MODULATION OF TUMOR HYPOXIA BY CONVENTIONAL CHEMOTHERAPEUTIC-AGENTS

Purpose: We have evaluated the capacity of a number of common cancer chemotherapeutic drugs to modulate the oxygenation of human tumor xenografts growing in murine hosts. Methods and Materials: Considerable effort has been expended on developing methods to radiosensitize hypoxic cells, or to selectively kill them with appropriate chemicals. Another approach, suggested by our ongoing studies with spheroids in vitro, is to modify tumor oxygenation by physiological means. The feasibility of this approach is illustrated in this article using human tumor xenografts in mice treated with doxorubicin or mitomycin C plus radiation. The therapeutic potential of the combination treatments has been assessed using fluorescence-activated cell sorting techniques to isolate and differentially study hypoxic vs. aerobic cell subpopulations from the xenografts. Additionally, drug-induced changes in blood flow have been quantified at the macroscopic level with laser Doppler flowmetry, and at the microregional level with image analysis techniques. Results: At doses which produced only modest amounts of tumor cell killing, doxorubicin and mitomycin C markedly altered tumor blood flow in all tumor types examined, and with all assays used. Conclusion: Common anti-cancer agents may find new use as blood flow modifiers for combined modality treatments, in addition to their conventional use as ''pure'' cytotoxins.