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Mutagen Treatment as a Means for Selecting Immunogenic Variants from Otherwise Poorly Immunogenic Malignant Murine Tumors¹

Department of Medicine, Long Beach Veterans Administration Hospital, Long Beach, California 90822 [P. F., E. B., W. C.]; Departments of Medicine and Microbiology, University of California, Irvine, California [P. F., R. T-B.]; and the Cancer Research Laboratories, Department of Pathology, Queens University, Kingston, Ontario, Canada [R. S. K.]

The selection of nontumorigenic (tum^-), highly immunogenic variants from four different tumorigenic but poorly immunogenic murine tumors by mutagen treatment and cloning is described. Several factors were found to determine the successful nature of this selection procedure including: the nature of the tumor used; the nature of the mutagen; the number of mutagen treatments; and the time at which cloning is performed after treatment.

In some cases, e.g., the TA3 adenocarcinoma or the BALB/c SS1 spontaneous mammary adenoacanthoma, a single treatment with ethyl methanesulfonate or N-methyl-N'-nitro-N-nitrosoguanidine led to a very high frequency of tum^- clones, whereas in others, e.g., the MDAY-D2 tumor line, no stable tum^- clones were obtained. The immunogenic clones selected were always immunologically cross-reactive with the parent tumor from which they were derived and were found to protect the murine host against challenge with the parent tumor in vivo. Thus, the cloned immunogenic variants share an antigen with the parent tumor. Additional evidence, however, suggested that each clone also expresses a new private or unique antigen. The frequency of immunogenic variant selection ranged from a low of 6% to a high of 95%. In some cases in which the frequencies were very high, cloning was not required to reveal the tum^- phenotype. Finally, we also noted that selection for drug resistance, e.g., resistance to 6-thioguanine, after mutagenesis could have an enhancing effect on the generation of highly immunogenic tum^- clones. The results show that the immunogenicity of poorly immunogenic tumors, including those of spontaneous origin, can be dramatically enhanced by appropriate mutagen treatments but that there is considerable variation in the ease with which highly immunogenic variants can be obtained.

¹ Supported by the Medical Research Council of Canada.

² Recipient of a grant from the Veterans Administration and Research Grant CA 28060 from the USPHS. To whom requests for reprints should be addressed at Long Beach Veterans Administration Hospital, 9501 East 7th Street N-S, Long Beach, CA 90082.

³ Research Associate of the National Cancer Institute of Canada.

⁴ Recipient of a grant from the National Cancer Institute of Canada.

Received 5/ 6/82. Accepted 10/12/82.