Recent findings published in Leukemia Research show that the experimental therapeutic leukotoxin (Leukothera?; LtxA; Actinobac Biomed, Inc) which binds to the leukocyte function antigen (LFA-1) on white blood cells (WBCs) and induces cell death via apoptosis or necrosis, combined with standard anti-leukemia agents, offers synergistic anti-leukemia effects.
The outcome of these in vitro experiments demonstrated that combining leukotoxin, with standard chemotherapeutic agents such as etoposide, mitoxantrone, daunorubicin, busulfan and imatinib, exhibited synergism with all these anti-cancer drugs. Researchers observed that leukotoxin specifically targets malignant and/or inflammatory white blood cells including the leukemia cell lines THP-1, GDM-1, HL-60, and KU-812 cells. The levels of synergy were dependent on the doses used and cell lines examined.
Targeting white blood cells
Leukotoxin, a membrane-active natural biologic protein toxin secreted by Aggregatibacter actinomycetemcomitans, a Gram-negative bacterium that colonizes the human oral cavity, functions by depleting and preventing migration of the activated immune cells involved in diseases of white blood cells. The cellular receptor for leukotoxinm, the leukocyte function antigen-1 (LFA-1) is only expressed on white blood cells. Researchers found that leukotoxin preferentially targets white blood cells with high levels of activated LFA-1, which is characteristic of many leukemias and lymphomas, and showed that leukotoxin exhibits significant anti-leukemia activity in vivo using the humanized SCID mouse model.
Very strong synergism
Combination index (CI) values were less than 0.1 for many of the combinations, indicating very strong synergism. In addition, leukotoxin alone was cytotoxic to primary cells from newly diagnosed, relapsed, and refractory patients with different hematological malignancies.
Based on the results, the researchers concluded that leukotoxin is highly effective at inducing rapid apoptosis both as a single agent and in combination with approved leukemia therapies.
Highly effective strategies
Scott Kachlany, PhD, Associate Professor Department of Oral Biology UMDNJ-New Jersey Dental School and founder of Actinobac Biomed, explained. “Drug combination therapies for cancer are now frequently considered by oncologists due to their many advantages, which include the possibility of reducing doses of toxic chemotherapeutic agents and a lower chance of developing drug resistance,” he said. “The biological mechanism of LeukotheraTM differs from that of other cancer drugs so including it to blood cancer treatment protocols may be a highly effective strategy.”
For more information:
Gupta A, Le A, Belinka BA, Kachlany SC In vitro synergism between LFA-1 targeting leukotoxin (Leukothera?) and standard chemotherapeutic agents in leukemia cells. Leuk Res. 2011 Jun 9. [Epub ahead of print] [Full article][Abstract]