From bench to bedside--preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A).
Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A) is just the second ruthenium-based anticancer agent after NAMI-A which was developed to the stage of clinical trials. Important steps in the mode of action of KP1019 are thought to be the binding to the serum protein transferrin and the transport into the cell via the transferrin pathway. Additionally, the selective activation by reduction in the tumor might contribute to the low side effects observed in in vivo studies. Apoptosis is induced at non-toxic levels via the mitochondrial pathway. These features distinguish it from the established platinum anticancer drugs and suggest that different types of cancer might be treatable with this drug. Indeed, promising activity against certain types of tumors, which are not successfully treatable with cisplatin, and only a very low incidence of acquired resistance has been observed in in vitro and in vivo studies. Recently, a clinical phase I trial was finished in which none of the treated patients experienced serious side effects, while disease stabilization in five of six evaluable patients was achieved. In this review, the preclinical and early clinical development of KP1019 - from bench to bedside - is recapitulated.
Hartinger
Christian G
CG
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria. christian.hartinger@univie.ac.at
Zorbas-Seifried
Stefanie
S
Jakupec
Michael A
MA
Kynast
Bernd
B
Zorbas
Haralabos
H
Keppler
Bernhard K
BK
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D009942:Organometallic Compounds; D017975:Ruthenium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D014168:Transferrin / Q000737:chemistry
D000970:Antineoplastic Agents; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; D014168:Transferrin; C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D004247:DNA