Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists
Vincent Goffin,
Sophie Bernichtein,
Philippe Touraine and
Paul A. Kelly
Institut National de la Santé et de la Recherche Médicale, Unit 584 (V.G., S.B., P.T., P.A.K.), Paris Cedex 15, France; Université René Descartes-Paris V (V.G., S.B., P.T., P.A.K.), 75730, Paris Cedex 15, France; and Service d’Endocrinologie et Médecine de la Reproduction (P.T.), Hôpital Necker-Enfants Malades, 75743 Paris Cedex 15, France
Correspondence: Address all correspondence and requests for reprints to: Dr. Vincent Goffin, Institut National de la Santé et de la Recherche Médicale Unit 584, Faculté de Médecine Necker, 156, rue de Vaugirard, 75730 Paris Cedex 15, France. E-mail: goffin{at}necker.fr
There is a large body of literature showing that prolactin (PRL)exerts growth-promoting activities in breast cancer, and possiblyin prostate cancer and prostate hyperplasia. In addition, increasingevidence argues for the involvement of locally produced (autocrine)PRL, perhaps even more than pituitary-secreted (endocrine) PRL,in tumor growth. Because dopamine analogs are unable to inhibitPRL production in extrapituitary sites, alternative strategiesneed investigation. To that end, several PRL receptor antagonistshave been developed by introducing various mutations into itsnatural ligands. For all but one of these analogs, the mechanismof action involves a competition with endogenous PRL for receptorbinding. Such compounds are thus candidates to counteract theundesired actions of PRL, not only in tumors, but also in dopamine-resistantprolactinomas. In this review, we describe the different versionsof antagonists that have been developed, with emphasis on thecontroversies regarding their characterization, and the limitsfor their potential development as a drug. The most recentlydeveloped antagonist, 1–9-G129R-hPRL, is the only onethat is totally devoid of residual agonistic activity, meaningit acts as pure antagonist. We discuss to what extent this newmolecule could be considered as a lead compound for inhibitingthe actions of human PRL in the above-mentioned diseases. Wealso speculate on the multiple questions that could be addressedwith respect to the therapeutic use of PRL receptor antagonistsin patients.
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1–9-G129R-hPRL, is the only one that is totally devoid of residual agonistic activity, meaning it acts as pure antagonist. We discuss to what extent this new molecule could be considered as a lead compound for inhibiting the actions of human PRL in the above-mentioned diseases. We also speculate on the multiple questions that could be addressed with respect to the therapeutic use of PRL receptor antagonists in patients. 
