The Activity of the Lipophilic Nucleoside Derivatives Elacytarabine and CP-4126 in a Panel of Tumor Cell Lines Resistant to Nucleoside Analogues

Abstract

The clinical activity of pyrimidine analogues (araC and gemcitabine) is impaired by different mechanisms of resistance and several efforts to overcome this problem have been undertaken. Elacytarabine (CP-4055, araC-5′elaidic acid ester) and CP-4126 (gemcitabine-5′elaidic acid ester) are lipophilic fatty acid derivatives of the nucleoside analogues araC and gemcitabine, respectively, that are currently investigated in clinical trials in solid tumors and hematological malignancies. Here, we present results on the activity of elacytarabine and CP-4126 in a panel of tumor cell lines that are resistant to araC and gemcitabine and we discuss the potential use of these agents in the treatment of patients with drug resistance phenotypes. We conclude that elacytarabine and CP-4126 are active in cells with deficient nucleoside membrane transport and altered mismatch repair. These results should be taking into consideration for future clinical development of elacyatrabine and CP-4126.

KEYWORDS:

• Pyrimidine analogues
• tumor cells
• lipophilic fatty acids
• elacytarabine

Notes

^aMean ± SD of IC₅₀ values expressed in μM. IC₅₀ values were obtained from dose response curves assessed by MTT assay after exposure to the drugs for 72 hours and are means of three separate experiments each of which were performed in triplicate.

^aMean ± SD of IC₅₀ values expressed in nM. IC₅₀ values were obtained from dose response curves assessed by MTT assay after 6 days of drug exposure, and are means of three separate experiments each of which were performed in triplicate.