Complete regression of MX-1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone-releasing hormone, AN-207

BACKGROUND. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast carcinomas. A highly potent cytotoxic a gent, 2-pyrrolinodoxorubicin (AN-201), was linked to the agonist [D-Lys(6)] LH-RH to form a cytotoxic LH-RH analog, AN-207, that can be targeted to LH- RH receptors on breast carcinomas. METHODS. Nude mice bearing MX-1 hormone-independent doxorubicin-resistant h uman breast carcinomas were injected intravenously with vehicle (control), 250 nmol/kg doses of AN-201, AN-207, or an unconjugated mixture of AN-201 a nd [D-Lys(6)]LH-RH. Tumor growth and changes in hematologic parameters were evaluated. Receptors for LH-RH were investigated by radioreceptor assays, and the expression of their mRNA was determined by reverse transcriptase-po lymerase chain reaction. RESULTS. AN-207 caused complete regression of MX-1 tumors in all 10 animals , and they were still tumor free 60 days after treatment. In contrast, afte r therapy with AN-201 or the mixture of AN-201 and [D-Lys(6)]LH-RH, the reg ression of most MX-1 tumors was only transitory. AN-201 caused the death of 1 of the 10 animals and significantly greater leukopenia than AN-207, whic h produced no toxic deaths. Radioreceptor assays revealed high affinity bin ding sites for LH-RH on tumor cell membranes. The expression of mRNA for LH -RH receptors also was found in tumors. CONCLUSIONS. The results of this study indicate that powerful, targeted cyt otoxic LH-RH analogs such as AN-207 could be considered for the treatment o f human breast carcinomas that possesses receptors for LH-RH. Cancer 1999; 85:2608-15, (C) 1999 American Cancer Society.