"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.

Department of Biophysics Faculty of Science Palacky University in Olomouc Slechtitelu 27 78371 Olomouc Czech Republic

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

Institute of Biophysics Czech Academy of Sciences Academy of Sciences Kralovopolska 135 61265 Brno Czech Republic

Institute of Medicinal and Pharmaceutical Chemistry Technische Universität Braunschweig Beethovenstrasse 55 38106 Braunschweig Germany

Citace poskytuje Crossref.org