Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells

Kurtzberg, Leslie; Rouleau, Cecile; Yao, Min; Teicher, Beverly A.

doi:10.1007/s00280-011-1658-0

Cited by 33 publications

(21 citation statements)

References 39 publications

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“…Extension of the hydrophobic chain decreased the aqueous solubility of the molecule, which likely self‐assembles into lamellar structures instead of micelles, as was claimed for a closely related structural analogue . As a consequence, the hemolytic potential was significantly reduced, which enabled intravenous (iv) administration that was not feasible with previous APLs …”

Section: Introductionsupporting

confidence: 90%

Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy

Gaillard

Seguin

Rémy

et al. 2019

Chemistry A European J

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Sixteen cationic prodrugs of the antitumora lkylphospholipid (APL) erufosine were rationally synthesized to provideo riginal gene delivery reagents with improvedc ytotoxicityp rofile. The DNA complexationp roperties of these cationic lipids were determined and associated transfection rates were measured. Furthermore, the self-assembly properties of the pro-erufosine compounds were investigated and their criticala ggregation concentration was determined. Their hydrolytic stability underp Hc onditions mimickingt he extracellulare nvironment and the late endosome milieu was measured. Hemolytic activity and cytotoxicityo ft he compoundsw ere investigated. The results obtained in various cell lines demonstrate that the prodrugs of erufosined isplay antineoplastic activity similar to that of the parent antitumor drug but are not associated with hemolytic toxicity,w hich is ad ose-limiting side effect of APLs and am ajor obstacle to their use in anticancer therapeutic regimen. Furthermore, by using lipoplexes prepared from ap rodrug of erufosine and a plasmid DNAe ncoding ap ro-apoptotic protein (TRAIL), evidencew as provided for selective cytotoxicityt owards tumor cells while nontumorc ells were resistant. This study demonstratest hat the combination approachi nvolving well tolerated erufosine cationic prodrugs and cancerg ene therapy holds significant promiseint umor therapy.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

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Section: Introductionsupporting

confidence: 90%

Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy

Gaillard

Seguin

Rémy

et al. 2019

Chemistry A European J

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“…It remains to be determined whether ErPC3 can elicit an apoptotic effect in these tumor stroma cell populations. However, it has been demonstrated that the toxicity of ErPC3 is selectively greater toward cancer cells than toward human or mouse bone marrow cells (21) and that ErPC3 could stimulate innate immunity by inducing human cord blood cells to form granulocytes/macrophage colonies (39).…”

Section: Discussionmentioning

confidence: 99%

“…Erucylphosphohomocholine (ErPC3; Erufosine [Genzyme]) is a congener of ErPC with higher water solubility and is able to cross the blood-brain barrier (19,20). Similarly to ErPC, ErPC3 exhibits potent antitumor activities in the micromolar range (21) and induces apoptosis in otherwise highly apoptosis-resistant glioblastoma cell lines (15). The mechanism of the cytotoxic and apoptotic actions of ErPC3 in several different cancer cell types has been linked to plasma membrane damage and direct or indirect disruption of Akt signaling (22).…”

mentioning

confidence: 99%

The Translocator Protein Radioligand ¹⁸F-DPA-714 Monitors Antitumor Effect of Erufosine in a Rat 9L Intracranial Glioma Model

Awde¹,

Boisgard²,

Thézé³

et al. 2013

J Nucl Med

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On the one hand, the translocator protein (TSPO) radioligand N, N-diethyl-2-(2-(4-(2-18 F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo [1,5-a]pyrimidin-3-yl)acetamide ( 18 F-DPA-714) has been suggested to serve as an alternative radiotracer to image human glioma, and on the other hand the alkylphosphocholine erufosine (ErPC3) has been reported to induce apoptosis in otherwise highly apoptosisresistant glioma cell lines. The induction of apoptosis by ErPC3 requires TSPO, a mitochondrial membrane protein highly expressed in malignant gliomas. In this preclinical study, we monitored the effect of ErPC3 treatment in vivo using 18 F-DPA-714 PET. Methods: In vitro studies investigated the antitumor effect of ErPC3 in 9L rat gliosarcoma cells. In vivo, glioma-bearing rats were imaged with 18 F-DPA-714 for the time of treatment. Results: A significant decrease in 9L cell proliferation and viability and a significant increase in apoptosis and caspase-3 activation were demonstrated on ErPC3 treatment in cell culture. In the rat model, ErPC3 administration resulted in significant changes in 18 F-DPA-714 tumor uptake over the course of the treatment. Immunohistochemistry revealed reduced tumor volume and increased cell death in ErPC3-treated animals accompanied by infiltration of the tumor core by CD11b-positive microglia/macrophages and glial fibrillary acidic proteinpositive astrocytes. Conclusion: Our findings demonstrate a potent antitumor effect of ErPC3 in vitro, in vivo, and ex vivo. PET imaging of TSPO expression using 18 F-DPA-714 allows effective monitoring and quantification of disease progression and response to ErPC3 therapy in intracranial 9L gliomas.

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“…The compounds have an insignificant effect on normal lymphocytes, which means they probably do not interfere with the main growth factors, cytokines and chemokines influencing the viability and proliferation of haematopoietic cells. The selectivity against cells derived from blood versus solid tumours was reported for some alkylphosphocholine analogues [35], being the premise of a good therapeutic potential. The behaviour of the prepared compounds is very similar.…”

Section: Antineoplastic Activitymentioning

confidence: 98%

Synthesis of structural analogues of hexadecylphosphocholine and their antineoplastic, antimicrobial and amoebicidal activity

Timko

Fischer‐Fodor

Garajová

et al. 2015

European Journal of Medicinal Chemistry

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Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells

Cited by 33 publications

References 39 publications

Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy

Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy

The Translocator Protein Radioligand ¹⁸F-DPA-714 Monitors Antitumor Effect of Erufosine in a Rat 9L Intracranial Glioma Model

Synthesis of structural analogues of hexadecylphosphocholine and their antineoplastic, antimicrobial and amoebicidal activity

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Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells

Cited by 33 publications

References 39 publications

Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy

Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy

The Translocator Protein Radioligand 18F-DPA-714 Monitors Antitumor Effect of Erufosine in a Rat 9L Intracranial Glioma Model

Synthesis of structural analogues of hexadecylphosphocholine and their antineoplastic, antimicrobial and amoebicidal activity

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The Translocator Protein Radioligand ¹⁸F-DPA-714 Monitors Antitumor Effect of Erufosine in a Rat 9L Intracranial Glioma Model