Friesen C, Herr I, Krammer P H, Debatin K M
Department of Hematology/Oncology, University Children's Hospital, Heidelberg, Germany.
Nat Med. 1996 May;2(5):574-7. doi: 10.1038/nm0596-574.
Cytotoxic drugs used in chemotherapy of leukemias and solid tumors cause apoptosis in target cells. In lymphoid cells the CD95 (APO-1/Fas)/CD95 ligand (CD95-L) system is a key regulator of apoptosis. Here we describe that doxorbicin induces apoptosis via the CD95/CD95-L system in human leukemia T-cell lines. Doxorubicin-induced apoptosis was completely blocked by inhibition of gene expression and protein synthesis. Also, doxorbicin strongly stimulates CD95-L messenger RNA expression in vitro at concentrations relevant for therapy in vivo. CEM and jurkat cells resistant to CD95-mediated apoptosis were also resistant to doxorbicin-induced apoptosis . Furthermore, doxorbicin-induced apoptosis was inhibited by blocking F(ab')2 anti-APO-1 (anti-CD95) antibody fragments. Expression of CD95-L mRNA and protein in vitro was also stimulated by other cytotoxic drugs such as methotrexate. The finding that apoptosis caused by anticancer drugs may be mediated via the CD95 system provides a new molecular insight into resistance and sensitivity toward chemotherapy in malignancies.
用于白血病和实体瘤化疗的细胞毒性药物可导致靶细胞凋亡。在淋巴细胞中，CD95（APO-1/Fas）/CD95配体（CD95-L）系统是凋亡的关键调节因子。在此我们描述阿霉素通过CD95/CD95-L系统在人白血病T细胞系中诱导凋亡。阿霉素诱导的凋亡被基因表达和蛋白质合成的抑制完全阻断。此外，阿霉素在与体内治疗相关的浓度下强烈刺激体外CD95-L信使核糖核酸的表达。对CD95介导的凋亡有抗性的CEM和Jurkat细胞对阿霉素诱导的凋亡也有抗性。此外，通过阻断F(ab')2抗APO-1（抗CD95）抗体片段可抑制阿霉素诱导的凋亡。体外CD95-L信使核糖核酸和蛋白质的表达也受到其他细胞毒性药物如甲氨蝶呤的刺激。抗癌药物引起的凋亡可能通过CD95系统介导这一发现为恶性肿瘤对化疗的抗性和敏感性提供了新的分子见解。
