Novel therapeutic strategies for leiomyomas: targeting growth factors and their receptors.
Leiomyomas (fibroids) are benign smooth-muscle cell (SMC) tumors of the uterus and are the most common pelvic tumors in women. These tumors occur primarily during the reproductive years and are the most common indication for hysterectomy in women. Unfortunately the only effective treatments for leiomyomas and the associated abnormal uterine bleeding are surgical, involving either hysterectomy, myomectomy, or hysteroscopic removal of the tumors. The goal of this paper is to discuss recent research findings that support the idea of using therapeutic compounds that block the actions of specific growth factors as therapeutic agents for treatment of leiomyomas and abnormal uterine bleeding. Most of the studies were carried out using cell cultures of leiomyoma or myometrial SMCs. Primary cultures of SMCs provide a system for investigation of the roles of growth factors and their receptors in proliferation of normal myometrial and leiomyoma SMCs. Several growth factors have been shown to be present and to have regulatory roles in the proliferation of uterine SMCs. Bioassay and Western blotting of fast protein liquid chromatography fractions of tissue extracts identified platelet-derived growth factor, heparin-binding epidermal growth factor, hepatoma-derived growth factor, and basic fibroblast growth factor in normal myometrium and fibroid tumors. The presence of heparin-binding growth factors suggests a possible focus for therapeutic agents. RG13577 (a heparinlike compound) and halofuginone (an alkyloid) reversibly inhibited DNA synthesis of normal myometrial and leiomyoma cells without toxic effects. Pirfenidone, a known antifibrotic drug, inhibited DNA synthesis and synthesis of collagen type I mRNA in normal and fibroid cells, and decreased collagen type III mRNA only in normal myometrial cells. Another hopeful therapeutic candidate, interferon-Alpha, significantly inhibited growth factor-stimulated proliferation in both normal and leiomyoma cells. These results suggest that future nonsurgical treatments for leiomyomas may include compounds that block the actions of specific growth factors that regulate proliferation and collagen production by uterine SMCs.
Nowak
R A
RA
Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School and the Center for Uterine Fibroids, Brigham and Women's Hospital, Boston, Massachusetts, USA. ranowak@uiuc.edu
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D002853:Chromatography, Liquid; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006133:Growth Substances / Q000032:analysis*; D006801:Humans; D007044:Hysterectomy; D015907:Hysteroscopy; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000627:therapeutic use; D007889:Leiomyoma / Q000473:pathology* / Q000628:therapy*; D010642:Phenoxyacetates / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines; D011108:Polymers / Q000494:pharmacology / Q000627:therapeutic use; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011728:Pyridones / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D052999:Quinazolinones; D017978:Receptors, Growth Factor / Q000032:analysis* / Q000037:antagonists & inhibitors*; D014594:Uterine Neoplasms / Q000473:pathology* / Q000628:therapy*
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D006133:Growth Substances; D016898:Interferon-alpha; D010642:Phenoxyacetates; D010880:Piperidines; D011108:Polymers; D011500:Protein Synthesis Inhibitors; D011728:Pyridones; D011799:Quinazolines; D052999:Quinazolinones; D017978:Receptors, Growth Factor; C090697:2-(4-hydroxyphenoxy)acetic acid-formaldehyde polymer; C093844:pirfenidone; C010176:halofuginone