【Abstract】
Background: Systemic chemotherapy is often the last resort of advanced cutaneous T-cell lymphoma (CTCL). Tumor recurrence and adverse effects of systemic chemotherapy are the main limitations.
Objective: We aim to investigate the metabolic alterations in tumor cells after CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) chemotherapy.
Methods and Results: In advanced CTCL, CHOP chemotherapy has no survival benefit and the duration of response is significantly inferior to other canonical treatments.HIF-1α is significantly elevated in lesions of advanced MF patients as well as tumor cell line Hut78 and tumor xenograft mice model. CHOP therapy also increased glycolytic activities in a HIF-1α-dependent manner. In CTCL xenograft tumor mice model, lesional cells showed a significant increase in IL-17F after chemotherapy, shifting toward a Th17 phenotype, which process is also regulated by HIF-1α. Echinomycin, HIF-1α inhibitor, was co-administered in xenograft tumor mouse models with CHOP and showed a significant reduction in tumor growth.
Conclusion: CHOP chemotherapy promotes glycolysis and IL-17 pathways in a HIF-1α-dependent fashion. Furthermore, HIF-1α blockade is promising as an accompanying agent in systemic chemotherapy for patients with advanced CTCL.
【中文摘要】
背景：系統性化療通常作為晚期皮膚T細胞淋巴瘤（CTCL）治療最後的選擇。化療的主要弊端在於腫瘤的復發和系統性化療的副作用。
目的：研究腫瘤細胞在CHOP化療後的代謝改變。
方法和結果：在晚期CTCL，患者CHOP化療後在生存時間和緩解時間未顯示明顯受益。HIF-1α在晚期MF患者的皮損病灶和腫瘤細胞株及CTCL腫瘤鼠模型中表達明顯升高。CHOP化療後顯示了HIF-1α依賴的糖酵解活性的增加及IL-17F明顯升高。HIF-1α的抑制劑（棘黴素）可抑制CHOP化療後糖酵解途徑的激活和IL-17F炎症因子的增加，抑制CTCL鼠模型腫瘤的生長。
結論：CHOP化療以HIF-1α依賴的方式激活糖酵解和IL-17F通路。阻斷HIF-1α是一種潛在的輔助晚期CTCL化療的方法。