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Genetic Instability Coupled to Clonal Selection as a Mechanism for Tumor Progression in the Dunning R-3327 Rat Prostatic Adenocarcinoma System¹

Johns Hopkins Oncology Center [J. T. I., D. S. C.] and Department of Urology [J. T. I., D. S. C.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and Departments of Genetics and Endocrinology, Roswell Park Memorial Institute, Buffalo, New York 14263 [N. W., A. A. S.]

The androgen-sensitive Dunning R-3327-H prostatic adenocarcinoma has been maintained by continuous serial passage in intact male rats for many years. While it has been possible to maintain the original characteristics of the well-differentiated H tumor over 16 years, there have evolved spontaneously, however, more aberrant sublines from this tumor at several subpassages in intact male rats. Serial passage of these individual sublines has established five additional R-3327 tumors each with distinct phenotypes and each more aberrant than the parent H tumor. In addition, it has been possible by passage of the H tumor in castrated male rats to obtain a well-differentiated slow-growing androgen-insensitive tumor termed the HI-S tumor. The continuous serial passage of this HI-S tumor has likewise resulted in the emergence of three new types of Dunning tumors. The results from the biochemical and chromosomal studies presented demonstrate that there is a consistent association in each of these tumor progressions between the expression of genetic instability, which results in the addition of phenotypically new clones of cells to the tumor population, and the subsequent selection of these newly developed clones. These results suggest that the process of genetic instability coupled to clonal selection is one mechanism for the change in tumor phenotype characteristically associated with tumor progression within this system of prostatic tumors.

¹ Supported in part by Grant CA 15416-07 and in part by Grant CA 15436 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 11/12/81. Accepted 2/25/82.

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