Effective elimination of lung metastases induced by tumor cells treated with hydrostatic pressure and N-acetyl-L-cysteine.
In previous studies, we have demonstrated that application of high hydrostatic pressure (P) to tumor cells in the presence of a slow-reacting membrane-impermeable cross-linker (CL), 2'-3'-adenosine dialdehyde, can rearrange cell surface proteins into immunogenic clusters. Here, we present evidence indicating that subsequent reduction of surface protein disulfides with N-acetyl-L-cysteine (NAC) further augments the immunogenic potential of PCL-modified tumor cells both in vitro and in vivo. Immunotherapy with PCL+NAC-modified 3LL-D122 Lewis lung carcinoma cells plus i.v. delivery of NAC in mice bearing established lung metastases provoked an antitumor response capable of eradicating the metastatic nodules as demonstrated by restoration of normal lung weight and histology. In addition, immunization with PCL+NAC-modified tumor cells gave rise to a strong delayed-type hypersensitivity recall response against parental D122 cells. We propose that this novel two-prong strategy, based on local immunization with autologous PCL+NAC-modified tumor cells and systemic boosting with NAC, could provide a practical, effective immunotherapeutic regimen for the treatment of human cancer.
Goldman
Y
Y
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Peled
A
A
Shinitzky
M
M
D000111:Acetylcysteine / Q000494:pharmacology*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D005260:Female; D006801:Humans; D006874:Hydrostatic Pressure; D006968:Hypersensitivity, Delayed; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control* / Q000556:secondary; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control; D013154:Spleen / Q000187:drug effects / Q000276:immunology*
D015704:CD4 Antigens; D016827:CD8 Antigens; C027579:periodate-oxidized adenosine; D000241:Adenosine; D000111:Acetylcysteine