title: Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy.
abstract: Tumor oxygenation is critical for tumor survival as well as for response to therapy, e.g., radiation therapy. Hormone ablation therapy in certain hormone-dependent tumors and antiangiogenic therapy lead to vessel regression and have also shown beneficial effects when combined with radiation therapy. These findings are counterintuitive because vessel regression should reduce oxygen tension (pO2) in tumors, decreasing the effectiveness of radiotherapy. Here we report on the dynamics of pO2 and oxygen consumption in a hormone-dependent tumor following hormone ablation and during treatment with 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 chambers in male severe combined immunodeficient mice. Thirteen days after the tumors were implanted, mice were treated with antiangiogenic therapy (anti-VEGFR-2 mAb, 1.4 mg/30 g body weight), hormone ablation by castration, or doxorubicin (6.5 mg/kg every 7 days) and cyclophosphamide (100 mg/kg every 7 days). A non-invasive in vivo method was used to measure pO2 profiles and to calculate oxygen consumption rates (Q(O2)) in tumors. Tumors treated with anti-VEGFR-2 mAb exhibited vessel regression and became hypoxic. Initial vessel regression was followed by a "second wave" of angiogenesis and increases in both pO2 and Q(O2). Hormone ablation led to tumor regression followed by an increase in pO2 coincident with regrowth. Chemotherapy led to tumor growth arrest characterized by constant Q(O2) and elevated pO2. The increased pO2 during anti-VEGFR-2 mAb and hormone ablation therapy may explain the observed beneficial effects of combining antiangiogenic or hormone therapies with radiation treatment. Thus, understanding the microenvironmental dynamics is critical for optimal scheduling of these treatment modalities.
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hansen-Algenstaedt
authors.forename: B R
authors.initials: BR
authors.lastname: Stoll
authors.forename: T P
authors.initials: TP
authors.lastname: Padera
authors.forename: D E
authors.initials: DE
authors.lastname: Dolmans
authors.forename: D J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: D
authors.initials: D
authors.lastname: Fukumura
authors.forename: R K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000728:Androgens / Q000502:physiology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D008163:Luminescent Measurements; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence / Q000379:methods; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000098:blood supply / Q000378:metabolism* / Q000628:therapy; D009919:Orchiectomy; D010100:Oxygen / Q000097:blood / Q000378:metabolism*; D010101:Oxygen Consumption; D010313:Partial Pressure; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D040262:Receptors, Vascular Endothelial Growth Factor
chemical_list: D000728:Androgens; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D017978:Receptors, Growth Factor; D004317:Doxorubicin; D003520:Cyclophosphamide; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D010100:Oxygen