F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

Abstract

The polyamine transport system (PTS) is an energy-dependent machinery frequently overactivated in cancer cells with a high demand for polyamines. We have exploited the PTS to selectively deliver a polyamine-containing drug to cancer cells. F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine tail supports three complementary functions: (a) facilitate formulation of a watersoluble compound, (b) increase DNA binding to reinforce topoisomerase II inhibition, and (c) facilitate selective uptake by tumor cells via the PTS. F14512 is 73-fold more cytotoxic to Chinese hamster ovary cells compared with CHO-MG cells with a reduced PTS activity. A decreased sensitivity of L1210 leukemia cells to F14512 was observed in the presence of putrescine, spermidine, and spermine. In parallel, the spermine moiety considerably enhances the drug-DNA interaction, leading to a reinforced inhibition of topoisomerase II. The spermine tail of F14512 serves as a cell delivery vehicle as well as a DNA anchor, and this property translates at the cellular level into a distinct pharmacologic profile. Twentynine human solid or hematologic cell lines were used to characterize the high cytotoxic potential of F14512 (median IC 50 of 0.18 Mmol/L). Finally, the potent antitumor activity of F14512 in vivo was evidenced with a MX1 human breast tumor xenograft model, with partial and complete tumor regressions. This work supports the clinical development of F14512 as a novel targeted cytotoxic drug and sheds light on the concept of selective delivery of drugs to tumor cells expressing the PTS. [Cancer Res 2008;68(23):9845-53]

Phase I Clinical Pharmacology Study of F14512, a New Polyamine-Vectorized Anticancer Drug, in Naturally Occurring Canine Lymphoma

“…A preferential and rapid uptake of F14512 by tumor cells, with an added cytotoxic effect brought by F16490 metabolite, may explain this strong tumoral cytotoxicity. We previously demonstrated the preferential uptake of F14512 by tumor cells (4,5), and as a consequence plasma levels of F14512 and F16490 may only partially reflect the concentrations reached in tumors. F16490 alone displays cytotoxic activity with an EC 50 of 74 nmol/L in the Namalwa cell line.…”

“…S1A) displayed strong efficacy in a human lymphoma cell line, both in vitro and in vivo in a mouse model (4,8). In this study, we further analyzed the effect of F14512 on the Burkitt's lymphoma cell line Namalwa.…”

“…The anticancer drug candidate F14512 is designed to target cancer cells through the polyamine transport system. It contains a spermine chain in place of the C4 glycosidic moiety of etoposide (4). The positively charged spermine tail contributes to (i) favoring the selective uptake of the drug by tumor cells via the polyamine transport system, (ii) increasing DNA binding to reinforce topoisomerase II inhibition, (iii) enhancing the water solubility of the drug.…”

“…The positively charged spermine tail contributes to (i) favoring the selective uptake of the drug by tumor cells via the polyamine transport system, (ii) increasing DNA binding to reinforce topoisomerase II inhibition, (iii) enhancing the water solubility of the drug. These properties translated into a favorable pharmacologic profile: F14512 has demonstrated potent in vitro and in vivo antitumor activities in preclinical studies, and shown to be superior to etoposide, its parent compound (4)(5)(6)(7)(8)(9)(10)(11).…”

“…Preclinical data showed that lymphoma could be an indication of interest for F14512 development (4). Dogs may be the most relevant animal model to study new therapies for this indication.…”