Experimental therapy of MDA-MB-231 human breast cancers with targeted cytotoxic analogue of somatostatin AN-162 (AEZS-124)

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New methods are needed for treatment of estrogen-receptor negative breast cancers. It has been shown that human breast cancers express receptors for LHRH and somatostatin. In our previous studies we demonstrated that the growth of human breast cancer cell lines xenographted into nude mice can be inhibited by targeted cytotoxic analogues of LHRH (AN-152 [AEZS-108] and AN-207) as well as by targeted cytotoxic analogue of somatostatin AN-238 [AEZS-110]. Targeting of cytotoxic radicals improves the response to therapy and decreases the toxicity. AN-152 (AEZS-108) is now in clinical phase II trials and a large scale synthesis of AN-238 (AEZS-110) is still in progress. Consequently we decided to test targeted cytotoxic analogue of somatostatin AN-162 (AEZS-124) consisting of Doxorubicin (DOX) conjugated through glutaric acid to somatostatin octapeptide RC-121, which acts as a carrier.
 Experimental design: The expression of mRNA for Somatostatin receptors in MDA-MB-231 human breast cancer cell line was proven by RT-PCR. Nude mice bearing xenographted MDA-MB-231 tumors were randomized into five groups, which received four i.v. injections once a week of AN-162 (AEZS-124), DOX, somatostatin analogue, somatostatin analogue + DOX or solvent, respectively. The study lasted 35 days. The Doses of AN-162 (AEZS-124) and somatostatin analogue were equivalent to 1.45 mg/kg DOX (2.5 µmol/kg).
 Results: The human breast cancer cell line MDA-MB-231 was positive for sstr-2, sstr-3 and sstr-4. Treatment with AN-162 (AEZS-124) significantly decreased the tumor volume (P<0.05) after 2 weeks compared to the other groups and the inhibition remained significant until the end of the study. Final tumor growth expressed as percent of the starting volume was 1540.71 % ± 26.04 % for the Control group, 1480.01 % ± 53.27 % for the DOX group and 542.95 % ± 19.90 % for animals treated with AN-162 (AEZS-124) (P<0.01 vs. Control and vs. DOX).
 Conclusion: Our results indicate that treatment with targeted somatostatin cytotoxic analogue AN-162 (AEZS-124) produces a greater inhibition of tumor growth than DOX in somatostatin receptor positive human breast cancers. Our findings support the concept of targeted chemotherapy based on cytotoxic peptide analogues for the treatment of breast and other cancers.