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Heterogeneity of X-Ray Cytotoxicity in Proliferating and Quiescent Murine Mammary Carcinoma Cells¹

University of Utah Medical Center, Department of Radiology, Section of Experimental Oncology, Salt Lake City, Utah 84132

A highly enriched (97%) quiescent (Q) tumor cell population can be induced in both the 66 and 67 murine mammary carcinoma lines in vitro by nutrient deprivation (7-day, unfed plateau cultures), while exponential cultures (2-day cultures) of this line are composed of >98% proliferating (P) cells. We have used these two cell lines to determine how the radiation sensitivity varies as a function of genetic heterogeneity (two cell lines derived from the same tumor) and proliferative status (physiological state). The 67 Q cells were significantly more sensitive than were the P cells to single doses of X-rays, with D₀s of 52 and 90 rads and D_qs of 188 and 250 rads, respectively. Cells from transition cultures (cells that have essentially stopped proliferation but are not in the biochemical state of Q cells) have a radiation sensitivity similar to that of P cells. When exponentially growing 67 cells were induced into a Q state by reducing the serum concentration (0.5 versus 15%), they, too, were more sensitive to X-rays than were their proliferating counterparts. This sensitivity of the Q cells was decreased by placing them 30 min prior to irradiation in either fresh medium, a balanced salt solution, or a balanced salt solution with 24 mM glucose. However, the Q cells in these conditions were still an order of magnitude more sensitive than the P cells after a 523-rad dose. Therefore, the increased sensitivity of the well-oxygenated 67 Q cells appears to be primarily related to physiological alterations accompanying the transition from P to Q. The radiation sensitivity of 66 cells has also been measured in P and Q states. These cells are significantly more radioresistant than are the 67 cells and, again, the 66 Q cells were more sensitive than were the 66 P cells, with D₀s of 90 and 109 rads and D_qs of 150 and 368 rads, respectively. Furthermore, the heterogeneous radiation response of the 66 and 67 cells continues to be expressed under various physiological states, albeit in qualitatively different ways; i.e., in 66 Q versus P cells, the shift in sensitivity is primarily due to a markedly reduced D_q while, in the 67 Q versus P cells, the lowered radiosensitivity is due to a marked reduction in both D₀ and D_q. At least in these cell lines, it is unlikely that Q cells will determine the response of the tumor to radiation.

¹ This work was supported by grants from the National Institutes of Health (CA 22188) and by the American Cancer Society (IN-154 and PDT-263).

² To whom requests for reprints should be addressed, at Radiation Biophysics, University of Kansas, Nuclear Reactor Center, West 15th Street, Lawrence, KS 66045.

Received 11/15/84. Revised 4/ 3/85. Accepted 4/ 5/85.

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