title: Metronomic scheduling of imatinib abrogates clonogenicity of neuroblastoma cells and enhances their susceptibility to selected chemotherapeutic drugs in vitro and in vivo.
abstract: Imatinib is currently in early clinical trials as targeted therapy for relapsed neuroblastomas and other childhood solid tumors expressing platelet-derived growth factor receptors (PDGFR) or c-Kit. Short-term treatment with imatinib in clinically achievable concentrations is ineffective in neuroblastoma in vitro. However, clinically, imatinib is administered daily over long time periods. The effects of combining imatinib with chemotherapy in neuroblastoma are unknown. Here, a panel of neuroblastoma cell lines (n = 5) were studied, representing tumors with different biological (MYCN-amplification +/-) and clinical (drug resistance) features. Using a protracted low-dose treatment schedule (1-3 weeks; 0.5-5microM) imatinib dose-dependently inhibited proliferation and clonogenic survival for all tested cell lines with IC50 <2.5microM. In contrast, short-term treatment (<96 hrs) was ineffective. Low-dose imatinib was synergistic in combination with doxorubicin and caused increased G2/M- and S-phase arrest and apoptosis as evidenced by enhanced caspase-3 activation and sub-G1 DNA accumulation. A significant but less pronounced effect was observed when imatinib was combined with etoposide or vincristine, as opposed to cisplatin, melphalan, or irinotecan. All cell lines expressed PDGFRbeta, whereas no protein expression of PDGFRalpha was detected in MYCN amplified cell lines. PDGF-BB caused PDGFRbeta phosphorylation and partially rescued neuroblastoma cells from doxorubicin-induced apoptosis, in an imatinib-sensitive manner. In vivo, treatment with imatinib in combination with doxorubicin induced a significant growth inhibition of established neuroblastoma xenografts. These findings suggest clinical testing of imatinib in combination with selected chemotherapeutic drugs, in particular doxorubicin, in children with high-risk neuroblastoma.
authors.affiliation: Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ebba
authors.initials: E
authors.lastname: Palmberg
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
authors.forename: Janna
authors.initials: J
authors.lastname: Paulsson
authors.forename: Helena
authors.initials: H
authors.lastname: Gleissman
authors.forename: Malin
authors.initials: M
authors.lastname: Wickström
authors.forename: Margareta
authors.initials: M
authors.lastname: Edgren
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.forename: Magnus
authors.initials: M
authors.lastname: Lindskog
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004334:Drug Administration Schedule; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000077214:Becaplermin; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta