LH-RH ANALOGS IN BREAST AND OVARIAN CANCER

Project: Research project

Project Details

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 and in nude mice and nude rats
bearing transplanted MCF-7, Beta T-20 and other human breast cancer
cell lines, human ovarian tumors (e.g. OVCAR-3 line) and
endometrial adenocarcinoma. Our studies will include the
investigation of mammary tumor growth inhibition induced by: 1)
controlled delivery systems based on the microcapsules or
microparticles of the agonist D-Trp-6-LH-RH in poly(D,L-lactide-
co-glycolide) (pLGA) for once-a-month administration; 2)
combination regimens of D-Trp-6-LH-RH microcapsules with a) other
peptides, especially superactive somatostatin analogs of D-Phe-Cys-
Tyr-D-Trp-Lys-Val-Cys-Trp-Nh2 (RC-160) class and microcapsules
thereof; b) with antiestrogens such as Tamoxifen; c)
chemotherapeutic agents such as Ifosfamide, Mitomycin C and
Cisplatinum; 3) controlled delivery systems based on the
microcapsule (pLGA) or implant formulations of new LH-RH
antagonists of X-R1-R2-D-Trp-Ser-Tyr-R6-Leu-Arg-Pro-R10-NH2 class;
4) combinations of LH-RH antagonists with somatostatin analogs,
antiestrogens, and chemotherapeutic agents; 5) continued synthesis
of various LH-RH analogs containing cytostatic radicals such as
Melphalan, Aziridine, Mitomycin C and their evaluation in models
of breast and ovarian cancer as targeted hormonal carriers for
chemotherapeutic agents; 6) in vitro evaluation of direct effects
of LH-RH analogs, somatostatin analogs and cytostatic effect of
peptides with antineoplastic radicals on human breast cancer lines;
7) measurements of membrane receptors for LH-RH, somatostatin,
prolactin and growth factors such as EGF and IGF-1 in tumor tissue
in the course of the treatment as well as blood and tissue levels
of EGF and IGF-1; 8) the microcapsules of D-Trp-6-LH-RH and of an
LH-RH antagonist given alone or in combination with chemotherapy
will be also investigated in various models of ovarian and uterine
tumors; 9) detailed histological evaluations will be performed to
correlate morphological changes with tumor regression. The aim of
this project will be to improve the response to LH-RH agonists in
mammary cancer by combined therapy with other agents, especially
somatostatin analogs, evaluate the usefulness of the LH-RH
antagonists and analogs with cytostatic radicals for the inhibition
of this tumor, and investigate the possible application of LH-RH
agonists and antagonists for the treatment of ovarian cancer and
neoplasms of the female genital tract.
StatusFinished
Effective start/end date1/1/906/30/92

Funding

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

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