D,L-BUTHIONINE-(S,R)-SULFOXIMINE POTENTIATES IN-VIVO THE THERAPEUTIC EFFICACY OF DOXORUBICIN AGAINST MULTIDRUG-RESISTANCE PROTEIN-EXPRESSING TUMORS

Intracellular glutathione (GSH) has been implicated as a regulatory de terminant of multidrug resistance protein (MRP) function, The objectiv e of the present study was to evaluate in vivo the ability of D,L-buth ionine-(S,R)-sulfoximine (D,L-BSO), a potent inhibitor of GSH biosynth esis, to reverse MRP-mediated drug resistance to doxorubicin. Athymic nude mice (nu/nu) bearing advanced parental human fibrosarcoma HT1080 and MRP-expressing HT1080/DR4 tumors were treated with the maximum tol erated dose of doxorubicin (10 mg/kg, i,v, push), This therapy produce d an overall response rate of 50% (20% complete response and 30% parti al response) in mice bearing parental HT1080 xenografts, whereas no si gnificant antitumor activity against HT1080/DR4 tumors was observed, T reatment of mice bearing HT1080 and HT1080/DR4 xenografts with a conti nuous i,v, infusion of nontoxic doses of D,L-BSO (300 and 600 mg/kg/da y) produced a 60% reduction of GSH plasma levels and greater than 95% reduction in GSH tumor levels in both parental and multidrug-resistant tumors; however, this treatment possessed no in vivo antitumor activi ty by itself, Under these treatment conditions, a combination of D,L-B SO with the maximum tolerated dose of doxorubicin administered at 24 h during a 48-h i,v, infusion of D,L-BSO completely restored the respon se of MRP-expressing HT1080/DR4 tumors to doxorubicin (overall respons e rate, 63%; complete response rate, 38%) with no potentiation of host toxicity, The D,L-BSO-induced in vivo reversal of MRP-mediated drug r esistance correlated in vitro with the restoration of intracellular do xorubicin retention in cultured HT1080/DR4 cells, Depletion of GSH by D,L-BSO in drug-sensitive HT1080 tumors that do not express MRP did no t alter the irt vivo response to doxorubicin, Using the same treatment schedule, dose, and administration of doxorubicin with and without D, L-BSO in nude mice bearing P-170 glycoprotein-expressing A2780/Dx5 tum ors, no potentiation of the therapeutic index of doxorubicin was found , demonstrating the in vivo selectivity of D,L-BSO-induced GSH depleti on on MRP-function, The data reported herein indicate that irt vivo fu nction of MRP as a mediator of doxorubicin resistance requires the pre sence of sufficient GSH pools, D,L-BSO may provide an example of an ef fective in vivo modulator of MRP-mediated drug resistance.