Cytotoxic activity of 2-Fluoro-ara-AMP and 2-Fluoro-ara-AMP-loaded erythrocytes against human breast carcinoma cell lines.
Fludarabine phosphate (2-Fluoro-ara-AMP) is a purine analogue approved for the clinical treatment of haematological malignancies. This antimetabolite has also shown 'in vitro' antiproliferative activity against experimental models of solid mammary tumor. In this perspective, we have determined the cytotoxic effects of 2-Fluoro-ara-AMP against two human breast cancer cell lines (the ER-positive MCF-7 and the ER-negative MDA-MB-435), by adding the drug both in its free form and encapsulated into erythrocytes, as a strategy to modify the pharmacokinetic profile of the compound in order to increase its efficacy and decrease its toxicity. Similar antiproliferative activity of 2-Fluoro-ara-AMP in the two cell lines was obtained, reaching an almost complete abrogation of growth already after just 24 h of free drug exposure at all the tested doses. Meanwhile, encapsulated 2-Fluoro-ara-AMP was successfully released from erythrocytes into the culture media in a time-dependent manner with an efficacy comparable to that of the free drug treatment. This result suggests the possibility of administering 2-Fluoro-ara-AMP in patients with breast cancer using autologous erythrocytes as a system to slowly and constantly deliver 2-Fluoro-ara-A into circulation. In addition, possible mechanisms involved in the antiproliferative activity of 2-Fluoro-ara-AMP, such as the effects on cell cycle progression, p53 expression and STAT1 pathway activation in ER+ and ER- cancer cell lines, are proposed.
Department of Biomolecular Sciences, University of Urbino, 61029 Urbino (PU), Italy.
Francesca
F
Pierigè
Cinzia
C
De Marco
Nicola
N
Orlotti
Sabrina
S
Dominici
Sara
S
Biagiotti
Sonja
S
Serafini
Nadia
N
Zaffaroni
Mauro
M
Magnani
Luigia
L
Rossi
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001088:Arabinonucleotides / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D013997:Time Factors; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D000970:Antineoplastic Agents; D001088:Arabinonucleotides; D003603:Cytotoxins; D004273:DNA, Neoplasm; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; C034957:2-fluoro-araATP