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

  • Authors:
    • E. Cagliero
    • R. Ferracini
    • E. Morello
    • K. Scotlandi
    • M. C. Manara
    • P. Buracco
    • A. Comandone
    • R. Baroetto Parisi
    • N. Baldini
  • View Affiliations

  • Published online on: November 1, 2004     https://doi.org/10.3892/or.12.5.1023
  • Pages: 1023-1031
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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 down-modulation of MDR.

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November 2004
Volume 12 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Cagliero E, Ferracini R, Morello E, Scotlandi K, Manara MC, Buracco P, Comandone A, Baroetto Parisi R and Baldini N: Reversal of multidrug-resistance using Valspodar® (PSC 833) and doxorubicin in osteosarcoma. Oncol Rep 12: 1023-1031, 2004.
APA
Cagliero, E., Ferracini, R., Morello, E., Scotlandi, K., Manara, M.C., Buracco, P. ... Baldini, N. (2004). Reversal of multidrug-resistance using Valspodar® (PSC 833) and doxorubicin in osteosarcoma. Oncology Reports, 12, 1023-1031. https://doi.org/10.3892/or.12.5.1023
MLA
Cagliero, E., Ferracini, R., Morello, E., Scotlandi, K., Manara, M. C., Buracco, P., Comandone, A., Baroetto Parisi, R., Baldini, N."Reversal of multidrug-resistance using Valspodar® (PSC 833) and doxorubicin in osteosarcoma". Oncology Reports 12.5 (2004): 1023-1031.
Chicago
Cagliero, E., Ferracini, R., Morello, E., Scotlandi, K., Manara, M. C., Buracco, P., Comandone, A., Baroetto Parisi, R., Baldini, N."Reversal of multidrug-resistance using Valspodar® (PSC 833) and doxorubicin in osteosarcoma". Oncology Reports 12, no. 5 (2004): 1023-1031. https://doi.org/10.3892/or.12.5.1023