SIDE-EFFECTS OF HEAD AND NECK CANCER TREATMENT AND POTENTIAL STRATEGIES TO REDUCE THEM

Abstract

not received. TARGETING ANGIOGENESIS OR VASCULOGENESIS IN CANCER THERAPY: ADVANTAGES AND POTENTIAL RISKS M. Brown, G. O. Ann, M. Kioi l , J. Williams 2 1 STANFORD UNIVERSITY SCHOOL OF MEDICINE, Department of Radiation Oncology, Stanford, USA 2 UNIVERSITY OF ROCHESTER CANCER CENTER, Department of Radiation Oncology, Rochester NY, USA Purpose/Objective: The objective of this talk is to discuss the concept that damage to blood vessels can be repaired by circulating proangiogenic cells (a process known as vasculogenesis) and that the response of tumors to irradiation can be increased by blocking angiogenesis. However, does this also increase the radiation damage to normal tissues? Material/Methods; We have tested the hypothesis that the radiation response of tumors can be increased by blocking vasculogenesis using two human tumors (FaDu and U251 glioma) transplanted into nude mice. We have also examined the response of normal skin and radiation-induced pneumonitis in mice. We have used a variety of bone marrow transplantation studies to identify bone marrow derived cells in tumors. Results: We show that an essential contributor to vasculogenesis in irradiated tumors are CD11b+ myelomonocytic cells expressing MMP-9, and circulating endothelial cells (ECs) or endothelial progenitor cells (EPCs). These are recruited to the irradiated tumors by stromal derived factor 1 (SDF-1) induced by increased levels of HIF-1 in the irradiated tumors. Importantly, a variety of ways of blocking this process (neutralizing antibodies to CD11b, inhibition of the interaction of SDF-1 with CXCR4 and with CXCR7, antibodies against CXCR4, and inhibition of HIF-1) render tumors less able to recur following irradiation. Thus, this is an important strategy for improving the cure rate of solid tumors by radiation. However, the exogenous transplantation of proangiogenic cells, including EPCs, has become an important strategy for accelerating the repair of normal tissue injury by vascular damage (such as in myocardial infarcts), so it is possible that inhibiting their accumulation in irradiated tissues might increase normal tissue damage by irradiation. We have tested this in two systems: acute skin reactions and radiation pneumonitis in mice. In neither case did the administration of neutralizing antibodies against CD11b+ monocytes following irradiation increase the radiation-induced injury. In fact in the case of the skin reactions we found a significant protection. We will discuss the evidence that inhibition of EPCs might increase normal tissue injury following irradiation. Conclusion: Blocking vasculogenesis can have a major positive impact on the response of solid tumors to irradiation. Much work remains to be done to determine if this is safe for normal tissues, but the initial evidence is that this strategy of blocking vasculogenesis does not increase radiation damage to normal tissues.