SYNTHESIS AND BIOLOGICAL EVALUATION OF CYTOTOXIC ANALOGS OF SOMATOSTATIN CONTAINING DOXORUBICIN OR ITS INTENSELY POTENT DERIVATIVE, 2-PYRROLINODOXORUBICIN

To create cytotoxic hybrid analogs of somatostatin (SST), octapeptides RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) and RC-121 (D-Phe-Cy s-Tyr-D-Trp-Lys-Val-Cys-Thr-NB2) were linked to doxorubicin (DOX) or i ts superactive derivative, 2-pyrrolino-DOX (AN-201). The conjugation w as performed by coupling N-9-fluorenylmethoxycarbonyl (N-Fmoc)-DOX-14- O-hemiglutarate or 2-pyrrolino-DOX-14-O-hemiglutarate to the amino ter minus of [Lys(Fmoc)(5)]RC-160 yielding AN-163 and AN-258, respectively , after deprotection. The respective cytotoxic conjugates of RC-121 (A N-162 and AN-238) were prepared similarly, In vitro tests on human can cer cell lines-MKN-45 gastric cancer, MDA-MB-231 breast cancer, PC-3 p rostate cancer, and MIA PaCa-2 pancreatic cancer-demonstrated that the antiproliferative activity of the cytotoxic radicals in these conjuga tes,vas virtually retained. In H-345 human small cell lung carcinoma c ell line, conjugates of RC-121 preserved the cytotoxic activity of the ir radicals, but the hybrids with RC-160 showed approximate to 10 time s lower activity. The ability of the carriers and the hybrids to inhib it the binding of I-125-labeled RC-160 to receptors for SST on rat pit uitary membrane preparation was also determined. The cytotoxic conjuga tes inhibited 50% of the specific binding of the radioligand in the na nomolar concentration range (IC50 < 80 nM). When SST-like activities o f AN-238 and its carrier, RC-121, were compared in the rat pituitary s uperfusion system, both compounds were found to suppress a stimulated growth hormone release at nanomolar concentrations. Preliminary studie s in animal models of breast and prostate cancers showed that AN-238 i s less toxic than AN-201 and more potent in inhibiting tumor growth. T hese highly active cytotoxic analogs of SST have been designed as targ eted antitumor agents for the treatment of various cancers expressing receptors for SST octapeptides.