Oxaliplatin Pt(IV) prodrugs conjugated to gadolinium-texaphyrin as potential antitumor agents
- 16 March 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (13), 7021-7029
- https://doi.org/10.1073/pnas.1914911117
Abstract
Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents.Keywords
This publication has 47 references indexed in Scilit:
- Overcoming biochemical pharmacologic mechanisms of platinum resistance with a texaphyrin–platinum conjugateBioorganic & Medicinal Chemistry Letters, 2011
- Gadolinium texaphyrin (Gd-Tex)-malonato-platinum conjugates: Synthesis and comparison with carboplatin in normal and Pt-resistant cell linesDalton Transactions, 2009
- The biology of ovarian cancer: new opportunities for translationNature Reviews Cancer, 2009
- Mouse xenograft models vs GEM models for human cancer therapeuticsDisease Models & Mechanisms, 2008
- Molecular mechanisms of resistance and toxicity associated with platinating agentsCancer Treatment Reviews, 2007
- Motexafin gadolinium: A novel redox active drug for cancer therapySeminars in Cancer Biology, 2006
- Reductase‐mediated metabolism of motexafin gadolinium (Xcytrin®) in rat and human liver subcellular fractions and purified enzyme preparationsJournal of Pharmaceutical Sciences, 2005
- Cisplatin: mode of cytotoxic action and molecular basis of resistanceOncogene, 2003
- Toxicity of platinum compoundsExpert Opinion on Pharmacotherapy, 2003
- Platinum Compounds: a New Class of Potent Antitumour AgentsNature, 1969