USE OF LH-RH AGONISTS &ANTAGONISTS IN PROSTATE CANCER

Project: Research project

Project Details

Description

Analogs of luteinizing hormone-releasing hormone (LH-RH) given
alone and in combination will be tested in rats bearing androgen-
dependent Dunning R3327H adenocarcinomas, Dunning R-3327AT
androgen-independent anaplastic prostate tumors, and other models
of prostate cancers and in nude mice or nude rats with transplanted
human prostate cancer cell lines e.g., LNCaP, DU-145, and PC-3.
Our studies will include: (1) the investigation of prostate tumor
growth inhibition induced by: (a) controlled delivery system based
on the microcapsules of the agonist D-Trp-6-LH-RH in poly (D,L-
lactide-co-glycolide) (pLGA) for once-a-month administration and
a comparison of the effectiveness of microcapsules given alone and
with various combinations, in inhibiting tumor growth; (b)
combinations of D-Trp-6-LH-RH microcapsules with microcapsules of
somatostatin superanalog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH
(RC-160); (c) New LH-RH antagonists such as (Ac-D-Nal (2), D-Phe
(pC1)2, D-Tr3p, D-Cit6, D2-Ala10) LH-RH, (SB-30), or another
related antagonist, administered as microcapsule formulations in
pLGA; d) combinations of LH-RH antagonist microcapsules with
somatostatin analog RC-160. Studies (1 alpha-d) will include long-
term experiments in Dunning R3327H model to establish the duration
of response. (2) continued synthesis of various agonists and
antagonists of LH-RH containing cytotoxic radicals such as
Melphalan, Aziridine and Mitomycin C, the evaluation of their
binding to LH-RH receptors and testing of their effects in animal
models of prostate cancer as targeted hormonal carriers for
chemotherapeutic agents; (3) in vitro evaluation in rat and human
prostate cancer cell lines of direct inhibitory effects of LH-RH
agonists and antagonists, somatostatin analog RC-160 and antitumor
effect of peptides with cytotoxic radicals; (4) Biochemical studies
such as DNA synthesis and measurement of protein phosphorylation.
(5) Determination of tumor membrane receptors for LH-RH,
somatostatin and prolactin in animals treated with LH-RH and
somatostatin analogs. Steroid (androgen) receptors will be also
measured. (6) Determination of blood levels of IGF-1, tumor
content of EGF, IGF-1, and the levels of receptors for EGF and IGF-
1. (7) Histological and histomorphometric evaluations to correlate
morphological changes with tumor regression. The aim of this
project will be to: a) improve the response to LH-RH agonists in
prostate cancer by combined therapy with somatostatin analog RC-
160; b) evaluate the usefulness of the new LH-RH antagonists and
targeted LH-RH analogs with cytotoxic radicals for the inhibition
of this tumor; c) elucidate the mechanism of action of these
analogs.
StatusFinished
Effective start/end date1/1/904/30/94

Funding

  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute

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