title: CLM29, a multi-target pyrazolopyrimidine derivative, has anti-neoplastic activity in medullary thyroid cancer in vitro and in vivo.
abstract: CLM29 (a pyrazolo[3,4-d]pyrimidine, that inhibits RET, epidermal growth factor receptor, vascular endothelial growth factor receptor, and has an anti-angiogenic activity) has anti-neoplastic activity in papillary dedifferentiated thyroid cancer. Here we tested CLM29 in medullary thyroid cancer (MTC), in primary MTC cells (P-MTC) obtained at surgery, and in TT cells harboring (C634W) RET mutation. CLM29 (10, 30, 50 μM) inhibited significantly (P<0.001) the proliferation, and increased the percentage of apoptotic P-MTC, TT and human dermal microvascular endothelial cells. The inhibition of proliferation by CLM29 was similar in P-MTC cells with/without RET mutation. TT cells were injected sc in CD nu/nu mice, and tumor masses became detectable between 20 and 30 days after xenotransplantation; CLM29 (50mg/kg/die) reduced significantly tumor growth and weight, and microvessel density. The anti-tumor activity of CLM29 has been shown in MTC in vitro, and in vivo, opening the way to a future clinical evaluation.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: alessandro.antonelli@med.unipi.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Antonelli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy; Istituto Toscano Tumori, Via Alderotti 27/n, Florence, Italy. Electronic address: guido.bocci@med.unipi.it.
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. Electronic address: lamotta@farm.unipi.it.
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: sm.ferrari@int.med.unipi.it.
authors.forename: Silvia Martina
authors.initials: SM
authors.lastname: Ferrari
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: puopak@int.med.unipi.it.
authors.forename: Poupak
authors.initials: P
authors.lastname: Fallahi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: corradoalda@gmail.com.
authors.forename: Alda
authors.initials: A
authors.lastname: Corrado
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: anna.fioravanti@libero.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Fioravanti
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. Electronic address: stefania.sartini@for.unipi.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: paolaorlandi21@libero.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Orlandi
authors.affiliation: Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: simona.piaggi@dps.unipi.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Piaggi
authors.affiliation: Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: alessandro.corti@med.unipi.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corti
authors.affiliation: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: g.materazzi@med.unipi.it.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Materazzi
authors.affiliation: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: galleridavid@hotmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Galleri
authors.affiliation: Department of Experimental Medicine, "Sapienza" University of Rome, Viale dell'Università 30, 00185 Rome, Italy. Electronic address: salvatore.ulisse@uniroma1.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ulisse
authors.affiliation: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: gabriella.fontanini@med.unipi.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: romano.danesi@med.unipi.it.
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. Electronic address: federico.dasettimo@farm.unipi.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.affiliation: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address: paolo.miccoli@dc.unipi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Miccoli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018278:Carcinoma, Neuroendocrine; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C556684:CLM29 compound; D011720:Pyrazoles; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A
keywords: CLM29; Medullary thyroid cancer; Pyrazolo[3,4-d]pyrimidine; Thyroid cancer; Tyrosine kinase inhibitors