Development of a severe combined immunodeficiency (SCID) mouse model consisting of highly disseminated human B-cell leukemia/lymphoma, cure of 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 of 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. Hind-leg paralysis preceded the death of the mice. Utility of the developed tumor model for the therapeutic studies was investigated by i.v. administration of an anti-B-cell monoclonal antibody SN7 (IgG1) and its conjugate with deglycosylated ricin A chain (dgRA). The therapy was initiated 2, 4, or 6 days after tumor inoculation using 4 x 24 microg of SN7-dgRA or 4 x 20 microg of SN7; the total dose (96 microg) of SN7-dgRA corresponded to 14% of the LD50 dose. SN7-dgRA showed a strong antitumor efficacy in all groups of treated mice. All of the day-2 group mice (n = 7) and six (66.7%) of the day-4 group mice (n = 9) survived healthily for as long as followed (240 days), whereas four (57.1%) of the day-6 group mice (n = 7) survived healthily for as long as followed (200 days). Unconjugated SN7 showed a significant antitumor efficacy but was less effective than SN7-dgRA. A PCR-based assay specific for the clonogenic BALL-1a tumor was developed and applied to determine tumors in various organs of BALL-1a-bearing SCID mice. The assay was highly sensitive in screening for trace quantities of residual tumors in various 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 powerful than the conventional histological analysis in detecting residual tumors. Furthermore, we could estimate quantities of the detected tumors 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 determined by the clonotype-specific PCR-based assay. The present results show the usefulness of the newly developed SCID mouse model, SN7-dgRA, and the clonotype-specific PCR-based molecular assay for the study of therapy of human B-cell leukemia/lymphoma.
Yoshida
M
M
Department of Molecular Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Rybak
R J
RJ
Choi
Y
Y
Greenberg
S J
SJ
Barcos
M
M
Kawata
A
A
Matsuno
F
F
Tsai
H
H
Seon
B K
BK
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D000922:Immunotoxins / Q000627:therapeutic use*; D007928:Lethal Dose 50; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction / Q000379:methods*; D012276:Ricin / Q000627:therapeutic use / Q000633:toxicity
D017931:DNA Primers; D007143:Immunoglobulin Heavy Chains; D000922:Immunotoxins; D012276:Ricin