Synthesis of conjugated spermine derivatives with 7-nitrobenzoxadiazole (NBD), rhodamine and bodipy as new fluorescent probes for the polyamine transport system

Guminski, Yves; Grousseaud, Martial; Cugnasse, Sandrine; Brel, Viviane; Annereau, Jean‐Philippe; Vispé, Stéphane; Guilbaud, Nicolas; Barret, Jean-Marc; Bailly, Christian; Imbert, Thierry

doi:10.1016/j.bmcl.2009.03.052

Cited by 44 publications

(25 citation statements)

References 12 publications

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“…Our objective was thus to find a procedure to identify tumors expressing a PTS highly active and therefore that might be more sensitive to F14512 treatment. Since the PTS has not been identified at the molecular level in mammalian cells, we propose a functional method based on the measurement of the cellular uptake of a fluorescent probe combining the same spermine moiety as F14512 with a fluorescent agent [8]. The fluorescent probe used in this study was the nitrobenzoxadiazole-spermine (NBD-sp) previously described by others [21], synthesized and coded F16746 (Fig.…”

Section: F14512 Induced Cell Deathmentioning

confidence: 99%

“…The spermine tail of F14512 serves as cell delivery vector as well as DNA anchor and this property translates at the cellular level into a pharmacological profile different from that of etoposide, a structurallyrelated compound (an epipodopyllotoxin without polyamine chain) [7]. Furthermore, the design and synthesis of fluorophor-labeled spermine analogs were also previously described with the objective to use these conjugates as probes to identify tumor cells expressing a highly active PTS [8]. The purpose of the present study was to characterize the in vivo preclinical profile of F14512 against a series of experimental tumors and to investigate whether fluorophorlabeled spermine probes could be used to select tumors with a highly active PTS and that might be sensitive to F14512.…”

Section: Introductionmentioning

confidence: 99%

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Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system

et al. 2009

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We have exploited the polyamine transport system (PTS) to deliver selectively a spermine-drug conjugate, F14512 to cancer cells. This study was aimed to define F14512 anticancer efficacy against tumor models and to investigate whether fluorophor-labeled polyamine probes could be used to identify tumors expressing a highly active PTS and that might be sensitive to F14512 treatments. Eighteen tumor models were used to assess F14512 antitumor activity. Cellular uptake of spermine-based fluorescent probes was measured by flow cytometry in cells sampled from tumor xenografts by needle biopsy. The accumulation of the fluorescent probe within B16 tumors in vivo was assessed using infrared fluorescence imaging. This study has provided evidence of a major antitumor activity for F14512. Significant responses were obtained in 67% of the tumor models evaluated, with a high level of activity recorded in 33% of the responsive models. Complete tumor regressions were observed after i.v., i.p. or oral administrations of F14512 and its antitumor activity was demonstrated over a range of 2-5 dose levels, providing evidence of its good tolerance. The level of cellular fluorescence emitted by the fluorescent probes was higher in cells sampled from tumors sensitive to F14512 treatments than from F14512-refractory tumors. We suggest that these probes could be used to identify tumors expressing a highly active PTS and guide the selection of patients that might be treated with F14512. These results emphasize the preclinical interest of this novel molecule and support its further clinical development.

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Section: F14512 Induced Cell Deathmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system

et al. 2009

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“…In our study, we observed in all tested cell lines the incorporation of the PTS vectorized probe F17073, which was designed to identify the cell uptake of the drug F14512 [19,7]. Interestingly, F14512 appeared more cytotoxic than etoposide in all cell lines, but, as expected, the cytotoxic effect of both drugs was clearly higher in the neuroblastoma than in the HGG cell lines, for which no IC 50 values were obtained.…”

Section: Discussionmentioning

confidence: 45%

Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines.

et al. 2014

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The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing radiation and chemotherapeutic agents, was investigated in vitro. The antitumor activity of F14512 was assessed in vivo using a liver-metastatic model of neuroblastoma. An active PTS was evidenced in all tested cell lines, providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Competition experiments confirmed the essential role of PTS in the cell uptake and cytotoxicity of F14512. This cytotoxicity appeared greater in neuroblastoma cells compared with HGG cells but appeared independent of PTS activity levels. In vivo evaluation confirmed a marked and prolonged antitumoral effect in neuroblastoma cells. The combinations of F14512 with cisplatin and carboplatin were often found to be synergistic, and we demonstrated the significant radiosensitizing potential of F14512 in the MYCN-amplified Kelly cell line. Thus, F14512 appears more effective than etoposide in pediatric tumor cell lines, with greater efficacy in neuroblastoma cells compared with HGG cells. The synergistic effects observed with platinum compounds and the radiosensitizing effect could lead to a clinical development of the drug in pediatric oncology.

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“…polyamine [6] and anion [7] transmembrane transport, phospholipidosis study [8], wortmannin action as an inhibitor of PI3 kinase [9], fluorescent tagging of proteins [10] and design of the actin probe [11];…”

Section: Introductionmentioning

confidence: 99%

Application of 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole in analysis: Fluorescent dyes and unexpected reaction with tertiary amines

Annenkov

Verkhozina

Shishlyannikova

et al. 2015

Analytical Biochemistry

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Synthesis of conjugated spermine derivatives with 7-nitrobenzoxadiazole (NBD), rhodamine and bodipy as new fluorescent probes for the polyamine transport system

Cited by 44 publications

References 12 publications

Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system

Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system

Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines.

Application of 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole in analysis: Fluorescent dyes and unexpected reaction with tertiary amines

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