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Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer.

Abstract
Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists--MIA-602, MIA-606, and MIA-690--on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.
AuthorsCale D Fahrenholtz, Ferenc G Rick, Maria I Garcia, Marta Zarandi, Ren-Zhi Cai, Norman L Block, Andrew V Schally, Kerry L Burnstein
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 3 Pg. 1084-9 (Jan 21 2014) ISSN: 1091-6490 [Electronic] United States
PMID24395797 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Androgens
  • Ligands
  • Receptors, G-Protein-Coupled
  • Growth Hormone-Releasing Hormone
  • Prostate-Specific Antigen
Topics
  • Androgens (metabolism)
  • Animals
  • Body Weight
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Screening Assays, Antitumor
  • Growth Hormone-Releasing Hormone (antagonists & inhibitors)
  • Humans
  • Hypothalamus (metabolism)
  • Ligands
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Prostate-Specific Antigen (metabolism)
  • Prostatic Neoplasms (drug therapy)
  • Prostatic Neoplasms, Castration-Resistant (drug therapy)
  • Receptors, G-Protein-Coupled (metabolism)
  • Time Factors

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