USE OF LH-RH ANALOGS IN BREAST AND OVARIAN CANCER

Project: Research project

Description

Analogs of luteinizing hormone-releasing hormone (LH-RH) given alone and in
combination will be tested in animal models of hormone-dependent mammary
carcinoma, ovarian cancer and neoplasms of the female genital tract and in
nude mice or nude rats bearing transplanted MCF-7 human breast cancer cell
line, human ovarian tumors (eg. OVCAR-3 line) and human endometrial
adenocarcinoma. Our studies will include the investigation of mammary
tumor growth inhibition induced by (1) continuous controlled delivery
system based on the microcapsule formulation of the agonistic analog
D-Trp-6-LH-RH in biodegradable poly(D-L-lactide-co-glycolide) (pLGA) for
once a month administratio7; (2) combination regimens of D-Trp-6-LH-RH
microcapsules with a) other peptides, especially somatostatin analogs, as
well as with b) antiestrogens, tamoxifen (Nolvadex, ICI 46474), nafoxidine,
Keoxifene (LY 156758), or LY 117018; and c) chemotherapeutic agents such as
cyclophosphamide, Mitoxantrone and Bisantrene; (3) continuous controlled
delivery system based on the microcapsule (pLGA) formulation of
N-Ac-D-p-Cl-Phe-1,2,D-Trp-3,D-Arg-6,D-Ala-10-LH-RH (Antagonist I),
Ac-Beta-D-Nal(2)-1,D-p-Cl-Phe-2,D-Trp-3,D-Arg-6,D-Ala-10-LH-RH (Antagonist
II) or another antagonist; (4) combination regimens of LH-RH antagonists
with somatostatin analogs, antiestrogens, and chemotherapeutic agents; (5)
evaluation in some models of mammary cancer of an analog of D-Trp-6-LH-RH
containing a cytostatic radical of alkylating agent Melphalan (nitrogen
mustard attached to Phenylalanine) as a hormonal carrier for
chemotherapeutic agent. Some biochemical studies such as DNA, RNA and
protein synthesis and measurement of protein phosphorylation as well as
protein kinases activities in cytoplasm and nuclei of mammary tumors and
histological evaluations will be performed to provide data to correlate
with tumor regression. The microcapsule formulations of D-Trp-6-LH-RH and
of LH-RH antagonist given alone or in combination with chemotherapy will be
also investigated in various models of ovarian and uterine tumors. The aim
of this project will be to improve the response to LH-RH agonists in
mammary cancer by combined therapy with other agents and provide new data
on the usefulness of the LH-RH antagonist given alone or in combination
regimens for the inhibition of this tumor as well as to determine the
possible application of both types of LH-RH analogs for the treatment of
ovarian cancer and neoplasms of the female genital tract.
StatusFinished
Effective start/end date9/1/856/30/92

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $169,204.00

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Gonadotropin-Releasing Hormone
Ovarian Neoplasms
Breast Neoplasms
Somatostatin
Capsules
Hormone Antagonists
Estrogen Receptor Modulators
Cytostatic Agents
Neoplasms
Tamoxifen
Mitomycin
Insulin-Like Growth Factor I
Epidermal Growth Factor
bisantrene
LY 117018
Animal Models
LHRH Receptors
Nafoxidine
Female Genital Neoplasms
Ifosfamide

ASJC

  • Medicine(all)