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Assessment of Radiogenic Cancer Initiation Frequency per Clonogenic Rat Mammary Cell in Vivo¹

Departments of Human Oncology [K. H. C., M. A. T., M. N. G.], Radiology [K. H. C.], Statistics [M. A. T.], and Medical Physics [M. N. G.], Wisconsin Clinical Cancer Center, University of Wisconsin, Madison, Wisconsin 53792

Radiogenic initiation of mammary cancer is here shown to be a common cellular event. With the aid of a rat mammary clonogen transplant system designed to maximize progression of initiated cells to overt neoplasia, the estimated absolute cancer risk per surviving 7 Gy-irradiated mammary clonogen was [4.1 ± 1.2 (SE)] x 10^-3, that is (5.8 ± 1.7) x 10^-4 initiated cells per clonogen-Gy. To maximize neoplastic progression, all clonogen graft recipient rats were glucocorticoid deficient (adrenalectomized with minimal mineralocorticoid replacement) and hyperprolactinemic (implanted intrasplenically with pituitary tissue and an estrone capsule). Each rat was grafted with 4 x 10⁶ "morphologically intact" monodispersed mammary cells in the interscapular white fat pad. Group A received cells which had been irradiated 1 day earlier with 7 Gy ¹³⁷Cs -rays. Groups B and C received unirradiated mammary cells. On day 35 after transplantation, the graft sites of group B were locally exposed to 7 Gy 140 kVp X-rays. Kaplan-Meier estimates (11) of the survivor functions were used to calculate the final tumor incidences corrected for intercurrent animal loss. Estimated mammary carcinoma frequencies so calculated were 65 tumors/131 graft sites in group A, 93/119 in group B, and 13/129 in group C. The relative cancer risks per rat due to the radiation exposure of the grafted cells were 5.0 for group A and 7.8 for group B. These data on neoplasia incidence in grafted mammary clonogens and data on autologous neoplasia in the host rat mammary glands were subjected to statistical analysis. The results indicate that both neoplasm frequency and latency are in large part dependent on initiation target cell number. The high frequency of radiogenic initiation per mammary clonogen observed in this study is in accord with findings with a similar thyroid clonogen transplant system.

¹ Supported in part by National Cancer Institute (Department of Health and Human Services) grants R01-CA13881 to K. H. C., R23-CA35464 to M. A. T., and R01-CA28954 to M. N. G. The authors received partial salary support from National Cancer Institute grant P30-CA-14520 to the Wisconsin Clinical Cancer Center. Some of these data were reviewed in a preliminary report (2).

² To whom requests for reprints should be addressed, at K4/312, Wisconsin Clinical Cancer Center, 600 N. Highland Ave., Madison, WI 53792.

Received 7/19/85. Revised 1/22/86. Accepted 1/31/86.

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