ABSTRACT
BACKGROUND: The present study investigated whether treatment with anginex, a novel antiangiogenic peptide, could block re-vascularization after radiation treatment. METHODS: A squamous cell (SCCVII) xenograft tumor mouse model was employed to assess the effects of anginex given post-radiation on tumor growth, microvessel density (MVD), and oxygen levels. The oxygen status was determined by the partial pressure of O2. RESULTS: Tumors in untreated mice increased threefold in 7.0 days, anginex-treated tumors (10 mg/kg intraperitoneal, twice) required 7.3 +/- 0.9 days, and tumors exposed to 8-Gy radiation increased threefold over 11 days. Combination treatment of anginex and radiation caused the tumors to grow threefold in 16.1 +/- 1.6 days, a delay which was significant and deemed supra-additive. Oxygen levels in tumors treated by stand-alone or combination therapies were significantly reduced; for example from 19.5 +/- 4.9 mmHg in controls to 9.7 +/- 1.9 mmHg in combination-treated, size-matched tumors. In addition, immunohistochemistry showed a decrease in MVD in the tumors treated with anginex, radiation, or the combination. These results suggest that a combination of anginex and radiation can greatly affect the amount of functional vasculature in tumors and prolong radiation-induced tumor regression. CONCLUSION: Antiangiogenesis therapy with anginex, in addition to radiotherapy, will be useful by blocking angiogenesis-dependent regrowth of vessels.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Carcinoma, Squamous Cell/blood supply , Carcinoma, Squamous Cell/drug therapy , Proteins/pharmacology , Vascular Neoplasms/blood supply , Vascular Neoplasms/drug therapy , Angiogenesis Inhibitors/adverse effects , Animals , Blood Vessels/drug effects , Blood Vessels/radiation effects , Carcinoma, Squamous Cell/radiotherapy , Cell Survival/drug effects , Cell Survival/radiation effects , Combined Modality Therapy , Endothelial Cells/drug effects , Endothelial Cells/radiation effects , Immunohistochemistry , Male , Mice , Mice, Inbred C3H , Neoplasms, Experimental , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/radiotherapy , Oxygen/analysis , Peptides , Skin/blood supply , Time Factors , Tumor Burden , Tumor Cells, Cultured , Vascular Neoplasms/radiotherapy , Xenograft Model Antitumor AssaysABSTRACT
The purpose of the present study was to investigate the effects of Pentoxifylline (PTX), Vinpocetine (VPT) and Ticlopidine Hydrochloride (TCD), used commonly for vascular disorders in humans, on the pO2 in SCCVII tumors of C3H/HeJ mice and on the radioresponse of SCCVII tumors. The pO2 in the SCCVII tumors, which were measured 30 min after intraperitoneal (i.p.) injection of PTX (5 mg/kg), VPT (5 mg/kg), or TCD (10 mg/kg) using polarography, was compared to that in saline-treated control tumors. All the three drugs, PTX, VPT and TCD, yielded significant increase of the pO2 in the SCCVII tumors from 25.6 to 26.9 mmHg, from 18.6 to 22.9 mmHg, and from 22.6 to 25.9 mmHg, respectively. Frequency histogram of the pO2 distribution in the saline-treated SCCVII tumors did not show hypoxic fraction of less than 10 mmHg. The radioresponses of the drugs were investigated by tumor growth delay assay. In the drug-treated groups, the SCCVII tumors were irradiated with a single dose of 15 Gy 30 min after injection of the drugs at the same doses as those used in the experiments for intratumoral pO2 measurement. Compared with the irradiation alone group, significant tumor growth delays were observed in all the drug-treated groups. The time required to reach a four-fold increase in the initial tumor volume were 4 days in the saline-treated control group, 22 days in the irradiation (IR) alone group, 28 days in the PTX + IR group, 29 days in the VPT + IR group, and 32 days in TCD + IR group. In conclusion, VPT and TCD are potentially promising drugs for increasing the intratumoral pO2 although the mechanism for radiopotentiation observed in the present study is unknown due to small hypoxic fraction in the SCCVII tumors. Further studies on other mechanisms for radiopotentiation of PTX, VPT or TCD, besides of increasing the pO2 in the tumor, are needed.
