Clinical & Experimental Metastasis

, Volume 7, Issue 1, pp 97–105 | Cite as

Mutagen-induced Imm+ variants: the need for viable and cloned Imm+ variants for effective protection against a primary murine tumor and its metastases

  • Avishay Sella
  • Barbara Hunt
  • Philip Frost


Immunogenic variants (Imm+) generated after the treatment of murine tumor cells with the mutagenN-methyl-N′-nitro-N-nitrosoguanidine (MNNG) can produce a strong protective response against non-mutagenized parent tumor cells. The use of this methodology to treat human tumors is currently thwarted by technological difficulties in applying the findings obtained with murine models to human disease. Two of these difficulties are described in this study. The first is that Imm+ variants lose most of their immunogenicity after treatment with X-irradiation or mitomycin C. The second is that mutagen-treated tumor cells must be cloned so as to select for Imm+ variants, for the presence of as few as 0·001 per cent tumorigenic cells within the bulk population will result in the failure of the protective effect of the Imm+ variants.

Because of these and other difficulties with mutagen-induced Imm+ variants, we have developed a different approach to producing such variants using transfection of tumor cells with foreign genes. In contrast to mutagen induced Imm+ variants, these variants have been shown to retain their immunogenicity after X-irradiation.


Tumor Cell Protective Effect Human Disease Human Tumor Murine Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    Berendt, M. J., andNorth, R. J., 1980, T-cell mediated suppression of anti-tumor immunity.Journal of Experimental Medicine,151, 69–80.PubMedGoogle Scholar
  2. [2]
    Boon, T., 1983, Antigenic tumor cell variants obtained with mutagens.Advances in Cancer Research,39, 121–151.PubMedGoogle Scholar
  3. [3]
    Boon, T., 1985, Tum variants: immunogenic variants obtained by mutagen treatment or tumor cells.Immunology Today,6, 307–311.Google Scholar
  4. [4]
    Boon, T., andKellekman, O., 1977, Rejection by syngeneic mice of cell variants obtained by mutagenesis of a malignant teratocarcinoma line.Proceedings of the National Academy of Sciences U.S.A.,74, 272–275.Google Scholar
  5. [5]
    Fearon, E. R., Itaya, T., Hunt, B., Vogelstein, B., andFrost, P., 1988, The induction of immunogenic tumor variants by transfection with a foreign gene.Cancer Research,48, 2975–2980.PubMedGoogle Scholar
  6. [6]
    Frost, P., andKerbel, R. S., 1986, Is the immunotherapy of metastasis feasible?Immunology and Cancer, edited by M. L. Kripke and P. Frost (Austin: University of Texas Press), p. 149.Google Scholar
  7. [7]
    Frost, P., Kerbel, R. S., Bauer, E., Tartamella-Biondo, T., andCefalu, W., 1983, Mutagen treatment as a means for selecting immunogenic variants from otherwise poorly immunogenic-malignant tumors.Cancer Research,43, 125–132.PubMedGoogle Scholar
  8. [8]
    Frost, P., Kerbel, R. S., andTartamella-Biondo, R., 1981, Generation of highly metastatic tumors in DBA/2 mice: oncogenicity of A strain tumor cells.Invasion and Metastasis,1, 22–33.Google Scholar
  9. [9]
    Frost, P., Liteplo, R. G., Donaghue, T. P., andKerbel, R. S., 1984, Selection of strongly immunogenic ‘Tum’ variants from tumors at high frequency using 5-azacytidine.Journal of Experimental Medicine,159, 1491–1501.PubMedGoogle Scholar
  10. [10]
    Frost, P., Prete, P., andKerbel, R. S., 1982, Eradication of thein vitro generation of the cytotoxic T cell response to a metastatic murine tumor: The role of suppressor T cells.International Journal of Cancer,20, 211–218.Google Scholar
  11. [11]
    Frost, P., Sella, A., andHunt, B., 1987, The promises and problems of adapting mutagen induced Imm+ variants to the therapy of human metastases,Occult Nodal Metastasis in Solid Carcinoma, edited by P. J. Moloy and G. L. Nicolson (New York: Praeger Publishers),Cancer Research Monographs, Vol. 5, pp. 61–67.Google Scholar
  12. [12]
    Hostetler, L. W., Ananthaswamy, H. N., andKripke, M. L., 1986, Generation of tumor-specific transplantation antigens by UV radiation can occur independently of neoplastic transformation.Journal of Immunology,137, 2721–2725.Google Scholar
  13. [13]
    Kerbel, R. S., 1979, Immunologic studies of membrane mutants of a highly metastatic murine tumor.American Journal of Pathology,97, 609–622.PubMedGoogle Scholar
  14. [14]
    Kerbel, R. S., Twiddy, R. R., andRobertson, D. M., 1978, Induction of a tumor with greatly increased metastatic growth potential by injection of cells from a low metastatic H-2 heterozygous tumor cell line into an H-2 incompatible parental strain.International Journal of Cancer,22, 583–594.Google Scholar
  15. [15]
    Peppoloni, S., Herberman, R., andGorelik, E., 1984, Induction of highly immunogenic variants of 3LL tumor by UV irradiation.Cancer Research,45, 2560–2564.Google Scholar
  16. [16]
    Wiltrout, R. H., Frost, P., andCummings, G. D., 1978, Isotope release cytotoxicity assay with the use of 111-indium: advantage over chromium-51 in long term assays.Journal of the National Cancer Institute,61, 183–188.PubMedGoogle Scholar

Copyright information

© Taylor & Francis Ltd 1989

Authors and Affiliations

  • Avishay Sella
    • 1
  • Barbara Hunt
    • 2
  • Philip Frost
    • 1
    • 2
  1. 1.Department of MedicineThe University of Texas M. D. Anderson Hospital and Tumor Institute at HoustonHoustonUSA
  2. 2.Department of Cell BiologyThe University of Texas M. D. Anderson Hospital and Tumor Institute at HoustonHoustonUSA

Personalised recommendations