitumor effect has been attributed to intercalation into the DNA minor groove, although other mechanisms such as electrostatic interaction or self-aggregating along the DNA strand cannot be excluded [8-11, 13, 15, 19].…”

Section: Introductionmentioning

confidence: 99%

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Discrepancy between in vitro and in vivo antitumor effect of a new platinum(II) metallointercalator

et al. 2010

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Platinum(II) metallointercalators represent a new class of DNA-damaging antitumor complexes active in cisplatin- and oxaliplatin-resistant cell lines. In the first part of our work, we have screened in vitro a serie of 18 metallointercalators with the structure [Pt(A(L))(I(L))](2+) where A(L) = ethylenediamine (EN) or diaminocyclohexane in R,R- (RR) or S,S- (SS) configuration ; and I(L) = 1,10-phenanthroline with different degree of methylation : no methylation (PHEN), mono-methylated in position 4 (4ME) or 5 (5ME), or di-methylated in positions 4 and 7 (47ME) or in positions 5 and 6 (56ME) or tetramethylated in positions 3,4,7 and 8 (3478ME). Eight compounds: PHENEN, 56MEEN, 47MERR, 56MERR, 4MESS, 5MESS, 47MESS and 56MESS exhibited significant cytotoxic effect, equivalent or higher than cisplatin, oxaliplatin or carboplatin in the human HCT8 colon and IGROV1 ovarian cancer cell lines for both 1 and 24 h incubation time. The high cytotoxicity of the most active compound, the 56MESS, could be related to the hydrophobicity of the phenanthroline ligand that increases cellular uptake in human HCT8, HT29 (colon) and IGROV1 (ovarian) as well as in rat PROb colon cell lines. Unfortunately, intravenous or intraperitoneal administration of 56MESS had no antitumoral activity in BD-IX rats with peritoneal carcinomatosis induced by an intraperitoneal PROb cells inoculation. Moreover, 56MESS displayed nephrotoxicity at pharmacological dose. Thus, these data query the in vivo/in vitro correlation and reconsider the place of the in vivo screening to select adequate candidate drug for further preclinical and clinical developments.

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Section: Discussionmentioning

confidence: 98%

Section: Drugsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discrepancy between in vitro and in vivo antitumor effect of a new platinum(II) metallointercalator

et al. 2010

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“…The molecular mechanisms of action of the [Pt(I L )(A L )] 2+ complexes in eukaryotic cells are not understood although a complex of this type had been tested in mice [19]. This study therefore seeks to develop and understand the cytotoxic effect of 56MESS on eukaryotes at gene expression level by the means of transcriptomics.…”

Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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“…8). With an average body weight of 25 grams per animal each hydrogel implant gives a total drug dose of ~1.2 mg/kg, which is well below the maximum tolerated dose of cisplatin in this bred of animal [33]. As such, the hydrogels were well tolerated by the mice with no significant change in body weight in the first two days after implantation.…”

Section: In Vivo Effectivenessmentioning

confidence: 90%

A cisplatin slow-release hydrogel drug delivery system based on a formulation of the macrocycle cucurbit[7]uril, gelatin and polyvinyl alcohol

Oun¹,

Plumb²,

Wheate³

2014

Journal of Inorganic Biochemistry

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The anticancer drug cisplatin was encapsulated within the cucurbit [7]uril macrocycle to form the host-guest complex: cisplatin@CB [7]. This was then incorporated into gelatin and 0-4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery vehicles. The hydrogels demonstrated predicable swelling and disintegration dependent on the PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with lower concentrations of PVA. The effect of the hydrogel PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells. Over the 24 h drug exposure time used, hydrogels containing 4% PVA showed a 20% decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 80% and 45% inhibition of cell growth, respectively. There was no measurable difference in the in vitro cytotoxicity of free cisplatin and cisplatin@CB [7] containing hydrogels. Finally, the in vivo effectiveness of a 2%-PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB [7] (30 µg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150 µg) at inhibiting tumour growth.

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In vivo studies of a platinum(ii) metallointercalator

Abstract: An in vivo study for determining the toxicity and efficacy of [Pt(S,S-dach)(phen)Cl(2).1.5H(2)O.0.5HCl (PHENSS) in female Specific Pathogen Free (SPF) Swiss nude mice bearing PC3 tumour xenografts revealed PHENSS to be non-toxic and effective in decreasing tumour growth.

Cited by 40 publications

References 25 publications

Discrepancy between in vitro and in vivo antitumor effect of a new platinum(II) metallointercalator

Discrepancy between in vitro and in vivo antitumor effect of a new platinum(II) metallointercalator

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

A cisplatin slow-release hydrogel drug delivery system based on a formulation of the macrocycle cucurbit[7]uril, gelatin and polyvinyl alcohol

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