Human Tumor Xenografts Recurring after Radiotherapy Are More Sensitive to Anti–Vascular Endothelial Growth Factor Receptor-2 Treatment than Treatment-Naive Tumors

Abstract

The effects of antiangiogenic therapy on tumors relapsing after irradiation are not known. To this end, we irradiated human tumors growing s.c. in nude mice with a single dose of 20 or 30 Gy. Compared with primary (treatment-naive) xenografts, the growth rate of recurrent tumors was 1.6-fold slower, which is consistent with the known ''tumor bed effect.'' For similar size tumors, recurrences had fewer functional vessels, a reduced vessel coverage by perivascular cells, and were more necrotic. Placenta growth factor concentration was significantly lower in relapses, whereas vascular endothelial growth factor (VEGF) levels were similar between primary and recurrent tumors. On the other hand, fibrillar collagen deposition was significantly increased in recurrent tumors. This radiation-induced fibrosis was partially responsible for the slower growth of recurrences; the i.t. injection of collagenase increased the growth rate of tumor relapses without affecting primary tumor growth. The mouse-specific VEGF receptor 2-blocking antibody DC101 induced a 2.2-fold longer growth delay in recurrent tumors compared with treatment-naive tumors. DC101 significantly decreased the interstitial fluid pressure and did not change the functional vessel density and perivascular cell coverage in both tumor variants. Interestingly, DC101 induced a rapid (2 days after treatment initiation) and significant decrease in tumor cell proliferation in recurrent but not in primary tumors. Thus, our results show that the stromal compartment and the response to antiangionenic therapy of primary and in-field recurrent tumors are significantly different. Our findings suggest that antiangiogenic agents could be effective in the treatment of patients with relapses after radiotherapy.

The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) Enhances the Radiation Responsiveness of Lung and Colorectal Tumor Xenografts

“…Radiation doses as low as 2 Gy could inhibit endothelial cell proliferation, survival, and invasion in vitro (40). As we showed that AZD6244 reduces the levels of VEGF that, when present, can protect from the damaging effects of radiation (21,22), the effect of combination therapy on vascular density and perfusion was assessed.…”

Tumor Vascular Microenvironment Determines Responsiveness to Photodynamic Therapy

“…For example, an antibody to VEGF-receptor increased vascular basement membrane in a murine mammary carcinoma at three days after its administration, in concert with decreases in vascular density and vascular diameter (4). Other approaches to increase collagen could include local injection of collagen-based tissue fillers, as used in plastic surgery (47), or subcurative ionizing radiation (48) .…”

Combination of antiangiogenesis with chemotherapy for more effective cancer treatment

“…For example, both radiation treatment and chemotherapy can augment the sensitivity of tumor blood vessels to VEGF inhibition, which leads to increased growth delay of human tumor xenografts in combination therapy settings (99, 100). When administered using an MTD schedule, conventional chemotherapeutic drugs not only damage tumor cells; they also kill proliferating cells in normal tissues, which mandates the introduction of a drug-free recovery period between treatment cycles.…”