title: AMD473 (ZD0473) exhibits marked in vitro anticancer activity in human tumor specimens taken directly from patients.
abstract: AMD473 (ZD0473; cis-amminedichloro[2-methylpyridine]platinum [II]) is a new generation anticancer agent that, in preclinical studies, shows evidence of an extended spectrum of antitumor activity and overcomes platinum resistance mechanisms. Here we evaluate the activity of AMD473 (ZD0473) in a panel of 120 human tumor specimens using a soft agar cloning assay (human tumor colony-forming assay). When tumor cells were treated with 1.0, 4.0 or 16.0 microg/ml AMD473 (ZD0473) for 2 h, in vitro responses were observed in 18% (9/51), 33% (17/51) and 44% (19/43) of assessable specimens. Treatment of tumor cells with the same concentrations of AMD473 (ZD0473) for 24 h resulted in responses of 33% (16/48), 63% (30/48) and 85% (35/41). AMD473 (ZD0473) (16 microg/ml; 24 h) demonstrated activity towards 100% of the non-small cell lung (5/5) and ovarian (8/8) cancer specimens and 73% (8/11) of the breast cancer specimens treated. Low levels of cross-resistance to cisplatin cyclophosphamide, 5-flurouracil, etoposide and gemcitabine were observed. There was a positive relationship between AMD473 (ZD0473) concentration and effect, and a significant difference between response to 2- versus 24-h exposure to 4 or 16 microg/ml (p=0.003 and p=0.001, respectively). These responses demonstrate efficacy at pharmacologically relevant concentrations, suggesting AMD473 (ZD0473) deserves further evaluation.
authors.affiliation: Human Tumor Cloning Laboratory, CTRC Institute for Drug Development, San Antonio, TX 78245-3217, USA. lmedina@idd.org
authors.forename: Leticia
authors.initials: L
authors.lastname: Medina-Gundrum
authors.forename: Cesario
authors.initials: C
authors.lastname: Cerna
authors.forename: Lionel R
authors.initials: LR
authors.lastname: Gomez
authors.forename: Michael
authors.initials: M
authors.lastname: Yochmowitz
authors.forename: Steven
authors.initials: S
authors.lastname: Weitman
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C110525:amminedichloro(2-methylpyridine)platinum(II)