Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Cell Line MeSH
- Cricetulus MeSH
- Carbonic Anhydrase IV chemistry metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Molecular Structure MeSH
- Organoplatinum Compounds chemical synthesis chemistry pharmacology MeSH
- Prodrugs chemical synthesis chemistry pharmacology MeSH
- Prohibitins MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CA4 protein, human MeSH Browser
- Carbonic Anhydrase IV MeSH
- Ligands MeSH
- Organoplatinum Compounds MeSH
- PHB protein, human MeSH Browser
- Prodrugs MeSH
- Prohibitins MeSH
- Antineoplastic Agents MeSH
"Multi-action" Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 complexes act as prodrugs for CA4 rather than as true multi-action prodrugs. In vivo tests (Lewis lung carcinoma) show that ctc-[Pt(NH3)2(PhB)(CA4)Cl2] inhibited tumor growth by 93% compared to CA4 (67%), cisplatin (84%), and 1:1:1 cisplatin/CA4/PhB (85%) while displaying <5% body weight loss compared to cisplatin (20%) or CA4 (10%). In this case, and perhaps with other extremely potent bioactive ligands, platinum(IV) acts merely as a self-immolative carrier triggered by reduction in the cancer cell with only a minor contribution to cytotoxicity.
Dipartimento di Scienze del Farmaco Universita di Padova Via Marzolo 5 35131 Padova Italy
Institute for Drug Research School of Pharmacy The Hebrew University 91120 Jerusalem Israel
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