Induction of antitumor immunity by indomethacin.
Irradiated tumor cells given, together with indomethacin, to syngeneic mice induced an antitumor response and conferred protection against a challenge of a lethal dose of murine mammary (4T1) and lung (3LL) carcinoma cells. Continuous administration of indomethacin was crucial throughout the entire period of immunization and challenge, as no protection was achieved when the drug was given during only one of these procedures. Antitumor immunity was long-lasting and, when tested in the 4T1 model, 48% of mice were resistant to a second challenge of lethal tumor cells. Tumor-free immune mice that were given indomethacin for more than 300 days remained healthy with normal white blood cell counts and normal spleen size. Cells isolated from immune mice were able to kill tumor cells in culture after in vitro activation by interleukin-2, in a manner similar to cells from naive normal control mice. In addition, the mitogenic response of their T cells was as high as that of the control naive mice. While indomethacin was able to induce antitumor immunity to 4T1 and 3LL murine carcinoma cells, both of which contain a high concentration of endogenic prostaglandin E(2) (PGE2), no such immunity was achieved to murine tumor cells with a low concentration of endogenic PGE2. These results suggest a correlation between PGE2 concentration and the ability of indomethacin to induce antitumor immunity. We therefore suggest that an immunotherapy protocol with long-term dispensation of a tolerable dose of an immunomodulator, given together with irradiated autologous tumor cells, may stimulate antitumor responses to tumors containing high concentrations of endogenic PGE2.
Morecki
S
S
Cancer Immunotherapy and Immunobiology Research Center, Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem 91120, Israel.
Yacovlev
E
E
Gelfand
Y
Y
Trembovler
V
V
Shohami
E
E
Slavin
S
S
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019496:Cancer Vaccines; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis; D004334:Drug Administration Schedule; D005260:Female; D007114:Immunization; D016219:Immunotherapy, Adoptive; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D008213:Lymphocyte Activation; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation; D014407:Tumor Cells, Cultured / Q000528:radiation effects
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007213:Indomethacin