Growth of sensitive and drug-resistant human myeloid leukemia cells in SCID mice.
Drug resistance is a critical problem in the therapy of hematologic malignancies. Recent advances in the transplantation of human normal and transformed hematopoietic cells into severe combined immunodeficient (SCID) mice provide an opportunity to study the biologic and molecular events that mediate resistance. We studied the engraftment of several human myelogenous leukemia cell lines sensitive and resistant to amsacrine (mAMSA), vincristine, hycamptamine, methotrexate, or doxorubicine (KBM3/AMSA, K562/Vcr, HL60/Hy10, K562/MTX, HL60/Dox). The distribution and growth potential of these cells was evaluated using molecular and histologic techniques. Inoculation of 2 x 10(7) leukemic cells led to manifestation of disease, and subsequent tissue analysis showed evidence of leukemia. The survival of mice varied from 21 to 135 days. Terminally, the animals showed symptoms of wasting, development of local tumors, or both. Massive leukemic dissemination with infiltration of bone marrow and various organs including lungs, spleen, liver, ovaries, and brain was detected in most cases. No differences were observed in the tissue distribution of sensitive as compared to resistant leukemia cells. These findings demonstrated that human leukemic cells retain, in SCID mice, the clinico-pathologic picture of the original disease in humans. The development of numerous drug-resistant phenotypes in vitro does not alter the subsequent behavior of resistant cells in vivo when compared with sensitive counterparts. The levels of resistance are not modified by passage through SCID mice. This model offers an opportunity for developing new preclinical in vivo systems for modulation of drug resistance, and the combination of this in vivo model with gene transfer methods will also provide an important system for testing the molecular alterations involved in drug resistance and leukemic progression.
Department of Hematology, Karolinska Hospital and Institute Stockholm, Sweden.
M
M
Beran
P
P
Pisa
H
H
Kantarjian
A
A
Porwit
M
M
Bjorkholm
D000208:Acute Disease; D000818:Animals; D002470:Cell Survival; D004273:DNA, Neoplasm / Q000235:genetics; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple / Q000276:immunology*; D005260:Female; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D016130:Immunophenotyping; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000276:immunology / Q000473:pathology; D010677:Philadelphia Chromosome; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen