Chimeric DNA vaccine reverses morphine-induced immunosuppression and tumorigenesis.
Although long-term use of morphine has been shown to promote tumor growth, the question whether tumorigenesis occurs as a result of an immunosuppressive effect remains to be investigated. In mice rendered tolerant to morphine, the efficacy and mechanism of a vaccination to rescue morphine-induced immunosuppression and prevent tumor growth was assessed both in vitro and in vivo. Herein, we found that morphine-injected mice exhibited higher tumor growth rates and lower percentages of CD8+ T lymphocytes. The mechanism of morphine suppression of immunity might be through the suppression of E7-specific CD8+ T lymphocyte proliferation and the promotion of apoptosis of these cells by the Bcl-2 and Bax pathways. The suppressive effect of E7-specific CD8+ T lymphocytes by morphine could be reversed by naloxone. We have previously shown that calreticulin linked with E7 (CRT/E7) could enhance the CD8+ T cell response and the anti-tumor effects (W. F. Cheng et al. (2001) J. Clin. Invest. 108, 669-678). CRT/E7 DNA vaccine could overcome the immunosuppressive effect of morphine and suppress tumor growth. Our findings reveal that long-term morphine treatment dose-dependently promotes tumor growth and a DNA vaccine may serve as a useful approach to treat the profound immunosuppressive function and prevent tumorigenesis after long-term morphine treatment.
Cheng
Wen-Fang
WF
Obstetrics and Gynecology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
Chen
Li-Kuei
LK
Chen
Chi-An
CA
Chang
Ming-Cheng
MC
Hsiao
Po-Ni
PN
Su
Yi-Ning
YN
Lee
Chien-Nan
CN
Jeng
Huei-Jiuan
HJ
Hsieh
Chang-Yao
CY
Sun
Wei-Zen
WZ
D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D007165:Immunosuppression Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000009:adverse effects*; D009292:Narcotic Antagonists / Q000494:pharmacology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014183:Transplantation, Heterologous; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000701:Analgesics, Opioid; D019496:Cancer Vaccines; D009292:Narcotic Antagonists; D050725:Papillomavirus E7 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019444:Vaccines, DNA; D051028:bcl-2-Associated X Protein; D009020:Morphine