Gemcitabine has significant immunomodulatory activity in murine tumor models independent of its cytotoxic effects.
Given reports that the chemotherapeutic agent gemcitabine (GEM) does not block T-lymphocyte recall responses and is not detrimental to specific anti-tumor immunity, studies to evaluate the use of GEM in combination with immunotherapy were initiated. When we tested the therapeutic effects of GEM as a single agent in various murine tumor models, we found that a single dose of GEM had impressive anti-tumor activity in a specific subset of tumors. Surprisingly, efficacy was not related to in vitro drug sensitivity, but instead, correlated with the immunogenicity of the tumor. A key role of the immune system in GEM's action was demonstrated in experiments showing that the anti-tumor effects of GEM were lost in nude mice. In addition, we saw equivalent anti-tumor effects of GEM in animals bearing tumors that were extremely resistant to the in vitro cytotoxic effects of GEM versus parental GEM-sensitive cells. This therapeutic efficacy was thus not due to direct cytotoxic effect on tumor cells, but rather to an enhancement of T-cell mediated anti-tumor immune effects. These data raise the exciting possibility that GEM may be a useful agent in combination with various types of tumor immunotherapy.
Suzuki
Eiji
E
Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Sun
Jing
J
Kapoor
Veena
V
Jassar
Arminder Singh
AS
Albelda
Steven M
SM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine