Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-06

AUTHORS

Andries M. Bergman, Auke D. Adema, Jan Balzarini, Skjalg Bruheim, Iduna Fichtner, Paul Noordhuis, Øystein Fodstad, Finn Myhren, Marit L. Sandvold, Hans R. Hendriks, Godefridus J. Peters

ABSTRACT

Gemcitabine is a deoxycytidine (dCyd) analog with activity in leukemia and solid tumors, which requires phosphorylation by deoxycytidine kinase (dCK). Decreased membrane transport is a mechanism of resistance to gemcitabine. In order to facilitate gemcitabine uptake and prolong retention in the cell, a lipophilic pro-drug was synthesized (CP-4126), with an elaidic fatty acid esterified at the 5'position. CP-4126 was tested in cell lines resistant to cytarabine, another dCyd analog or gemcitabine. Activity of gemcitabine and the derivative was comparable in the parent cell lines, while in dCK deficient cells all compounds were inactive. However, inhibition of nucleoside transport increased the IC(50) for gemcitabine up to 200-fold, but not for CP-4126, underlining the independence of a nucleoside transporter. For in vivo evaluation, nude mice bearing a human xenograft were treated intraperitoneally every third day for five doses at the maximal tolerated dose. In melanoma, sarcoma, lung, prostate, pancreatic and breast cancer xenografts, gemcitabine and CP-4126 were equally and highly effective; in four other xenografts moderately but equally active. In contrast to gemcitabine, CP-4126 could be administered orally, with a schedule and dose dependent toxicity and antitumor activity. In a colon cancer xenograft, antitumor activity of orally administered CP-4126 was equal to the intraperitoneally administered drug. In conclusion, CP-4126 is membrane transporter independent. Intraperitoneally administered CP-4126 was as effective as gemcitabine in several xenografts and CP-4126 is tolerated when orally administered. CP-4126 seems to be a promising new anticancer drug. More... »

PAGES

456-466

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10637-009-9377-7

DOI

http://dx.doi.org/10.1007/s10637-009-9377-7

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1002295981

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20066470


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