Reversal of multidrug-resistance using Valspodar® (PSC 833) and doxorubicin in osteosarcoma

E. Cagliero, R. Ferracini, E. Morello, K. Scotlandi, M. C. Manara, P. Buracco, A. Comandone, R. Baroetto Parisi, N. Baldini

Research output: Contribution to journalArticlepeer-review

Abstract

High-grade osteosarcoma is an extremely aggressive neoplasm, where over 80% of patients present with life-threatening micrometastases at diagnosis. Systemic control of the disease is therefore critical for the treatment of these patients and neoadjuvant chemotherapy using various drugs, including doxorubicin (DXR), which has been demonstrated to be the most effective regimen. Multidrug resistance (MDR) to some anticancer agents, including DXR, mediated by the MDR1 gene product P-glycoprotein (Pgp), has been shown to be a major cause of chemotherapy failure in osteosarcoma. We analyzed the effect of a cyclosporine A derivate Valspodar® (PSC 833) on MDR human osteosarcoma cells. We also evaluated Pgp expression in sporadic appendicular canine osteosarcoma. Moreover, dogs were treated with combined administration of DXR and PSC 833. Several blood samples were collected for the determination of DXR and PSC 833 levels. PSC 833 induced a complete reversal of the resistant phenotype at concentrations compatible with the clinical use. Pgp was present in 12/18 (66.6%) of the cases. At the time of DXR administration, adequate blood concentrations of PSC 833, to provide a complete MDR reversal, were obtained without clinical or laboratory findings of toxicity. Combination therapy with DXR and PSC 833 allowed a 30% decrease in DXR dose infusion with equivalent therapeutic exposure. The high incidence of Pgp expression in osteosarcoma confers to the study a rationale for an effective regimen based on downmodulation of MDR.

Original languageEnglish
Pages (from-to)1023-1031
Number of pages9
JournalOncology Reports
Volume12
Issue number5
Publication statusPublished - Nov 2004

Keywords

  • Doxorubicin
  • Multidrug-resistance
  • Osteosarcoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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