A combined approach for purging multidrug-resistant leukemic cell lines in bone marrow using a monoclonal antibody and chemotherapy.
Selective removal of malignant cells (purging) from bone marrow (BM) is a concern in autologous BM transplantation (ABMT). Use of vincristine, etoposide, or doxorubicin for purging could be rendered ineffective by the presence of multidrug-resistant (MDR) tumor cells. To circumvent this particular problem, we investigated whether 17F9, a monoclonal IgG2b antibody directed against the cell surface product of the MDR gene, P-glycoprotein, is effective in selective removal of MDR cells from BM when used with rabbit complement (C'). Using two different cell lines we have demonstrated that 17F9 + C' selectively lyses MDR-positive cells. Three rounds of antibody + C' resulted in 96.4% +/- 3.6% kill of K562/DOX and 100% +/- 0% of CEM/VLB cells. Mixtures of malignant cells and normal BM resulted in 99.85% removal of K562/DOX and 99.91% removal of CEM/VLB clonogenic cells. This treatment did not affect normal committed precursors compared with C' alone. The addition of the cytotoxic agent etoposide (VP-16) following antibody purging results in a 4.6 log reduction of malignant cells. Furthermore, this antibody was effective when used against patients' leukemic blasts. These results suggest the use of 17F9 + C' is effective and selective for removal of MDR cells from BM before ABMT and the addition of VP-16 enhances the purging efficacy.
Aihara
M
M
Department of Medicine, Stanford University School of Medicine, CA.
Aihara
Y
Y
Schmidt-Wolf
G
G
Schmidt-Wolf
I
I
Sikic
B I
BI
Blume
K G
KG
Chao
N J
NJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000473:pathology*; D016026:Bone Marrow Transplantation; D002469:Cell Separation / Q000379:methods*; D002860:Chromium Radioisotopes; D003165:Complement System Proteins; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000276:immunology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002860:Chromium Radioisotopes; D008562:Membrane Glycoproteins; D005047:Etoposide; D003165:Complement System Proteins