Mechanisms of anti-tumor effects underlying sorafenib treatment: Evaluation of tumor oxygen states using ¹⁸F-FMISO in a human lung cancer xenograft

Objectives Although sorafenib has an anti-angiogenic property, it is not clear whether its action mechanism can be ascribed to “tumor hypoxia/tumor starvation” or “enhanced effects of combination chemo- or radio-therapy due to tumor vascular normalization”. The accurate evaluation of tumor responses after anti-angiogenic therapy is important for optimizing treatment strategy. Thus, to clarify the mechanism of anti-tumor effects of sorafenib, we evaluated the tumor oxygen states using ¹⁸F-FMISO in human lung cancer xenograft (H1975).

Methods H1975 xenograft was established in nude mice, and assigned to control (n=5) and sorafenib treatment groups (n=9). Mice in treatment groups were treated with sorafenib (40 or 80 mg/kg/day, p.o.) for 3 days. Mice were i.v. injected with ¹⁸F-FMISO and pimonidazole (a hypoxia marker), 4 and 2 h before sacrifice, respectively. Tumor ¹⁸F-FMISO uptake was quantified by %ID/g. Pimonidazole and CD31 (a vascular marker) immunohistochemistry (IHC) were performed.

Results Tumor ¹⁸F-FMISO uptake was significantly increased up to 1.7- and 2.0-fold by 40 and 80 mg sorafenib treatment, respectively (p<0.01 for both: control, 1.5±0.3; 40-mg treatment, 2.6±0.2; 80-mg treatment, 3.1±0.5%ID/g). Pimonidazole positive areas were also significantly increased up to 2.3- and 2.2-fold by the treatment, respectively (p<0.01 for both: control, 12.2±3.8; 40-mg treatment, 28.1±6.4; 80-mg treatment, 27.3±5.0%positive cells). The numbers of microvessels in tumors were markedly suppressed to 39 and 22% of the control by the treatment, respectively (p<0.05 for both: control, 4.6±2.4; 40-mg treatment, 1.8±1.1; 80-mg treatment, 1.0±0.6 vessels/mm²)

Conclusions ¹⁸F-FMISO uptake in the tumor was increased in relation to pimonidazole positive areas and reduction of microvessels with sorafenib treatment. These results indicate that the present treatment protocol of sorafenib may induce “tumor hypoxia/tumor starvation” in human lung cancer xenograft (H1975) owing to its anti-angiogenic property.