DEVELOPMENT OF A SEVERE COMBINED IMMUNODEFICIENCY (SCID) MOUSE MODEL CONSISTING OF HIGHLY DISSEMINATED HUMAN B-CELL LEUKEMIA LYMPHOMA, CUREOF THE TUMORS BY SYSTEMIC ADMINISTRATION OF IMMUNOTOXIN, AND DEVELOPMENT/APPLICATION OF A CLONOTYPE-SPECIFIC POLYMERASE CHAIN REACTION-BASED ASSAY/

A new severe combined immunodeficiency (SCID) mouse model consisting o f highly disseminated human B-cell leukemia/lymphoma was developed by i.v. inoculation of BALL-1a, an in vivo adapted malignant B-cell line, A 100% transplantability was achieved in nonpreconditioned SCID mice using various BALL-1a doses between 2.5 x 10(4) and 6 x 10(6) cells, H ind-teg paralysis preceded the death of the mice. Utility of the devel oped tumor model for the therapeutic studies was investigated by i.v. administration of an anti-B-cell monoclonal antibody SN7 (IgG1) and it s conjugate with deglycosylated ricin A chain (dgRA), The therapy was initiated 2, 4, or 6 days after tumor inoculation using 4 x 24 mu g of SN7-dgRA or 4 x 20 mu g of SN7; the total dose (96 mu g) of SN7-dgRA corresponded to 14% of the LD(50) dose, SN7-dgRA showed a strong antit umor efficacy in all groups of treated mice, All of the day-2 group mi ce (n = 7) and six (66.7%) of the day-4 group mice (n = 9) survived he althily for as long as followed (240 days), whereas four (57.1%) of th e day-6 group mice (n = 7) survived healthily for as long as followed (200 days), Unconjugated SN7 showed a significant antitumor efficacy b ut was less effective than SN7-dgRA. A PCR-based assay specific for th e clonogenic BALL-1a tumor was developed and applied to determine tumo rs in various organs of BALL-1a-bearing SCID mice. The assay was highl y sensitive in screening for trace quantities of residual tumors in va rious organs of SCID mice, and it could detect 1 malignant cell/2.5 x 10(5) tissue cells. The PCR-based assay was shown to be much more powe rful than the conventional histological analysis in detecting residual tumors. Furthermore, we could estimate quantities of the detected tum ors by the PCR-based assay, It is remarkable to find that all examined organs of some of the SN7-dgRA-treated mice were tumor-free as determ ined by the clonotype-specific PCR-based assay. The present results sh ow the usefulness of the newly developed SCID mouse model, SN7-dgRA, a nd the clonotype-specific PCR-based molecular assay for the study of t herapy of human B-cell leukemia/lymphoma.