Abstract 3518: In vitro and in vivo synergistic effects of F14512, a novel targeted cytotoxic agent in phase I clinical study, in combination with other anticancer drugs
Authors: Isabelle Vandenberghe, Jean-Philippe Annereau, Viviane Brel, Stéphane Vispe, Jean-Marc Barret, Bruno GOMES, Vanessa Offrete, Karine Andre, Sabine Roy, Caroline Castano, Fiona Celestin, Yves Guminski, Thierry Imbert, Anna Kruczynski, Nicolas Guilbaud, Christian Bailly
Journal: Cancer Research (2011)

Abstract Targeted anticancer therapies represent an increasing subject of interest in order to improve tumor cell selectivity. Extensive study suggests that the Polyamine Transport System (PTS) is an energy-dependent machinery generally hyper-activated in cancer cells with a high demand for polyamines. This system can be viewed as a suitable molecular target to deliver selectively polyamine-based molecules into cancer cells. We exploited this strategy to target a potent cytotoxic agent to PTS-positive tumor cells with F14512, a novel polyamine-epipodophyllotoxin conjugate that exhibits a high in vivo anti-tumor activity in a series of experimental murine and human tumors. F14512 has recently entered into clinical development. This preclinical study was undertaken to investigate its potential in combination chemotherapy therapies. The in vitro cytotoxicity of F14512 against the A549 human non-small cell lung cancer cell line was investigated following simultaneous incubation with a variety of cytotoxic/cytostatic drugs. When using median effect analysis, F14512 in combination with 5-fluorouracil, camptothecin, gemcitabine or mitoxantrone showed synergistic cytotoxicity. Additive effects were demonstrated when F14512 was combined with bortezomib, doxorubicin or SAHA while antagonistic anti-proliferative effects were observed only with co-incubation of F14512 and etoposide, vinorelbine or paclitaxel. Combinations inducing synergistic anti-proliferative activities were also investigated against the HL-60 human acute myeloid leukemia cell line, confirming the synergy with gemcitabine. Cellular effects of F14512 are characterized by a DNA damage induction, a cell cycle blockage in G2 phase and a cell death induction. Such characteristics were investigated in A549 cells treated with this combination in order to propose mechanistic explanation of this synergy. In vivo, F14512 combined with irinotecan, gemcitabine, mitoxantrone or doxorubicin showed a gain of anti-tumor activity against P388 murine leukemia grafted intravenously. As an example, the administration of sub-optimal doses of F14512 (0.63 mg/kg, q1d4 schedule) and mitoxantrone (1.25 mg/kg, single dose) alone resulted in an increased life span of only 29% compared to untreated mice, while combined treatments improved survival of tumor bearing mice with an increase life span of 57%. Moreover, F14512 combined with doxorubicin displayed an increased antitumor activity against MX-1 human breast cancer in nude mice.F14512 appears to be a promising candidate for combination chemotherapy, especially with DNA-damaging agents and antimetabolites. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3518. doi:10.1158/1538-7445.AM2011-3518