CP‐4055 and CP‐4126 are active in ara‐C and gemcitabine‐resistant lymphoma cell lines

Galmarini, Carlos M.; Myhren, Finn; Sandvold, Marit Liland

doi:10.1111/j.1365-2141.2008.07467.x

Cited by 33 publications

(28 citation statements)

References 8 publications

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“…3) (35,36), gemcitabine (CP-4126, Fig. 3) (37)(38)(39)(40), and troxacitabine-lipid conjugates (41). Similar to studies on AraC, results of these lipid prodrugs showed increased efficacy in various types of in vitro and in vivo tumor models.…”

Section: Tumor Targeting Of Anticancer Drugssupporting

confidence: 61%

Lipid-Based Drug Carriers for Prodrugs to Enhance Drug Delivery

Zaro

2014

AAPS J

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ABSTRACT. The combination of lipid drug delivery systems with prodrugs offers several advantages including improved pharmacokinetics, increased absorption, and facilitated targeting. Lipidization and use of lipid carriers can increase the pharmacological half-life of the drug, thus improving pharmacokinetics and allowing less frequent dosing. Lipids also offer advantages such as increased absorption through the intestines for oral drug absorption and to the CNS for brain delivery. Furthermore, the use of lipid delivery systems can enhance drug targeting. Endogenous proteins bind lipids in the blood and carry them to the liver to enable targeting of this organ. Drugs with significant side effects in the stomach can be specifically delivered to enterocytes by exploiting lipases for prodrug activation. Finally, lipids can be used to target the lymphatic system, thus bypassing the liver and avoiding first-pass metabolism. Lymphatic targeting is also important for antiviral drugs in the protection of B and T lymphocytes. In this review, both lipid-drug conjugates and lipid-based carriers will be discussed. An overview, including the chemistry and assembly of the systems, as well as examples from the clinic and in development, will be provided.

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Section: Tumor Targeting Of Anticancer Drugssupporting

confidence: 61%

Lipid-Based Drug Carriers for Prodrugs to Enhance Drug Delivery

Zaro

2014

AAPS J

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“…It has been shown before that elaidic acid esterification of nucleoside drugs can modulate their cellular uptake mechanisms (15,17,29). Transport proteins that have been associated with azacytidine uptake include hCNT1 (13), hCNT3, (30) and hENT1 (31).…”

Section: Resultsmentioning

confidence: 99%

“…In an independent approach, cytidine analogues have been modified by esterification with a fatty acid. In this context, it has been shown that elaidic acid esterification of cytarabine, a cytosine analogue closely related to azacytidine, modified the cellular uptake mechanisms of the drug and rendered it more active in human solid tumor models (15)(16)(17). Because the drug must enter into cells to interact with its target, the knowledge of the transport mechanisms is a key aspect for understanding its extended mode of action.…”

Section: Introductionmentioning

confidence: 99%

Delivery of 5-Azacytidine to Human Cancer Cells by Elaidic Acid Esterification Increases Therapeutic Drug Efficacy

Brueckner

Rius

Markelova

et al. 2010

Molecular Cancer Therapeutics

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Azacytidine is an established nucleoside drug that is well known for its ability to modulate epigenetic gene regulation by inhibition of DNA methylation. Despite recent advances in the clinical development of azacytidine, the use of the drug is limited by its low bioavailability and dependen cy on variably expressed nucleoside transporters for cellular uptake. We show here that CP-4200, an elaidic acid derivative of azacytidine, has strong epigenetic modulatory potency in human cancer cell lines, as evidenced by efficient depletion of DNA methyltransferase protein, genome-wide DNA demethylation, and robust reactivation of epigenetically silenced tumor suppressor genes. Importantly, however, the cellular uptake of CP-4200 was substantially less dependent on the nucleoside transporters that are known to be involved in azacytidine uptake. In agreement with this notion, CP-4200 showed a significantly higher antitumoral activity than azacytidine in an orthotopic mouse tumor model for acute lymphocytic leukemia. Together, these data represent a detailed characterization of the CP-4200 mode of action and suggest that elaidic acid modification improves the therapeutic efficacy of azacytidine. Mol Cancer Ther; 9(5); 1256-64. ©2010 AACR.

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“…Activation of survival pathways such as Akt and ERK1/2 by factors produced in the microenvironment, including the chemokine CXCL12, protects CLL cells from apoptosis. 8,9 Consequently, alterations in the expression or function of proteins regulating these survival pathways, including the PHLPP phosphatases, can influence how CLL cells respond to growth/survival cues and contribute to CLL pathogenesis.…”

mentioning

confidence: 99%

“…1,2 Reduced hENT1 expression and/or activity is associated with adverse therapeutic outcomes in patients with acute myeloid leukemia (AML) treated with ara-C. 3,4 Elacytarabine (CP-4055) (Figure 1), the lipophilic 5 0 -elaidic acid ester of ara-C, enters cells independently of hENT1 and is active in both ara-C-resistant cell lines 5 --7 and animal tumor xenograft models. 8,9 In patients with…”

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confidence: 99%