Elimination of malignant clonogenic T cells from human bone marrow using chemoimmunoseparation with 2'-deoxycoformycin, deoxyadenosine and an immunotoxin.
Autologous bone marrow transplantation may contribute to the treatment of several types of lymphoreticular malignancies. Recent studies have suggested that a combination of chemoseparation and immunoseparation may be more effective than either modality alone in eliminating malignant cells from human bone marrow. In this report an immunotoxin has been prepared by conjugating pokeweed antiviral protein (PAP) to the 3A1 murine monoclonal antibody that recognizes a 40 kD (CD7) determinant expressed by most T cell acute lymphoblastic leukemias and a majority of normal mature peripheral T cells. When HSB-2 T lymphoma cells were mixed with normal human bone marrow and incubated with 3A1-PAP and 100 microM chloroquine, approximately 3 logs of clonogenic T cells could be eliminated from a 20-fold excess of bone marrow. Treatment of cell mixtures with 2'deoxycoformycin (2'-dCF) and deoxyadenosine (dAdo) eliminated 2 logs of clonogenic tumor cells. The use of 3A1-PAP and chloroquine with dCF/dAdo was more effective than either single modality, eliminating up to 6 logs of HSB-2 tumor cells in optimal experiments. Anti-tumor activity of the combined treatment extended to T leukemia cells taken directly from patients. Although 3A1-PAP reduced CFU-GM by only 13% and BFU-E by 36%, the addition of 2'-dCF and dAdo was more toxic for normal marrow precursors, further reducing CFU-GM, GEMM and BFU-E as well as preventing recovery of CFU-GM in long-term bone marrow culture.(ABSTRACT TRUNCATED AT 250 WORDS)
Montgomery
R B
RB
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Kurtzberg
J
J
Rhinehardt-Clark
A
A
Haleen
A
A
Ramakrishnan
S
S
Olsen
G A
GA
Peters
W P
WP
Smith
C A
CA
Haynes
B F
BF
Houston
L L
LL
D000998:Antiviral Agents; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D002460:Cell Line; D002469:Cell Separation / Q000379:methods*; D002738:Chloroquine; D003839:Deoxyadenosines / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology; D015458:Leukemia, T-Cell / Q000473:pathology; D008223:Lymphoma / Q000473:pathology; D009699:N-Glycosyl Hydrolases; D015649:Pentostatin / Q000494:pharmacology; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D013234:Stem Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D014410:Tumor Stem Cell Assay
D000998:Antiviral Agents; D003839:Deoxyadenosines; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D015649:Pentostatin; D002738:Chloroquine; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein