Novel tumor-inhibiting metal complexes: Preclinical efficacy and toxicity of the lanthanum(III) complex [tris(1,10-phenantroline)lanthanum]trithiocyanate FFC24

Abstract

3166 Background: The search for new agents with favorable activity in different types of cancer revealed the novel lanthanide complex FFC24 with 1,10-phenatroline as ligand and lanthanum as central metal. This complex was chosen among different lanthanide complexes for further development due to its high activity in-vitro with a GI50 value of 1.28 μM and an activity profile and a mode of action being different compared to classical platinum drugs. Methods: FFC24 was examined in vivo concerning toxicity by determining the acute intravenous median lethal dose (LD50) and the no-observed-adverse-effect-level in the rat and in the mouse. The in-vivo efficacy screening of FFC24 was performed in the DLD-1 colon adenocarcinoma xenograft model in nude mice using intravenous application. Results: Examination of the acute intravenous toxicity in Sprague Dawley rats at a dose level of 7.5, 15 or 17.5 mg/kg in 0.9 saline revealed a LD50 of 21.60 mg/kg for all animals and 11.46 mg/kg for females only after extrapolation. The NOAEL was determined to be 7.5 mg/kg. In the mouse (outbred albino), FFC24 was administered at doses of 10, 15 or 17 mg/kg and the LD50 was extrapolated to 62 mg/kg for females and males together and 26.6 for males alone. The NOAEL in the mouse was 10 mg/kg. The in-vivo efficacy testing in the DDL-1 xenograft model in comparison to MTX and CisPt was performed at 4, 8, or 12 mg/kg on days 0, 1, 2, 3 and 4 (qd5). The anti-tumor activity of FFC24 in terms of relative tumor volume doubling time respectively growth delay was comparable to CisPt and MTX without any signs of toxicity. Only slight differences concerning activity with respect to the administered dose of FFC24 were observed. Conclusions: With FFC24 a new, very promising non-platinum anti-tumor agent with a different profile of activity and a new mode of action has entered the preclinical development. No significant financial relationships to disclose.