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- W2053298497 abstract "Drugs specifically vectorized to cancer cells may offer a reinforced activity, resulting in an improved therapeutic index. In this context, F14512 exploits the Polyamines Transport System (PTS) to accumulate into cells and exhibits an enhanced anti-proliferative activity on a large panel of tumor cell lines as compared to etoposide. At the molecular level, the spermine tail of F14512 contributes to enhance the water solubility of the drug, and reinforces the activity of the drug toward its primary molecular target, topoisomerase II. This observation has encouraged the set up of a phase 1 clinical study with F14512 in patients with relapsed or refractory acute myeloid leukemia (AML). In order to determine how these molecular properties translate at the cellular level, we have compared the kinetic of cell cycle modulation associated with the inhibition of cell proliferation. F14512 proved to be >30-fold more cytotoxic than etoposide against A549 non-small cell lung cancer cells and triggers less but unrecoverable DNA damages and does not lead to a marked accumulation in the S-phase of the cell cycle, unlike etoposide. Interestingly, A549 cells treated with F14512 were less prone to undergo apoptosis (neither caspases-dependent, nor caspases-independent pathways) or autophagy but preferentially entered into senescence. Drug-induced senescence was characterized qualitatively and quantitatively by an increased -galactosidase activity, both by cytochemical staining and by flow cytometry. A morphological analysis by electron microscopy revealed the presence of numerous multi-lamellar and vesicular bodies and large electron-lucent vacuoles in F14512-treated cell samples. The mechanism of drug-induced cell death is thus distinct for F14512 as compared to etoposide, and this difference may account for their distinct pharmacological profiles and the superior activity of F14512 in vivo. The identification of such response markers for senescence are currently pursued on in vivo MX-1 models by following a transcriptomic analysis focused on cell death cascades including apoptosis and senescence. This study suggests that senescence markers should be considered as potential pharmacodynamic biomarkers of F14512 antitumor response, applicable in clinical trial. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B37." @default.
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- W2053298497 date "2011-11-12" @default.
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- W2053298497 title "Abstract B37: F14512, a polyamine-vectorized anticancer drug, triggers senescence cell death mechanism." @default.
- W2053298497 doi "https://doi.org/10.1158/1535-7163.targ-11-b37" @default.
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