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Clinical Applications of Mifepristone (RU486) and Other Antiprogestins Assessing the Science and Recommending a Research Agenda (1993) / Chapter Skim
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Animals as Models for Studying Antiprogestins
Pages 57-62

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From page 57...
... ; address animal and cell culture models for their relevance to evaluating the treatment potential of these compounds for breast cancer and mammary tumors (Henderson, IOM workshop; Horwitz, Appendix By; describe species specificity of receptor binding and the effect of amino acid substitutions within the progestin-receptor-binding site (Weigel, Appendix By; and discuss research on antiprogestin effects on estrogen-receptor levels and induction of labor in primates versus humans (Baird, Appendix B4; Ulmann and Silvestre, Appendix By. The committee has concluded from these discussions that results in most animal models appear to have been fairly predictive of the effects of antiprogestins in humans despite the fact that there are major differences between humans and other species, including nonhuman primates, in terms of the pharmacokinetics of the antiprogestins and the type of placentation (Van Look and van Hertzen, 57
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From page 58...
... Conversely, replacing the key glycine in the human progesterone receptor with cysteine renders the receptor incapable of binding mifepristone (Baulieu, Appendix By. This exquisite sensitivity of progestin-receptor binding to a single amino acid substitution suggests that studies of the molecular actions of antagonists that have potential clinical applications should be conducted by using human steroid receptors, since receptors from other species may respond somewhat differently (Weigel, Appendix Bib.
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From page 59...
... Chwalisz of Schering AG pointed out that the rabbit progesterone receptor was anomalous and many antiprogestins that exhibit antagonist effects in other animals often exhibit agonist effects in rabbits. Therefore, the rabbit does not appear to be a good model for evaluating antiprogestins for potential application in humans.
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From page 60...
... Various animal models of hormone-dependent mammary cancer have been used to study the antiproliferative properties of progesterone antagonists and estrogen antagonists. These include rats that have chemically induced tumors and mice bearing transplanted tumor lines (Horwitz, Appendix By.
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From page 61...
... Neill, J.D., Johansson, E.D., and Knobil, E Patterns of circulating progestone concentrations during the fertile menstrual cycle and the remainder of gestation in the rhesus monkey.
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Key Terms

  • von hertzen
  • van look
  • breast cancer
  • progesterone receptor
  • guinea pig

  • pig model
  • amino acid
  • single amino
  • pregnant guinea
  • clinical studies

  • clinical applications
  • progesterone antagonists
  • antagonist effects
  • mammary tumors
  • progesterone receptors

  • bind mifepristone
  • menstrual cycle
  • hamster progesterone
  • using animal
  • rhesus monkey

  • models versus
  • advanced breast
  • evaluating potential
  • rabbit progesterone
  • primates versus

  • antiprogestins including
  • induced tumors
  • key glycine
  • medicine workshop
  • acid substitutions


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