Inhibition of Small-cell Lung Cancer Angiogenesis by Irinotecan Metronomic Chemotherapy and Irinotecan Plus Everolimus.

BACKGROUND/AIM: Few drugs are effective against small-cell lung cancer (SCLC) after second-line treatment, and suppressing rapid angiogenesis in tumor tissues has been considered an option. Metronomic chemotherapy can suppress angiogenesis while reducing toxicity, and irinotecan has antitumor effects against SCLC. Everolimus is an mTOR inhibitor that inhibits angiogenesis. This study investigated the inhibition of SCLC angiogenesis by irinotecan (CPT-11) metronomic chemotherapy and irinotecan plus everolimus.

MATERIALS AND METHODS: Human SCLC cell lines N417, H82, and H187 were used. Cell viability was measured using the WST-8 assay. VEGFA gene expression was quantified using reverse transcription quantitative PCR (RT-qPCR). An orthotopic human SCLC xenograft model was used to assess cytotoxicity and angiogenesis after intravenous administration of irinotecan and everolimus. Immunohistochemistry for CD31 was performed to detect blood vessels in the tumor. Terminal transferase dUTP nick end labeling (TUNEL) staining was performed for in situ detection of apoptosis.

RESULTS: CPT-11 and everolimus alone inhibited the growth of SCLC cells in vitro. The combination of everolimus and irinotecan did not alter the cytotoxic effects of CPT-11. Irinotecan and everolimus did not induce VEGFA expression. Immunohistochemistry revealed that the microvessel density upon daily CPT-11 and weekly irinotecan plus everolimus was comparable to that of weekly CPT-11 (positive control). Daily administration of CPT-11 inhibited vascular angiogenesis, whereas the concomitant administration of CPT-11 and everolimus did not. In contrast, the combination of CPT-11 and everolimus induced tumor apoptosis.

CONCLUSION: Daily administration of CPT-11 may have significant antitumor effects based on its anti-angiogenic effects. Daily administration of CPT-11 may be a novel second-line option for SCLC.