Pieretti-Vanmarcke Rafael, Donahoe Patricia K, Szotek Paul, Manganaro Thomas, Lorenzen Mary K, Lorenzen James, Connolly Denise C, Halpern Elkan F, MacLaughlin David T
Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
Clin Cancer Res. 2006 Mar 1;12(5):1593-8. doi: 10.1158/1078-0432.CCR-05-2108.
Mullerian inhibiting substance (MIS) is a glycoprotein hormone that causes Mullerian duct regression in male embryos. In short-term experiments, recombinant human MIS (rhMIS) inhibits xenotransplanted human ovarian cancer cell lines that are thought to be of Mullerian origin. Because this highly lethal cancer has a high recurrence rate after conventional chemotherapy, new treatments are warranted. We examined whether rhMIS as a novel, nontoxic, naturally occurring growth inhibitor can be an effective anticancer drug in long-term studies in vivo against allograft tumors that recapitulate human ovarian carcinoma.
Mouse ovarian carcinoma (MOVCAR) cell lines expressing the early region of the SV40 virus, including the large and small T-antigen genes under transcriptional control of a portion of the murine MIS receptor type II (MISRII) gene promoter, were derived from TgMISIIR-TAg transgenic mice. rhMIS was tested against MOVCAR cells in growth inhibition assays in vitro, and in vivo in 6-week-old female nude mice. Tumor growth in animals was measured at weekly intervals for up to 20 weeks.
MOVCAR cells and tumors express MISRII by Western blot, immunohistochemical, and Northern blot analyses. rhMIS significantly inhibited MOVCAR cell growth in vitro and in vivo in three separate long-term allotransplantation experiments.
Because rhMIS is an effective anticancer agent in in vitro and in long-term in vivo preclinical experiments against MISRII-positive tumors, we predict that rhMIS can be used safely and effectively to treat human ovarian malignancies.
苗勒管抑制物质（MIS）是一种糖蛋白激素，可导致雄性胚胎中的苗勒管退化。在短期实验中，重组人MIS（rhMIS）可抑制异种移植的人卵巢癌细胞系，这些细胞系被认为起源于苗勒管。由于这种高致死性癌症在传统化疗后复发率很高，因此需要新的治疗方法。我们研究了rhMIS作为一种新型、无毒、天然存在的生长抑制剂，在针对模拟人卵巢癌的同种异体移植肿瘤的长期体内研究中是否可以成为一种有效的抗癌药物。
表达SV40病毒早期区域的小鼠卵巢癌（MOVCAR）细胞系，包括在部分鼠II型MIS受体（MISRII）基因启动子转录控制下的大、小T抗原基因，源自TgMISIIR-TAg转基因小鼠。在体外生长抑制试验中以及在6周龄雌性裸鼠体内对rhMIS进行了针对MOVCAR细胞的测试。每周测量动物的肿瘤生长情况，最长持续20周。
通过蛋白质免疫印迹、免疫组织化学和Northern印迹分析，MOVCAR细胞和肿瘤表达MISRII。在三项独立的长期同种异体移植实验中，rhMIS在体外和体内均显著抑制了MOVCAR细胞的生长。
由于rhMIS在体外和针对MISRII阳性肿瘤的长期体内临床前实验中是一种有效的抗癌剂，我们预测rhMIS可安全有效地用于治疗人类卵巢恶性肿瘤。
