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McDowell, H.P. et al.

McDowell, Meco, Riccardi, Tanno, Berardi, Raschellà, Riccardi, Dominici,

Imatinib mesylate potentiates topotecan antitumor activity in rhabdomyosarcoma preclinical models.

High levels of PDGFR expression in primary rhabdomyosarcoma (RMS) have been associated with disease progression. To date however, there are no reports on the activity of imatinib mesylate, a selective PDGFR inhibitor, in RMS preclinical models. A panel of 5 RMS cell lines was used to investigate the expression of PDGFRalpha and PDGFRbeta, c-Kit and the multidrug transporter ABCG2 (also inhibited by imatinib). In vitro and in vivo experiments were performed using RD (embryonal) and RH30 (alveolar) cell lines to determine the efficacy of imatinib as single agent and in combination with topotecan (TPT). PDGFRbeta was significantly expressed in all cell lines, with the highest levels in RD, while PDGFR alpha and ABCG2 were significantly expressed only in RH30 and RMZ-RC2. c-Kit was not detected. PDGFRbeta signaling was active in RD but not in RH30, whilst PDGFRalpha signaling was not active in either cell lines. Significant ABCG2- mediated extrusion of Hoechst 33342 was demonstrated in RH30 but not in RD, and was inhibited by imatinib and the specific ABCG2 inhibitor Ko143. In vitro, imatinib was not active as a single agent at therapeutic concentrations, but significantly potentiated TPT antitumor activity in both cell lines. In vivo experiments using tumor xenografts confirmed the synergistic interaction in both cell lines. These results suggest that at least 2 different mechanisms-inhibition of ABCG2 and/or PDGFRbeta-are involved in the synergistic interaction between imatinib and TPT, and support the use of this combination for the treatment of high-risk RMS patients. (c) 2006 Wiley-Liss, Inc.[1]

References

Imatinib mesylate potentiates topotecan antitumor activity in rhabdomyosarcoma preclinical models. McDowell, H.P., Meco, D., Riccardi, A., Tanno, B., Berardi, A.C., Raschellà, G., Riccardi, R., Dominici, C. Int. J. Cancer (2007) [Pubmed]

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