ovurelin and folligen

We developed a group of synthetic analogs of GnRH and Somatostatin to inhibit the tumor growth of different kind. The GnRH analogs decreasing the gonadotroph and steroid hormone levels act on the hormone dependent tumors and influence their growth. One of the most effective antitumor analog was patented under the name FOLLIGEN which inhibited the breast cancer caused by DMBA in rats without any side-effects. Other inhibitory analogs of GnRH with long-lasting effect were effective in the treatment of breast, ovary and prostate tumors. Another analog [alpha-Asp(DEA)]6,Gln8-hGnRH showed a very low endocrine but high antitumor effect in both in vitro and in vivo experiments. Its tritium labeled derivative exhibited specific binding sites on human tumor cell lines. We synthesized the analogs of GnRH-III with effective selective antitumor activity which does not alter the ovarian cycle of rats but inhibits the colony-formation of human breast cancer cell lines and has a significant antiproliferative effect. We also synthesized conjugates of potent GnRH analogs with a branched chain polylysine backbone which induce a 33-35% decrease of cell numbers of MCF-7 and MDA-MB-231 human breast cancer cell lines and 45-50% inhibition of cell proliferation. Another conjugate decreased the tumor growth of MDA-MB-231 xenografts by 80% in a treatment of 9 weeks and even tumor free animals could be found among the ones treated. Using these radiolabeled peptide hormone analogs we found that human tumor cell lines and xenografts specifically bind the GnRH conjugates. We also synthesized a series of Somatostatin analogs which inhibit tyrosine kinases and the growth of several breast, prostate and colon tumor cell lines. One of our best analogs was a heptapeptide, TT-232, which strongly inhibited the tyrosine kinase activity and the cell-proliferation in different colon tumor cells. However, it did not inhibit the growth hormone release either in vitro or in vivo from rat pituitary cells. The TT-232 was found to be effective on 60 human tumor cell lines, it significantly inhibited the tumor growth on different animal tumor models, and induced apoptosis, as a result of which some animals became tumor free. The TT-232 inhibited the tumor growth of PC3 prostate xenografts with 60% and caused a 100% survival of mice 60 days after the transplantation. It is being preclinically tested at present. We have shown that the new GnRH analogs acting without any hormonal effect and the Somatost

Topics: Animals; Antineoplastic Agents, Hormonal; Buserelin; Gonadotropin-Releasing Hormone; Mammary Neoplasms, Animal; Neoplasms, Experimental; Oligopeptides; Somatostatin

A series of novel gonadotropin releasing hormone (GnRH) and Somatostatin analogs have been developed in our laboratory and were screened for antiproliferative and signal transduction inhibitory effect. Our GnRH analog Folligen, had significant antitumor activity on DMBA induced mammary carcinomas in rats without blocking ovarian functions. The direct effect of Folligen and Buserelin has been compared on the human breast cancer cell line MDA-MB-231. Folligen was found to be more effective in inhibiting cell proliferation and significant differences were found in the signal transduction pathways activated by these analogs. Our novel Somatostatin analogs were screened for tyrosine kinase inhibition and for antiproliferative effect on human colon tumor cells and for growth hormone (GH) release inhibition in vitro and in vivo. The analog TT-2-50 was significantly more active inhibiting GH release in superfused rat pituitary cells and in vivo than native Somatostatin and it strongly inhibited tyrosine kinase and proliferation while it stimulated protein kinase C activity.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Breast Neoplasms; Buserelin; Cell Division; Colonic Neoplasms; Drug Screening Assays, Antitumor; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Molecular Sequence Data; Peptides; Protein-Tyrosine Kinases; Rats; Rats, Inbred Strains; Signal Transduction; Somatostatin; Tumor Cells, Cultured

Progesterone secretion of cultured human granulosa cells treated with LHRH or its analogues was measured. Granulosa cells were also stimulated with LH, FSH, cAMP or forskolin. No differences could be observed in the progesterone basal secretion of cultures treated with or without LHRH or its analogues and after the various stimulations. It was concluded that the clinical experience that the sensitivity of ovaries for gonadotropins after LHRH desensitization is decreased could not be explained with the peripheral effects of LHRH on the granulosa cells. From the data obtained, the lack of LHRH receptors in the ovaries are suggested in humans.

Topics: Female; Gonadotropin-Releasing Hormone; Granulosa Cells; Humans; In Vitro Techniques; Progesterone; Triptorelin Pamoate

A novel chicken gonadotropin-releasing hormone (GnRH) analogue (Folligen), which has a different mechanism of action than superactive mammalian GnRH analogues, has been developed. In this study we report that in 9,10-dimetyl-1,2-bezanthracene- induced mammary carcinomas in rats, Folligen caused an almost 100% tumour remission during a 3-week daily treatment, without blocking ovarian functions. It decreased oestradiol but not to castration levels, while progesterone was not decreased at all; instead, it was slightly stimulated. The histological picture of the ovaries showed no signs of the inhibition of ovarian functions, but the presence of developing follicles and corpora lutea. In comparison, superactive mammalian GnRH analogues caused similar tumour remission but with hormonal castration and a complete block of ovarian functions.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Buserelin; Estradiol; Female; Gonadotropin-Releasing Hormone; Goserelin; Mammary Neoplasms, Experimental; Organ Size; Progesterone; Rats; Rats, Inbred Strains; Time Factors; Uterus