Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy

Tumor oxygenation is critical for tumor survival as well as for response to therapy, e.g., radiation therapy, Hormone ablation therapy in certain horm one-dependent tumors and antiangiogenic therapy lead to vessel regression a nd have also shown beneficial effects when combined with radiation therapy. These findings are counterintuitive because vessel regression should reduc e oxygen tension (pO(2)) in tumors, decreasing the effectiveness of radioth erapy. Here we report on the dynamics of pO(2) and oxygen consumption in a hormone-dependent tumor following hormone ablation and during treatment wit h an anti-VEGFR-2 monoclonal antibody (mAb) or a combination of doxorubicin and cyclophosphamide; the latter combination is not known to cause vessel regression at doses used clinically. Androgen-dependent male mouse mammary carcinoma (Shionogi) was implanted into transparent dorsal skin-fold chambe rs in male severe combined immunodeficient mice, Thirteen days after the tu mors were implanted, mice were treated with antiangiogenic therapy (anti-VE GFR-2 mAb, 1.4 mg/30 g body weight), hormone ablation by castration, or dox orubicin (6.5 mg/kg every 7 days) and cyclophosphamide (100 mg/kg every 7 d ays). A non-invasive in vivo method was used to measure pO(2) profiles and to calculate oxygen consumption rates (Q(O2)) in tumors, Tumors treated wit h anti-VEGFR-2 mAb exhibited vessel regression and became hypoxic. Initial vessel regression was followed by a "second wave" of angiogenesis and incre ases in both pO(2) and Q(O2). Hormone ablation led to tumor regression foll owed by an increase in pO(2) coincident with regrowth. Chemotherapy led to tumor growth arrest characterized by constant Q(O2) and elevated pO(2). The increased pO(2) during anti-VEGFR-2 mAb and hormone ablation therapy may e xplain the observed beneficial effects of combining antiangiogenic or hormo ne therapies with radiation treatment. Thus, understanding the microenviron mental dynamics is critical for optimal scheduling of these treatment modal ities.