title: Expression of multidrug resistance-associated proteins in paediatric             soft tissue sarcomas before and after chemotherapy.
abstract: Expression of multidrug resistance (MDR) proteins is thought to significantly contribute to the different biological/clinical behaviour of soft tissue sarcomas (STS) of various histological types and clinicopathological stages, as they are responsible for active efflux of cytotoxic drugs from tumour cells. We investigated the expression of 3 MDR proteins, i.e., permeability glycoprotein 1 (P-gp), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance 3 (MDR3), in 43 STS specimens from newly-diagnosed paediatric patients, 31 with rhabdomyosarcoma (RMS) and 12 with non-RMS STS. To assess the influence of chemotherapy on STS drug resistance, the number of MDR-associated protein-positive cells was determined in 15 patients on both primary lesions before chemotherapy and on residual tumour after chemotherapy. At least one of the MDR-associated proteins tested was detected in 84% of primary untreated STS specimens. In these specimens, MRP1 was detected in a high percentage (70%) of the cases, followed by MDR3 in 58% and P-gp in 44%. Many specimens showed co-expression of two different MDR proteins. Interestingly, MDR3 was significantly associated with the presence of PAX3/PAX7-FKHR transcripts in RMS (p<0.05). Moreover, expression of MRP1 and MDR3 was significantly more frequent in group III and IV tumours as compared with those of groups I and II (p<0.01). After chemotherapy MRP1, MDR3 and, to a lesser extent, P-gp expression was found to be increased in most of the samples. The frequent expression of these MDR-associated proteins in primary tumour cells before chemotherapy and the increase of their levels after chemotherapy, suggest that these proteins play a pivotal role in conferring drug resistance and in producing therapy-induced differentiation on STS.
authors.affiliation: Pathology Department, IRCCS, Ospedale Pediatrico Bambino Gesù,                     I-00165 Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Citti
authors.forename: Renata
authors.initials: R
authors.lastname: Boldrini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Inserra
authors.forename: Anna
authors.initials: A
authors.lastname: Alisi
authors.forename: Rosanna
authors.initials: R
authors.lastname: Pessolano
authors.forename: Angela
authors.initials: A
authors.lastname: Mastronuzzi
authors.forename: Angelica
authors.initials: A
authors.lastname: Zin
authors.forename: Luigi
authors.initials: L
authors.lastname: De Sio
authors.forename: Angelo
authors.initials: A
authors.lastname: Rosolen
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Doriana
authors.initials: D
authors.lastname: Fruci
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism*; D018709:Statistics, Nonparametric; D014565:Urogenital Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015514:Oncogene Proteins, Fusion; C095122:multidrug resistance protein 3; C421109:multidrug resistance-associated protein 1