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
Somatostatin analogs with strong antitumor and
tyrosine kinase inhibitory activity but no hormonal effect may represent a breakthrough in the research of the antitumor
peptides, having direct effect on
tumor cells.