CARDIOTOXICITY IN THE SCID MOUSE FOLLOWING ADMINISTRATION OF DOXORUBICIN AND CYCLOSPORINE-A

Multiple myeloma is a plasma cell malignancy which is generally incura ble in spite of a high initial response to chemotherapy. Relapsing dis ease commonly heralds an increase in the incidence of drug resistance which is often mediated by the product of the MDR-1 gene, P-glycoprote in (Pgp). One approach to modulating drug resistance due to Pgp overex pression has involved the use of agents known as chemomodulators which inhibit its function. We have developed a human xenograft model of mu ltiple myeloma using the SCID mouse to evaluate the efficacy and toxic ities of new MDR-1 chemomodulators. Cyclosporin A (CsA) is a widely us ed immunosuppressant which has been demonstrated to be a potent inhibi tor of Pgp in vitro at concentrations which are clinically achievable. Preliminary studies revealed an acute toxicity in our SCID model whic h was associated with the combination of CsA and doxorubicin, and whic h was not observed with either drug alone, nor with cremaphor, the veh icle for CsA. In the current study, non-tumor bearing SCID mice were d osed with doxorubicin or the combination of doxorubicin with cremaphor , verapamil or CsA. Animals were sacrificed and tissues harvested for morphologic examination and for HPLC analysis of doxorubicin levels. I n all tissues examined, there was a marked increase in tissue levels o f doxorubicin when combined with CsA. Results also revealed a higher i ncidence and severity of myocardial damage in those animals receiving the combination of doxorubicin and CsA than in those receiving other c ombinations. The elevations in tissue levels observed with doxorubicin and CsA may contribute to the acute toxicities observed in the SCID m ouse model.