THE LIFETIME OF HYPOXIC HUMAN TUMOR-CELLS

Purpose: For hypoxic and anoxic cells in solid tumors to he a therapeu tic problem, they must live long enough to be therapeutically relevant , or else be rapidly recruited into the proliferating compartment duri ng therapy. We have, therefore, estimated lifetime and recruitment rat e of hypoxic human tumor cells in multicell spheroids in vitro, or in xenografted tumors in SCID mice. Materials and Methods: Cell turnover was followed by flow cytometry techniques, using antibodies directed a t incorporated halogenated pyrimidines. The disappearance of labeled c ells was quantified, and verified to be cell loss rather than label di lution. Repopulation was studied in SiHa tumor xenografts during twice -daily 2.5-Gy radiation exposures. Results: The longevity of hypoxic h uman tumor cells in spheroids or xenografts exceeded that of rodent ce ll lines, and cell turnover was slower in xenografts than under static growth as spheroids, Human tumor cells remained viable in the hypoxic regions of xenografts for 4-10 days, compared to 35 days in spheroids , and 13 days for most rodent cells in spheroids. Repopulation was obs erved within the first few radiation treatments for the SiHa xenograft s and, with accumulated doses of more than 10 Gy, virtually all recove red cells had progressed through at least one S-phase. Conclusion: Our results suggest an important difference in the ability of human vs. r odent tumor cells to withstand hypoxia, and raise questions concerning the increased longevity seen in vivo relative to the steady-state sph eroid system. (C) 1998 Elsevier Science Inc.