title: Balance between proliferation and apoptosis in leukemic cell lines resistant to cytostatics.
abstract: Resistance to apoptosis may contribute to tumorigenesis and, in part, explains treatment failures in neoplastic diseases. We evaluated in vitro drug-induced apoptosis in leukemic cells using TdT-dependent labeling of DNA breaks with digoxigenine-dUTP and PI DNA staining in multiparameter flowcytometry. In cell lines developing drug resistance, a significant inhibition of proliferation and increased cell clearance via apoptosis was shown. Moreover, in drug resistant sub-lines and in blasts from AML patients, a variable apoptotic response to in vitro exposure to cytostatics was seen. Half of the studied AML cases were completely resistant to Novantrone-induced apoptosis with no correlation between sensitivity to Novantrone and bcl-2 expression. One case showed intraclonal heterogeneity with two coexisting populations: an immature blast population resistant to Novantrone and a differentiating blast population showing apoptotic response. Another case showed complete resistance to various cytostatics, but incubation with anti-CD95 monoclonal antibody resulted in a considerable apoptotic response. This case demonstrates that a lack of apoptotic response to cytostatics does not preclude sensitivity to other apoptotic stimuli. Our results confirm the role apoptosis plays in selection of drug-resistant clones and suggest different signaling pathways for apoptosis operating in various leukemic blasts.
authors.affiliation: Department of Pathology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Macnamara
authors.forename: K A
authors.initials: KA
authors.lastname: Palucka
authors.forename: A
authors.initials: A
authors.lastname: Porwit-MacDonald
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008942:Mitoxantrone / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D008942:Mitoxantrone