Heterogeneity of X-ray cytotoxicity in proliferating and quiescent murine mammary carcinoma cells.

A highly enriched (greater than or equal to 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 greater than 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 Dos of 52 and 90 rads and Dqs 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 Dos of 90 and 109 rads and Dqs 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 Dq while, in the 67 Q versus P cells, the lowered radiosensitivity is due to a marked reduction in both Do and Dq. At least in these cell lines, it is unlikely that Q cells will determine the response of the tumor to radiation.