oxi-4503 and Kidney-Neoplasms

4T1 mouse mammary adenocarcinomas and Caki-1 human renal cell carcinomas grown in mouse dorsal window chambers were serially treated with the vascular disrupting agent (VDA) OXi4503 and their responses compared. The real-time in vivo response was assessed using spectral imaging of microvascular hemoglobin saturation. To our knowledge this is the first use of spectral imaging technology for investigation of vascular disrupting agents. Previous research showing tumor size dependence in the treatment response to VDAs suggested that for the size of tumors used in this study only a moderate response would be observed; however, the tumors unexpectedly had very different responses to treatment. Caki-1 tumors showed little permanent vessel damage and experienced transient vessel collapse with time-dependent oxygenation changes followed by recovery starting at 6 h after treatment. Caki-1 tumors did not manifest necrotic avascular regions even after repeated treatments. These results are consistent with those obtained using other imaging modalities and histology. In contrast, similarly sized 4T1 tumors showed extensive vessel disintegration, minor vascular collapse, and a drop in tumor oxygenation up to 6 h post-treatment, after which reperfusion of collapsed vessels and extensive vascular remodeling and neovascularization of the tumor rim occurred from 8-48 h. The completely disintegrated vessels did not recover and left behind avascular and apparently necrotic regions in the tumor core. Spectral imaging appears to be a useful technique for in vivo investigation of vascular disrupting agents. The differential responses of these two tumor-types suggest that further investigation of the mechanisms of action of VDAs and individual characterization of tumor VDA-responses may be needed for optimal clinical use of these agents.

Topics: Animals; Carcinoma, Renal Cell; Diphosphates; Female; Humans; Kidney Neoplasms; Mammary Neoplasms, Experimental; Mice; Oxygen; Stilbenes; Xenograft Model Antitumor Assays

The present study evaluated the treatment efficacy of the vascular disrupting agents CA4P and OXi4503 in an orthotopically transplanted human renal cell carcinoma xenograft model (Caki-1). Experiments used vascular casting, vessel density assessments as well as tumour necrosis measurements to evaluate the efficacy of these agents. After treatment with either agent, assessment of the vascular casts showed an almost total eradication of tumour blood vessels. Histological evidence further supported this observation, showing extensive central tumour necrosis with only a small viable rim of tumour cells remaining at the periphery. These results suggest that vascular disrupting agents CA4P and OXi4503 may have utility in the treatment of renal cell carcinoma, an encouraging result given that current conventional therapies have been currently largely unsuccessful in managing this disease.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Diphosphates; Female; Humans; Kidney Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Silicon; Stilbenes; Transplantation, Heterologous