Peptides and antitumor activity - Development and investigation of some peptides with antitumor activity

We developed a group of synthetic analogs of GnRH and Somatostatin to inhib it the tumor growth of different kind. The GnRH analogs decreasing the gona dotrop and steroid hormone levels act on the hormone dependent tumors and i nfluence their growth. One of the most effective antitumor analog was paten ted under the name FOLLIGEN which inhibited the breast cancer caused by DMB A in rats without any side-effects. Other inhibitory analogs of GnRH with l ong-lasting effect were effective in the treatment of breast, ovary and pro state tumors. Another analog [alpha-Asp(DEA)](6),Gln(8)-hGnRH showed a very low endocrine but high antitumor effect in both in vitro and in vivo exper iments. Its tritium labeled derivative exhibited specific binding sites on human tumor cell lines. We synthesized the analogs of GnRH-III with effecti ve selective antitumor activity which does not alter the ovarian cycle of r ats 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 ind uce 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 conj ugate decreased the tumor growth of MDAMB-231 xenografts by 80% in a treatm ent of 9 weeks and even tumor free animals could be found among the ones tr eated. 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 ki nases and the growth of several breast, prostate and colon tumor cell lines . One of our best analogs was a heptapeptide, TT-232, which strongly inhibi ted the tyrosine kinase activity and the cell-proliferation in different co lon tumor cells. However, it did not inhibit the growth hormone release eit her in vitro or in vivo from rat pituitary cells. The TT-232 was found to b e effective on 60 human tumor cell lines, it significantly inhibited the tu mor growth on different animal tumor models, and induced apoptosis, as a re sult of which some animals became tumor free. The TT-232 inhibited the tumo r 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 Somatostatin analogs with strong antitumor and tyrosine kinase inhi bitory activity but no hormonal effect may represent a breakthrough in the research of the antitumor peptides, having direct effect on tumor cells.