Apoptotic killing of B-chronic lymphocytic leukemia tumor cells by allicin generated in situ using a rituximab-alliinase conjugate.
Allicin, a highly active component from freshly crushed garlic, is produced upon the reaction of the small molecular weight molecule alliin, with the enzyme alliinase (EC 4.4.1.4). Because allicin was shown to be toxic to various mammalian cells in vitro, we devised a novel approach for the therapy of B-cell malignancies based on site-directed generation of allicin. Alliinase was conjugated to the monoclonal antibody rituximab, which recognizes the CD20 antigen, and the resulting conjugate was targeted to CD20+ B chronic lymphocytic leukemia (B-CLL) and other B-cell lymphomas. Upon addition of alliin, allicin was formed in situ, killing the CD20+ tumor B cells via apoptosis. Following a 72-hour treatment, an 85% and 96% reduction was observed in the number of viable B-CLL and EBV-transformed B cells, respectively. Using the human/mouse radiation chimera for the evaluation of allicin targeting in a preclinical animal model, we showed a significant reduction in the number of recovered B-CLL, mantle cell lymphoma, or EBV-transformed B cells. We conclude that our system offers a new powerful and less toxic therapy for B-CLL and other B-cell malignancies. Furthermore, combining alliinase with the appropriate monoclonal antibody may extend the application of this approach to other conditions in which the elimination of a specific cell population is desired.
Arditti
Fabian D
FD
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Rabinkov
Aharon
A
Miron
Talia
T
Reisner
Yair
Y
Berrebi
Alain
A
Wilchek
Meir
M
Mirelman
David
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D013437:Carbon-Sulfur Lyases / Q000737:chemistry / Q000627:therapeutic use*; D002678:Chimera; D004220:Disulfides; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D000069283:Rituximab; D013441:Sulfinic Acids / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D004220:Disulfides; D000922:Immunotoxins; D013441:Sulfinic Acids; C502340:rituximab-alliinase conjugate; C006452:allicin; D000069283:Rituximab; D013437:Carbon-Sulfur Lyases; C019243:alliin lyase