Retinoic acid-induced CD38 antigen as a target for immunotoxin-mediated killing of leukemia cells.

Abstract

A major obstacle in the successful delivery of antibody-based therapeutics to tumor cells is the heterogeneity of target antigen expression. We reported previously that retinoic acid (RA) is a potent and selective inducer of the cell-surface antigen CD38 in myeloid leukemia cells. The purpose of this study was to determine whether the RA-induced CD38 antigen could be a target for an anti-CD38-based immunotoxin to induce selective killing of leukemia cells. The combination of RA and the anti-CD38 gelonin immunotoxin induced a synergistic killing of leukemia cells. Thus, coculture of myeloid leukemia cells and cell lines with as little as 1 nM RA in the presence of immunotoxin induced substantial killing (>90%) of leukemia cell clones. More importantly, the blasts of myeloid leukemia patients, irrespective of their morphological and phenotypic features, also responded to the RA and immunotoxin combination when cultured ex vivo. A similar synergistic effect between RA and immunotoxin was observed against a multidrug-resistant variant subline of HL-60 cells. However, another variant of HL-60 cells, HL-60R, in which the retinoid receptor function has been abrogated by a trans-dominant-negative mutation, exhibited complete resistance to the immunotoxin-induced killing effect in the presence or absence of RA. Our results suggest that RA combined with anti-CD38-based therapeutic agent may offer exciting opportunities for the treatment of myeloid leukemias despite their multiplicity of genetic and clinical varieties.

• Authors: Kapil Mehta, Larry Ocanas, Fabio Malavasi, John W Marks, Michael G Rosenblum
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 3 Issue 3 Pg. 345-52 (Mar 2004) ISSN: 1535-7163 [Print] United States
• PMID: 15026555 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• Antineoplastic Agents
• DNA, Complementary
• Immunotoxins
• Membrane Glycoproteins
• Plant Proteins
• Ribosome Inactivating Proteins, Type 1
• Tretinoin
• GEL protein, Gelonium multiflorum
• ADP-ribosyl Cyclase
• CD38 protein, human
• ADP-ribosyl Cyclase 1

Topics

• ADP-ribosyl Cyclase (biosynthesis, therapeutic use)
• ADP-ribosyl Cyclase 1
• Antibodies, Monoclonal (chemistry)
• Antigens, CD (biosynthesis, therapeutic use)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• DNA, Complementary (metabolism)
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple
• HL-60 Cells
• Humans
• Immunotherapy (methods)
• Immunotoxins (chemistry, metabolism, therapeutic use)
• Leukemia (therapy)
• Membrane Glycoproteins
• Mutation
• Plant Proteins (chemistry)
• Ribosome Inactivating Proteins, Type 1
• Tretinoin (metabolism, pharmacology)