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Recombinant Human Mullerian Inhibiting Substance Inhibits Long-term Growth of MIS Type II Receptor–Directed Transgenic Mouse Ovarian Cancers In vivo

Authors' Affiliations: ¹ Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital; ² Institute for Technology and Assessment, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and ³ Fox Chase Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Rafael Pieretti, Pediatric Surgical Research Laboratories, Massachusetts General Hospital, 185 Cambridge Street, CPZN 6200, Boston, MA 02114. Phone: 617-724-1617; Fax: 617-726-5057; E-mail: rpierettivanmarcke{at}partners.org.

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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.

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