Posters— Basic Science/Biology

DOXORUBICIN AND VALSPODAR (PSC 833) COMBINED THERAPY IN CANINE OSTEOSARCOMA ACCORDING TO P-GLYCOPROTEIN EXPRESSION

Cagliero E,¹ Scotlandi K,² Morello E,³ Manara MC,² Buracco P, ³ Baroetto R,¹ Ferracini R.^{1 1}Istituto per la Ricerca e la Cura del Cancro, Candiolo, Italy (10060); ² Istituti Ortopedici Rizzoli, Bologna, Italy (40136); ³ Dipartimento di Patologia Animale,Torino, Italy (10126)

Background: Osteosarcoma of the appendicular skeleton is one of the most life-threatening canine neoplasms. Only 10% of dogs treated with surgery alone survive one year after treatment. Even with the current most effective treatment, surgery combined with adjuvant chemotherapy, 65% of dogs die within one year and 85% of the dogs die within two years. In human osteosarcoma, it has been shown that P-glycoprotein (Pgp), which confers multidrug resistance (MDR) to some anticancer agents, including doxorubicin, might be a major cause of failure of disease control. We evaluated Pgp expression in osteosarcoma of dogs treated with combined administration of doxorubicin and the MDR modulator PSC 833 and examined the pharmacokinetic between the two drugs.

Patients and methods: dogs presenting appendicular osteosarcoma without detectable lung metastaseis at the time of diagnosis, underwent surgery consisting of amputation or of limb sparing technique when applicable. Post operatively dogs received doxorubicin alone in the first cycle, and in the following four cycles they received a combination of doxorubicin and PSC 833. According to predictable pharmacokinetic interactions, doxorubicin dose was reduced of 30%. Several blood samples were collected for the determination of doxorubicin and PSC 833 levels. Pgp expression was monitored on tumor tissue samples from surgical excision prior to treatment using immuno-histochemistry with anti-Pgp monoclonal antibodies.

Results: All the dogs treated were tested for Pgp expression prior to filing for treatment. Pgp was found to be expressed in 13/15 (87%) of the samples. At the time of doxorubicin administration, adequate blood concentrations (ie, 2.5 mM) of PSC 833, that are needed to reverse MDR, were achieved at the dose of 7.5 mg/Kg/day. Dogs did not show clinical or laboratory findings of toxicity. In order to maintain the same exposure and to control dose- related toxicity of doxorubicin, we verified that similar plasma levels of doxorubicin were achieved after both the standard full dose and with the reduced dose in animals given PSC 833.

Discussion: Current treatment of canine osteosarcoma using surgery and adjuvant therapy is not satisfactory. Combination therapy with doxorubicin and PSC 833 allows a decrease in doxorubicin dose infusions with equivalent therapeutic exposure. The high incidence of Pgp expression in tumor samples prior to treatment confers to the study a rationale for down-modulation of MDR. Further investigations are needed to evaluate concentrations of doxorubicin in the tumor tissues and to validate the efficacy of the treatment in ongoing clinical trials.