Effect of an investigational CYP17A1 inhibitor, orteronel (TAK-700), on estrogen- and corticoid-synthesis pathways in hypophysectomized female rats and on the serum estradiol levels in female cynomolgus monkeys

  title={Effect of an investigational CYP17A1 inhibitor, orteronel (TAK-700), on estrogen- and corticoid-synthesis pathways in hypophysectomized female rats and on the serum estradiol levels in female cynomolgus monkeys},
  author={Masuo Yamaoka and Takahito Hara and Hideo Araki and Tomohiro Kaku and Takenori Hitaka and Akihiro Tasaka and Masami Kusaka},
  journal={The Journal of Steroid Biochemistry and Molecular Biology},
  • M. Yamaoka, T. Hara, M. Kusaka
  • Published 1 November 2013
  • Biology, Medicine
  • The Journal of Steroid Biochemistry and Molecular Biology
Structural and Kinetic Basis of Steroid 17α,20-Lyase Activity in Teleost Fish Cytochrome P450 17A1 and Its Absence in Cytochrome P450 17A2*
Pulse-chase and kinetic spectral experiments and modeling established that the two-step P450 17A1 Prog oxidation is more distributive than the Preg reaction, i.e. 17α-OH product dissociates more prior to the lyase step.
Pushing estrogen receptor around in breast cancer.
This review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER.
Structural and Kinetic Basis of Steroid 17 , 20-Lyase Activity in Teleost Fish Cytochrome P 450 17 A 1 and Its Absence in Cytochrome P 450 17 A 2 *
This work results in a new generation of high-performance liquid chromatography platforms that can be integrated into the fabric of DNA and provide new insights into the building blocks of DNA replication.
Multi-Step Binding of the Non-Steroidal Inhibitors Orteronel and Seviteronel to Human Cytochrome P450 17A1 and Relevance to Inhibition of Enzyme Activity.
Kinetic tests and modeling indicate that the further change to the iron-complexed form of the orteronel- or seviteronel-P450 complex is not a pre-requisite for enzyme inhibition, and the inclusion of heme-binding heterocyclic nitrogen moieties in P450 17A1 inhibitors may not be necessary to achieve inhibition but may nevertheless augment the process.
Targeting the androgen receptor in prostate and breast cancer: several new agents in development.
An overview of available agents which target the AR axis in both PCa and BCa is offered and insights into the novel drugs in development for targeting this signaling pathway are provided.


Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole.
It is reported that androgens, such as the aromatizable androstenedione and the non-aromatizable 5alpha-dihydrotestosterone, inhibit MCF-7 cell proliferation and suppression of the estrogen-induced antiapoptotic protein Bcl-2 may be involved in the antiproliferative effects of androgens and letrozole.
High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: a renewed role for adrenalectomy.
Oophorectomies with either aminoglutethimide therapy or adrenalectomy were effective remedies for breast cancer progression due to high DHEA-S, and tissue culture results supported the role of DHEa-S as an estrogenic agent.
Intracellular aromatase and its relevance to the pharmacological efficacy of aromatase inhibitors
Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?
Together these data suggest that once a certain threshold of aromatase inhibition is reached, small differences in oestrogen suppression between the third-generation AIs do not lead to clinically significant differences in overall efficacy.
A rationale for inhibiting progesterone-related pathways to combat breast cancer.
  • M. Moore
  • Biology, Medicine
    Current cancer drug targets
  • 2004
A building body of evidence, from cell culture, animal studies, and, most recently, several major clinical studies involving hormone replacement therapy, strongly supports the notion that progestins generally stimulate breast cancer.
The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders.
Understanding steroidogenesis is of fundamental importance to understanding disorders of sexual differentiation, reproduction, fertility, hypertension, obesity, and physiological homeostasis.
Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones.
This review presents a detailed description of the enzymes involved in the biosynthesis of active steroid hormones, with emphasis on the human and mouse enzymes and their expression in gonads, adrenal glands, and placenta.
Adrenal androgens stimulate the proliferation of breast cancer cells as direct activators of estrogen receptor alpha.
Transactivation assays with transfected ER-alpha reporter genes reveal a direct activation of ER- alpha by dehydroepiandrosterone (DHEA), 5alpha-androstene-3beta,17beta-diol, testosterone, and the two nonaromatizable androgens, dihydrotestosterone and 5 alpha- androstane-3 beta,17 beta-Diol.
Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer.
It is concluded that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17beta-estradiol on breast cancer cells.