SEVERE COMBINED IMMUNODEFICIENCY (SCID) MOUSE MODELING OF P-GLYCOPROTEIN CHEMOSENSITIZATION IN MULTIDRUG-RESISTANT HUMAN MYELOMA XENOGRAFTS

We have established a reproducible in vivo model of human multiple mye loma in the severe combined immunodeficiency (SCID) mouse using both t he drug-sensitive 8226/S human myeloma cell line and the P-glycoprotei n-expressing multidrug-resistant 8226/C1N subline, As demonstrated pre viously, the SCID mouse is well suited as a model for myeloma because: (a) human SCID xenografts are readily attained; (b) human myeloma xen ografts are readily detected by their immunoglobulin secretion; and (c ) differential therapy effects in drug-sensitive versus drug-resistant cell lines are readily demonstrable by monitoring mouse urinary human immunoglobulin output, In the current study, we have utilized this mo del to evaluate the in vivo efficacy of chemomodulators of P-glycoprot ein-related multidrug resistance, In our initial experiments, doxorubi cin alone was effective in treating the 8226/S human myeloma xenograft s but had no effect on the drug-resistant 8226/C1N xenografts, in the absence of the chemosensitizing agent verapamil, In subsequent experim ents, the combination of verapamil and doxorubicin resulted in both a decrease in human lambda light chain urinary excretion and an increase in survival of those animals bearing the 8226/C1N tumor, The median s urvival time of animals injected with 8226/C1N cells and subsequently treated with doxorubicin was 48.6 +/- 7 days, which compared to a surv ival of 89.6 +/- 18 days in animals receiving the 8226/S cell line and treated with doxorubicin alone (P < 0.001), When verapamil was added to the treatment regimen of those animals bearing the 8226/C1N xenogra fts, there was a 179% increase in their life span (P < 0.001), which c orresponded with the observed decreased light chain in the urine, In a nimals receiving multiple courses of chemotherapy, an attenuated respo nse to verapamil and doxorubicin was observed, in a manner analogous t o the clinical setting of human drug-resistant myeloma escape from che mosensitivity, The SCID human myeloma xenograft model thus offers a me ans of evaluating the in vivo efficacy and potential toxicities of new therapeutic approaches directed against P-glycoprotein in multidrug-r esistant human myeloma.