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

✍ Scribed by Zsuzsanna Kahán; Attila Nagy; Andrew V. Schally; Gábor Halmos; José M. Arencibia; Kate Groot

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 126 KB
• Volume: 85
• Category: Article
• ISSN: 0008-543X
• DOI: 10.1002/(sici)1097-0142(19990615)85:12<2608::aid-cncr17>3.0.co;2-h

✦ Synopsis

BACKGROUND. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast carcinomas. A highly potent cytotoxic agent, 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 human breast carcinomas were injected intravenously with vehicle (control), 250 nmol/kg doses of AN-201, AN-207, or an unconjugated mixture of AN-201 and [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-polymerase 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, after therapy with AN-201 or the mixture of ]LH-RH, the regression 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, which produced no toxic deaths.

Radioreceptor assays revealed high affinity binding 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 cytotoxic LH-RH analogs such as AN-207 could be considered for the treatment of human breast carcinomas that possesses receptors for LH-RH.