title: In vitro activity of 2-chlorodeoxyadenosine (CdA) in primary cultures of human haematological and solid tumours.
abstract: 2-Chlorodeoxyadenosine (CdA) is a deaminase-resistant purine analogue which has shown clinical activity against various haematological tumours, and is currently undergoing phase II trials. In the present study, the semiautomated fluorometric microculture cytotoxicity assay (FMCA) was used for in vitro evaluation of CdA activity in cell suspensions from both haematological and solid tumours. A total of 133 samples from various diagnoses were successfully tested with continuous drug exposure. CdA showed high in vitro activity against samples from chronic and acute lymphocytic leukaemia and acute myelocytic leukaemia, but little or no response was observed in the solid tumour groups. Cross-resistance analysis with standard drugs revealed the following rank order of correlation coefficients: cytosine arabinoside (AraC) > daunorubicin > doxorubicin > vincristine > prednisolone > 4-hydroperoxycyclophosphamide > etoposide > cisplatin. The high correlation between CdA and AraC was maintained even if the analysis was based only on the haematological tumours. The results indicate that CdA is differentially active against haematological tumours with little or no activity against solid tumours. CdA also appears highly cross resistant with AraC. If this disease-specific information is substantiated in further clinical trials and extended to other phase I-II drugs, non-clonogenic drug resistance assays such as the FMCA may become useful in new drug evaluation, and in targeting specific diagnoses and patients for phase II trials.
authors.affiliation: Division of Clinical Pharmacology, University Hospital, Uppsala, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Larsson
authors.forename: H
authors.initials: H
authors.lastname: Fridborg
authors.forename: J
authors.initials: J
authors.lastname: Liliemark
authors.forename: K
authors.initials: K
authors.lastname: Csoka
authors.forename: J
authors.initials: J
authors.lastname: Kristensen
authors.forename: M
authors.initials: M
authors.lastname: de la Torre
authors.forename: P
authors.initials: P
authors.lastname: Nygren
mesh_terms: D018268:Adrenocortical Carcinoma / Q000188:drug therapy; D001943:Breast Neoplasms / Q000188:drug therapy; D017338:Cladribine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D014407:Tumor Cells, Cultured
chemical_list: D017338:Cladribine