DEVELOPMENT OF AN ORTHOTOPIC SCID MOUSE-HUMAN TUMOR XENOGRAFT MODEL DISPLAYING THE MULTIDRUG-RESISTANT PHENOTYPE

Multiple myeloma is a plasma cell malignancy which is generally incura ble in spite of a high initial response to chemotherapy. While animal models of myeloma are known, the recent developments of human xenograf ts in nude and SCID mice suggests a promising experimental model. The SCID model, in particular, holds promise because these animals readily accept hematopoietic and lymphoid transplantation and do not generall y develop graft versus host reaction. We have developed two drug-resis tant variants of the human multiple myeloma cell line ARH-77 by in vit ro exposure to gradually increasing concentrations of doxorubicin (ARH -D60) or mitoxantrone (ARM-80). When injected into irradiated SCID mic e, the ARH-D60 cell line grew in an orthotopic pattern with the develo pment of osteolytic lesions. This is in contrast to the 8226/C1N human myeloma cell line which grows in a disseminated but nonorthotopic man ner in the SCID mouse. Both the ARH-D60 and ARM-80 cell are resistant to doxorubicin and cross-resistant to mitoxantrone, vinca alkaloids, t axol and m-AMSA while maintaining sensitivity to antimetabolites and a lkylating agents. Growth characteristics and cell cycle kinetics, incl uding S-phase, were not altered in the resistant sublines. The ARH-D60 and ARM-80 cell lines both displayed a classic multidrug-resistance ( MDR) phenotype which was partially reversed by the addition of verapam il. These two cell lines represent the first MDR human myeloma cell li nes which have demonstrated an orthotopic growth pattern in the SCID m ouse and thus may be of value in studying the pathophysiology of this disease.