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Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
Reversal of multidrug-resistance using Valspodar (PSC 833) and doxorubicin in osteosarcoma
E Cagliero1, R Ferracini, E Morello
1Istituto per la Ricerca e la Cura del Cancro (I.R.C.C.), 10060 Candiolo, Italy.
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.
Insights
Valspodar (PSC 833) effectively reversed multidrug resistance (MDR) in osteosarcoma cells. This combination therapy with doxorubicin (DXR) showed promise for treating aggressive osteosarcoma by overcoming P-glycoprotein (Pgp) mediated resistance.
Area of Science:
- Oncology
- Pharmacology
- Veterinary Medicine
Background:
- High-grade osteosarcoma is aggressive, often presenting with widespread micrometastases.
- Doxorubicin (DXR) is a key neoadjuvant chemotherapy, but multidrug resistance (MDR) via P-glycoprotein (Pgp) limits its efficacy.
- MDR is a significant challenge in osteosarcoma treatment, leading to chemotherapy failure.
Purpose of the Study:
- To investigate the efficacy of Valspodar (PSC 833), a cyclosporine A derivative, in overcoming MDR in human osteosarcoma cells.
- To assess Pgp expression in canine appendicular osteosarcoma.
- To evaluate the safety and efficacy of combined DXR and PSC 833 treatment in dogs with osteosarcoma.
Main Methods:
- In vitro analysis of PSC 833's effect on MDR human osteosarcoma cells.
- Immunohistochemical evaluation of Pgp expression in canine osteosarcoma tissues.
- In vivo study involving combined administration of DXR and PSC 833 to dogs, with pharmacokinetic monitoring.
Main Results:
- PSC 833 reversed the MDR phenotype at clinically relevant concentrations.
- Pgp expression was detected in 66.6% of canine osteosarcoma cases.
- Combined DXR and PSC 833 treatment achieved therapeutic DXR exposure with a 30% dose reduction and no significant toxicity.
Conclusions:
- PSC 833 demonstrates potential for reversing Pgp-mediated MDR in osteosarcoma.
- The high incidence of Pgp in osteosarcoma supports MDR-targeted therapeutic strategies.
- Combination therapy with DXR and PSC 833 offers a promising approach to enhance osteosarcoma treatment outcomes.
