Evaluation of Satraplatin in Dogs with Spontaneously Occurring Malignant Tumors

Selting, Kimberly Anne; Wang, X.; Gustafson, Daniel L.; Henry, Carolyn J.; Villamil, J. Armando; McCaw, Dudley L.; Tate, Deborah J.; Beittenmiller, M.; Garnett, Crystal L; Robertson, John

doi:10.1111/j.1939-1676.2011.0727.x

Cited by 8 publications

(2 citation statements)

References 16 publications

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“…6–9 Nevertheless, owing to their suboptimal efficacy, only a few Pt(IV) compounds have entered, or are under consideration for, clinical trials. 2, 10, 11 A better understanding of their molecular mechanisms of action is necessary in order to generate potent Pt(IV) complexes with improved clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…Cisplatin and other platinum-based anticancer drugs are widely used to treat cancer, including testicular, head and neck, prostate, ovarian, breast, and lung. , Acquired resistance and unpleasant side effects, however, have prompted the investigation of Pt(IV) complexes as an alternative for safer and more effective delivery of platinum. − Many octahedral Pt(IV) prodrugs have been reported with axial ligands designed to optimize physical, redox, and/or pharmacokinetic properties. − Nevertheless, owing to their suboptimal efficacy, only a few Pt(IV) compounds have entered, or are under consideration for, clinical trials. ,, A better understanding of their molecular mechanisms of action is necessary in order to generate potent Pt(IV) complexes with improved clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations

Song

Suntharalingam

Yeung³

et al. 2013

Bioconjugate Chem.

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Pt(IV) anticancer compounds typically operate as prodrugs that are reduced in the hypoxic environment of cancer cells, losing two axial ligands in the process to generate active Pt(II) species. Here we report the synthesis of two fluorescent Pt(IV) prodrugs of cisplatin in order to image and evaluate the Pt(IV) reduction process in simulated and real biological environments. Treatment of the complexes dissolved in PBS buffer with reducing agents typically encountered in cells, glutathione or ascorbate, afforded a 3- to 5-fold fluorescence turn-on owing to reduction and loss of their fluorescein-based axial ligands, which are quenched when bound to platinum. Both Pt(IV) conjugates displayed moderate cytotoxicity against human cancer cell lines, with IC50 values higher than that of cisplatin. Immunoblotting and DNA flow cytometry analyses of one of the complexes, Pt(IV)FL2, revealed that it damages DNA, causing cell cycle arrest in S or G2/M depending on exposure time, with ultimately triggering of apoptotic cell death. Fluorescence microscopic studies prove that Pt(IV)FL2 enters cells intact and undergoes reduction intracellularly. The results are best interpreted in terms of a model in which the axial fluorescein ligands are expelled through lysosomes, with the platinum(II) moiety generated in the process binding to genomic DNA, which results in cell death.

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