Demetri G D, Fletcher C D, Mueller E, Sarraf P, Naujoks R, Campbell N, Spiegelman B M, Singer S
Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3951-6. doi: 10.1073/pnas.96.7.3951.
Agonist ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma have been shown to induce terminal differentiation of normal preadipocytes and human liposarcoma cells in vitro. Because the differentiation status of liposarcoma is predictive of clinical outcomes, modulation of the differentiation status of a tumor may favorably impact clinical behavior. We have conducted a clinical trial for treatment of patients with advanced liposarcoma by using the peroxisome proliferator-activated receptor-gamma ligand troglitazone, in which extensive correlative laboratory studies of tumor differentiation were performed. We report here the results of three patients with intermediate to high-grade liposarcomas in whom troglitazone administration induced histologic and biochemical differentiation in vivo. Biopsies of tumors from each of these patients while on troglitazone demonstrated histologic evidence of extensive lipid accumulation by tumor cells and substantial increases in NMR-detectable tumor triglycerides compared with pretreatment biopsies. In addition, expression of several mRNA transcripts characteristic of differentiation in the adipocyte lineage was induced. There was also a marked reduction in immunohistochemical expression of Ki-67, a marker of cell proliferation. Together, these data indicate that terminal adipocytic differentiation was induced in these malignant tumors by troglitazone. These results indicate that lineage-appropriate differentiation can be induced pharmacologically in a human solid tumor.
核受体过氧化物酶体增殖物激活受体γ的激动剂配体已被证明可在体外诱导正常前脂肪细胞和人脂肪肉瘤细胞的终末分化。由于脂肪肉瘤的分化状态可预测临床结果，调节肿瘤的分化状态可能会对临床行为产生有利影响。我们开展了一项使用过氧化物酶体增殖物激活受体γ配体曲格列酮治疗晚期脂肪肉瘤患者的临床试验，并对肿瘤分化进行了广泛的相关实验室研究。我们在此报告3例中高级别脂肪肉瘤患者的结果，曲格列酮给药在这些患者体内诱导了组织学和生化分化。这些患者在服用曲格列酮期间进行的肿瘤活检显示，与治疗前活检相比，肿瘤细胞有广泛脂质蓄积的组织学证据，且核磁共振检测到的肿瘤甘油三酯大幅增加。此外，脂肪细胞谱系中几种分化特征性mRNA转录物的表达被诱导。细胞增殖标志物Ki-67的免疫组化表达也显著降低。这些数据共同表明，曲格列酮在这些恶性肿瘤中诱导了终末脂肪细胞分化。这些结果表明，在人类实体瘤中可通过药物诱导出与谱系相应的分化。
