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Eradication of a disseminated mouse lymphoma by 1,3‐BIS(2‐chloroethyl)‐1‐nitrosourea is immunologically mediated and accompanied by de novo generation of anti‐tumor cytotoxicity
Author(s) -
Sensi Marialuisa,
Bergomi Marzia,
Formelli Franca,
Parmiani Giorgio
Publication year - 1990
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910460623
Subject(s) - ctl* , carmustine , cytotoxicity , cytotoxic t cell , splenocyte , immunology , spleen , lymphoma , nitrosourea , lymphokine , pharmacology , medicine , immunosuppression , immune system , cancer research , chemotherapy , in vitro , biology , cyclophosphamide , cd8 , biochemistry
The anti‐tumor effect of 1, 3‐bis(2‐chloroethyl)‐I‐nitrosourea (BCNU) was examined in BALB/c mice bearing increasing burdens of a syngeneic lymphoma (YCB). A single i. p. injection of the drug resulted in over 75% of cures when given at day 3, 5, 7 or 10 after an i. v. inoculum of 10 4 YCB cells. The efficacy of BCNU on mice bearing large tumor burdens (from day 5 on) was not only due to its tumoricidal activity, but was immunologically mediated. Residual tumorigenic cells could be recovered in the livers of 5‐day tumor bearers (TB) up to 2 weeks after BCNU treatment and only a low percentage of cures could be achieved when BCNU was administered to nude mice. In addition, BCNU‐cured mice specifically rejected a lethal YC8 challenge and their splenocytes developed anti‐tumor cytotoxicity in response to in vitro stimulation with YC8 cells. During kinetic experiments a 2‐week period elapsed after BCNU injection before an anti‐tumor cytotoxic T‐lymphocyte (CTL) response could be generated by spleen cells of BCNU‐treated 5‐day TB. This period was characterized by immunosuppression as evaluated from impairment in the generation of lymphokine‐activated killer (LAK) cells or of allospecific primary CTL responses by spleen cells from BCNU‐treated 5‐day TB and BCNU‐treated normal mice. LAK cells first recovered and could be generated 7 days later, whereas primary allospecific CTL responses could only be detected by day 14. concomitantly with the generation of antitumor cytotoxicity by 5‐day TB. The development of secondary in vitro CTL responses, however, was permanently abrogated. Spleen cells from BALB/c mice immunized either with YC8 or with DBA/2 minor histocompatibility antigens and treated with BCNU I week after the last immunization failed to mount an in vitro CTL response to their immunizing antigen, even when the cultures were supplemented with recombinant interleukin‐2.