Targeted diflomotecan- and camptothecin-containing somatostatin analogs specifically inhibit the growth of SCLCs rich in somatostatin receptors

Proc Amer Assoc Cancer Res, Volume 46, 2005 566 Receptors for somatostatin are found in a number of human tumors, especially SCLC. Diflomotecan and camptothecin were linked to a SSTR2 somatostatin analog each with novel linkers that target the tumor cells expressing SSTR2 receptors. The camptothecin and diflomotecan conjugates retained high-affinity to sst2 receptor in the in vitro binding assays. In vitro internalization was both time and temperature dependent and was observed only in the cells expressing sst2 receptors. Internalization was blocked by a specific sst2 receptor antagonist. Potent in vitro cytotoxicity was observed only in the cells expressing sst2 receptors. Cytotoxicity was blocked by specific sst2 receptor antagonists suggesting that binding and internalization were required to bring the cytotoxic agents into the cells. We evaluated the effects of these two original analogs in the NCI-H69, SCLC xenograft model (sst2 receptor positive) and in the negative control HT-29 colon xenograft model (sst2 receptor negative). Nude mice bearing the tumors were administered the analogs on a qwk x 6, i.v. schedule at doses equivalent to 1 to 6-fold of the MTD of the parent cytotoxic agents. The results of the in vivo experiments suggest that specific cytotoxic efficacy could be observed at doses up to 6X the parent cytotoxic with no added toxicity. Preliminary acute toxicity analysis showed that the analogs did not decrease white blood count, neutrophils, and platelets while camptothecin and diflomotecan did. Taken together, it seems that the somatostatin-directed cytotoxic conjugates selectively target the cancer cells expressing SSTR2 receptors in vitro and in vivo .