title: Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia cells in vitro, as single agent and in drug combination.
abstract: The mammalian target of rapamycin inhibitor rapamycin and its analogues show promising anticancer activity in various experimental tumor models and are presently evaluated in clinical trials. We, here, evaluated the in vitro activity of rapamycin with regard to tumor-type specificity and possible mechanisms of drug resistance in 97 tumor cell samples from patients and in a resistance-based cell line panel, using the fluorometric microculture cytotoxicity assay. Rapamycin was dose-dependently cytotoxic in patient tumor cells and in cell lines. In primary cells, rapamycin was more active in hematological than in solid tumor samples, with chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia being the most sensitive tumor types. Considerable inter-individual differences in sensitivity were apparent among CLL samples, but no difference was observed between IGHV mutated and unmutated CLL samples, whereas a tendency to lower rapamycin sensitivity was indicated for samples displaying poor-prognostic genomic markers. Combination experiments in CLL cells indicated that rapamycin acted synergistically with vincristine, cisplatin, chlorambucil and taxotere. These results and the clinically-experienced good tolerance to rapamycin analogues encourage clinical studies of rapamycin in CLL treatment as single agent but also in combination with, e.g., vincristine and chlorambucil.
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden. anna.aleskog@medsci.uu.se
authors.forename: Anna
authors.initials: A
authors.lastname: Aleskog
authors.forename: Maria
authors.initials: M
authors.lastname: Norberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.forename: Linda
authors.initials: L
authors.lastname: Rickardson
authors.forename: Meena
authors.initials: M
authors.lastname: Kanduri
authors.forename: Gerard
authors.initials: G
authors.lastname: Tobin
authors.forename: Magnus
authors.initials: M
authors.lastname: Aberg
authors.forename: Mats G
authors.initials: MG
authors.lastname: Gustafsson
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.forename: Elin
authors.initials: E
authors.lastname: Lindhagen
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002699:Chlorambucil; D002945:Cisplatin; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D020123:Sirolimus / Q000494:pharmacology*; D043823:Taxoids; D014407:Tumor Cells, Cultured; D014750:Vincristine
chemical_list: D000903:Antibiotics, Antineoplastic; D043823:Taxoids; D000077143:Docetaxel; D002699:Chlorambucil; D014750:Vincristine; D002945:Cisplatin; D020123:Sirolimus