title: Imatinib mesylate potentiates topotecan antitumor activity in rhabdomyosarcoma preclinical models.
abstract: 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.
authors.affiliation: Department of Oncology, Royal Liverpool Children's NHS Trust Alder Hey, Liverpool, United Kingdom. Heather.McDowell@RLC.NHS.UK
authors.forename: Heather P
authors.initials: HP
authors.lastname: McDowell
authors.forename: Daniela
authors.initials: D
authors.lastname: Meco
authors.forename: Anna
authors.initials: A
authors.lastname: Riccardi
authors.forename: Barbara
authors.initials: B
authors.lastname: Tanno
authors.forename: Anna C
authors.initials: AC
authors.lastname: Berardi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Raschellà
authors.forename: Riccardo
authors.initials: R
authors.lastname: Riccardi
authors.forename: Carlo
authors.initials: C
authors.lastname: Dominici
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000188:drug therapy*; D019772:Topotecan / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D019772:Topotecan; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor