title: In-vitro and in-vivo anti-cancer activity of a novel gemcitabine-cardiolipin conjugate.
abstract: Our objectives were to study the biological activity of a novel gemcitabine-cardiolipin conjugate (NEO6002) and compare that with gemcitabine. Cytotoxicity in vitro was determined against several gemcitabine-sensitive parental and gemcitabine-resistant cancer cell lines using the sulforhodamine B assay. The in vivo toxicity was examined by changes in body weight and hematologic indices of conventional mice. Immunodeficient SCID mice bearing P388 and BxPC-3 tumor xenografts were used to evaluate the in-vivo therapeutic efficacy. Both NEO6002 and gemcitabine showed pro-apoptotic and cytotoxic effects against all gemcitabine-sensitive cell lines tested. Unlike gemcitabine, the cytotoxicity of NEO6002 was independent of nucleoside transporter (NT) inhibitors, indicating a different internalization route of NEO6002. The conjugate demonstrated a favorable activity not only in ARAC-8C, a NT-deficient gemcitabine-resistant human leukemia cell line, but also in several other gemcitabine-resistant cell lines. At the in-vivo level, a comparative toxicity study showed a significant body weight loss and a decrease in white blood cell counts in gemcitabine-treated mice, whereas the influence of NEO6002 was mild. Treatment of NEO6002 at 27 micromol/kg increased the median survival of CD2F1 mice bearing P388 cells by up to 73%, while at the same doses and schedule of gemcitabine resulted in toxic deaths of all treated mice. At a dose of 18 micromol/kg, NEO6002 inhibited the growth of BxPC-3 xenografts by 52%, while only 32% of tumor inhibition was achieved with gemcitabine. We conclude that NEO6002 may be an effective chemotherapeutic agent with improved tolerability and can potentially circumvent NT-deficient, gemcitabine-resistant tumors.
authors.affiliation: Research and Development, NeoPharm Inc., Waukegan, Illinois 60085, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Chen
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chien
authors.forename: Abdul R
authors.initials: AR
authors.lastname: Khan
authors.forename: Saifuddin
authors.initials: S
authors.lastname: Sheikh
authors.forename: Shoukath M
authors.initials: SM
authors.lastname: Ali
authors.forename: Moghis U
authors.initials: MU
authors.lastname: Ahmad
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002308:Cardiolipins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D007958:Leukocyte Count; D051379:Mice; D016513:Mice, SCID; D009503:Neutropenia / Q000139:chemically induced; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D002308:Cardiolipins; C514352:NEO 6002; D033703:Nucleoside Transport Proteins; D003841:Deoxycytidine; D013868:Thioinosine; D004176:Dipyridamole; C001789:4-nitrobenzylthioinosine; D000093542:Gemcitabine