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.