Anti-Vascular Endothelial Growth Factor Treatment Augments Tumor Radiation Response under Normoxic or Hypoxic Conditions
2000
Recent studies in experimental animals have shown that combining
antiangiogenic therapy with radiation can enhance tumor response.
Whether this enhancement is mainly attributable to angiogenesis
inhibition, endothelial cell radiosensitivity, tumor cell apoptosis, or
a decrease in the number of hypoxic cells (improved oxygenation) is not
known. We designed this study to discern the role of tumor oxygenation.
We chose an anti-vascular endothelial growth factor (anti-VEGF)
monoclonal antibody (mAb) which has a known target, human VEGF. We also
measured interstitial fluid pressure (IFP) to test the hypothesis that
the decreased vascular permeability induced by the anti-VEGF mAb can
lower IFP. The effect of anti-VEGF mAb on vascular density, partial
oxygen tension (pO 2 ), and apoptosis was also measured.
Athymic NCr/Sed nu/nu mice bearing 6-mm xenograft of the human
glioblastoma multiforme (U87), or colon adenocarcinoma (LS174T) were
treated with anti-VEGF mAb injected i.p. on alternate days for a total
of six injections at a dosage of 100 μg/injection/mouse. For combined
anti-VEGF and radiation, single radiation doses were given under normal
blood flow (20 and 30 Gy) or clamped hypoxic conditions (30 and 40 Gy)
24 h after the sixth injection of mAb. The inhibition of the
growth of U87 and LS174T tumors by the anti-VEGF mAb was associated
with a significant reduction in tumor vascular density and a relatively
small increase in the number of apoptotic cells. Compared with
size-matched controls, IFP decreased by 74% in LS174T, and 73% in U87
in mice treated with anti-VEGF mAb. After antibody treatment
pO 2 increased significantly in U87, but did not change in
LS174T tumors. Combined treatment induced in U87 tumors a tumor-growth
delay (TGD) which was greater than additive; in LS174T except for the
40-Gy hypoxic group, the effect was only additive. In both U87 and
LS174T the TGD induced by the antibody was independent of oxygen levels
in the tumor at the time of radiation. The fact that the increase in
TGD occurred under both normoxic and hypoxic conditions suggests that
anti-VEGF mAb treatment can compensate for the resistance to radiation
induced by hypoxia.
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