Inhibition of tumor growth by a novel approach: in situ allicin generation using targeted alliinase delivery.
Allicin (diallyl thiosulfinate), a highly active component in extracts of freshly crushed garlic, is the interaction product of non-protein amino acid alliin (S-allyl-L-cysteine sulfoxide) with the enzyme alliinase (alliin lyase; EC 4.4.1.4). Allicin was shown to be toxic in various mammalian cells in a dose-dependent manner in vitro. We made use of this cytotoxicity to develop a novel approach to cancer treatment, based on site-directed generation of allicin. Alliinase from garlic was chemically conjugated to a mAb directed against a specific tumor marker, ErbB2. After the mAb-alliinase conjugate was bound to target tumor cells, the substrate, alliin, was added. In the presence of alliin, tumor-localized alliinase produced allicin, which effectively killed N87 and CB2, both ErbB2-expressing cells in vitro, whereas 32D cells (a murine hematopoietic progenitor cell line, devoid of the ErbB2 receptors) were not affected. Moreover, using N87, a human tumor cell line xenograft in athymic nude mice, we demonstrated for the first time, a high antitumor activity of allicin that was produced in situ by the conjugate, on alliin administration in vivo, while at the same time other tissues were unharmed due to the inert nature of alliin and the high clearance rate of allicin. The effect of the treatment on tumor growth arrest became significant 2 weeks after its onset, and it continued to rise, reaching highly significant inhibition a week later. Ten days after the end of the treatment (day 18), tumor growth inhibition was still the same.
Miron
Talia
T
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Mironchik
Marina
M
Mirelman
David
D
Wilchek
Meir
M
Rabinkov
Aharon
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D013437:Carbon-Sulfur Lyases / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D006224:Cricetinae; D004220:Disulfides; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013441:Sulfinic Acids / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D004220:Disulfides; D013441:Sulfinic Acids; C006452:allicin; D013437:Carbon-Sulfur Lyases; C019243:alliin lyase