Recombinant human Mullerian inhibiting substance inhibits long-term growth of MIS type II receptor-directed transgenic mouse ovarian cancers in vivo.
OBJECTIVE
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.


METHODS
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.
Pieretti-Vanmarcke
Rafael
R
Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. rpierettivanmarcke@partners.org
Donahoe
Patricia K
PK
Szotek
Paul
P
Manganaro
Thomas
T
Lorenzen
Mary K
MK
Lorenzen
James
J
Connolly
Denise C
DC
Halpern
Elkan F
EF
MacLaughlin
David T
DT
D000818:Animals; D054304:Anti-Mullerian Hormone; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D015152:Blotting, Northern; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006023:Glycoproteins / Q000627:therapeutic use*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009095:Mullerian Ducts; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics* / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins / Q000627:therapeutic use*; D013735:Testicular Hormones / Q000627:therapeutic use*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000952:Antigens, Polyomavirus Transforming; D006023:Glycoproteins; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D013735:Testicular Hormones; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone; D017346:Protein Serine-Threonine Kinases