title: Incidence of P-glycoprotein overexpression and multidrug resistance (MDR) reversal in adult soft tissue sarcoma.
abstract: Multidrug resistance (MDR) is a widespread problem in the treatment of neoplastic diseases and may limit the effectiveness of treatment of adult soft tissue sarcomas (STS). We examined the levels of expression of the MDR marker P-glycoprotein (Pgp) in fresh, surgical material and matched paraffin-embedded tissue using MRK-16 and JSB-1 monoclonal antibodies. Using fresh tumour material in short-term culture an assessment of doxorubicin sensitivity (MTT assay) and MDR modulation using PSC-833 in daunorubicin (DNR) accumulation experiments (FACS analysis) was carried out. 44 patients were studied at various disease stages with a mean follow-up duration of 487 days (range: 45-1095 days). Immunocytochemistry and immunohistochemistry showed 62% and 58%, respectively, of STS samples were positive for Pgp. Patients showing negative Pgp expression had a median survival of 544 days versus 431 days for Pgp-positive patients (P=0.311), with disease-free survival medians of 508 and 355 days, respectively (P=0.203). In vitro doxorubicin sensitivity was not informative in this respect and there was no apparent relationship between this and Pgp expression. Eleven out of 29 samples evaluated for MDR modulation showed enhanced tumour cell DNR accumulation. However, the effects of PSC-833 on drug accumulation in clinical material were modest compared with those seen for MDR cell lines, with a maximum of only 20% enhancement. Moreover, there was no relationship between the extent of PSC-833 effects on accumulation and the levels of Pgp seen in the STS samples. Nevertheless, we show evidence that a proportion of cases of STS express moderate to high levels of Pgp. There may be a role for MDR modulating agents in association with doxorubicin in the treatment of these tumours, either in the adjuvant setting or at first relapse.
authors.affiliation: CRC Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Rd, Sutton, UK. h.coley@surrey.ac.uk
authors.forename: H M
authors.initials: HM
authors.lastname: Coley
authors.forename: M W
authors.initials: MW
authors.lastname: Verrill
authors.forename: S E
authors.initials: SE
authors.lastname: Gregson
authors.forename: D E
authors.initials: DE
authors.lastname: Odell
authors.forename: C
authors.initials: C
authors.lastname: Fisher
authors.forename: I R
authors.initials: IR
authors.lastname: Judson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002648:Child; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004317:Doxorubicin