RESUMEN
Classical descriptions of tumor physiology suggest two origins for tumor hypoxia; steady-state (diffusion-limited) hypoxia and cycling (perfusion-modulated) hypoxia. Both origins, primarily studied and characterized in murine models, predict relatively small, isolated foci or thin shells of hypoxic tissue interspersed with contrasting oxic tissue. These foci or shells would not be expected to scale with overall tumor size since the oxygen diffusion distance (determined by oxygen permeability and tissue oxygen consumption rate) is not known to vary dramatically from tumor to tumor. We have identified much larger (macroscopic) regions of hypoxia in rat gliosarcoma tumors and in larger human tumors (notably sarcomas and high-grade glial tumors), as indicated by biochemical binding of the hypoxia marker, EF5. Thus, we considered an alternative cause of tumor hypoxia related to a phenomenon first observed in window-chamber tumor models: namely longitudinal arteriole gradients. Although longitudinal arteriole gradients, as originally described, are also microscopic in nature, it is possible for them to scale with tumor size if tumor blood flow is organized in an appropriate manner. In this organization, inflowing blood would arise from relatively well-oxygenated sources and would branch and then coalesce to poorly-oxygenated outflowing blood over distances much larger than the length of conventional arterioles (multi-millimeter scale). This novel concept differs from the common characterization of tumor blood flow as disorganized and/or chaotic. The organization of blood flow to produce extended longitudinal gradients and macroscopic regional hypoxia has many important implications for the imaging, therapy and biological properties of tumors. Herein, we report the first experimental evidence for such blood flow, using rat 9L gliosarcoma tumors grown on the epigastric artery/vein pair.
RESUMEN
One method to make hypoxic, radioresistant cells more radiation sensitive has been to increase the oxygen carrying capacity of normal blood using liquid perfluorochemical emulsions combined with breathing high pO2 gases. We investigated the ability of dodecafluoropentane (DDFP) to sensitize the moderately radiation-resistant Morris 7777 hepatoma based on our previous inability to modify the radiation response of this tumor. DDFP is used in very small quantities compared with perfluorchemicals reported previously. Rats under isoflurane anesthesia were administered EF5 3 h before irradiation to monitor the pretreatment level of tissue hypoxia. At -40 min, DDFP was administered i.v. at 3.5 ml/kg over 30 min. At -10 min, the rats were either continued with air (for controls) or switched to carbogen. The tumors were then irradiated and processed for evaluation of radiation response. Tumor-cell survival for DDFP treatment with air-breathing animals was not significantly different from controls treated without DDFP. Carbogen alone provided minimal sensitization. DDFP plus carbogen caused dramatic radiosensitization, and the radiation response of cells from these tumors was the same as a completely aerobic radiation response. DDFP plus carbogen appears to completely reverse the hypoxic cell radioresistance in this tumor model.