Highly purified Mullerian inhibiting substance inhibits human ovarian cancer in vivo

Purpose: Mullerian inhibiting substance (MIS) causes Mullerian duct regression in mammalian, avian, and reptilian embryos; MIS also inhibits growth in vitro of Mullerian-derived cell lines and primary cells from human ovarian carcinomas. We hypothesize that highly purified MIS delivered parenterally inhibits ovarian cancer in vivo. Experimental Design: To test the efficacy of highly purified MIS against ovarian cancer cell lines in vivo, we treated immunosuppressed mice with MIS after implanting OVCAR 8 or IGROV 1 human ovarian cancer cells beneath the renal capsules and measured tumor volume over time. Animals were treated with daily injections of 10 mug of purified exogenous recombinant human MIS or by endogenous MIS secreted from cells growing on biodegradable mesh. Results: The average graft size ratio (change in size compared with starting size) of the OVCAR 8 tumor implants was larger in the control animals than in animals treated for 2 weeks (P < 0.019) or 3 weeks (P < 0.001) with parenteral MIS, or after treating with MIS produced from transfected cells, which impregnated the biodegradable mesh (P = 0.02). The average graft size ratio of the IGROV I tumors was also larger in the control animals than in those treated with injected MIS (P = 0.0174). Conclusions: Highly purified recombinant human MIS, delivered parenterally, or MIS produced endogenously causes inhibition of human ovarian cancer cell lines in vivo, providing convincing preclinical evidence to support the use of MIS as a parenteral agent for the treatment of ovarian cancer.