Macrophages play a critical role in the anti-tumor activity of Virulizin.
Virulizin, a novel biological response modifier (BRM), has been demonstrated to have a high level of anti-tumor activity against pancreatic cancer and melanoma in many clinical trials and preclinical studies. However, its anti-tumor mechanism has not been fully elucidated. The purpose of this study was to define the mechanism of Virulizin anti-tumor activity in cultures and in a murine xenograft model. The presence of Virulizin stimulated in a dose-dependent manner the cytolytic activity against tumor cells by splenocytes and macrophages, but not by non-adherent splenocytes. The cytotoxic activity of macrophages was significantly increased (approximately 5-fold) in cultures containing 2.5% of Virulizin compared to that of cultures without Virulizin (p<0.001). An increase of 21% in the protease secretion was observed in Virulizin (2.5%)-stimulated macrophages compared to PBS-treated cells (p<0.0001). Moreover, the anti-tumor efficacy of Virulizin observed in CD-1 nude mice was abrogated in mice that were depleted of macrophages, thus stimulation of macrophages may be one mechanism through which Virulizin acts. These results suggest that macrophages may play a critical role in the anti-tumor activity of Virulizin.
Du
Caigan
C
R&D Department, Lorus Therapeutics Inc., Toronto, Ontario M9W 4Z7, Canada.
Feng
Ningping
N
Jin
Hongnan
H
Lee
Vivian
V
Wang
Ming
M
Wright
Jim A
JA
Young
Aiping H
AH
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001646:Bile; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D014020:Tissue Extracts
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D014020:Tissue Extracts; C087098:virulizin; D010450:Endopeptidases