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

Abstract

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-Lys6]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-Lys6]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 AN-201 and [D-Lys6]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.

• Authors: Z Kahán, A Nagy, A V Schally, G Halmos, J M Arencibia, K Groot
• Journal: Cancer (Cancer) Vol. 85 Issue 12 Pg. 2608-15 (Jun 15 1999) ISSN: 0008-543X [Print] United States
• PMID: 10375109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• RNA, Messenger
• Receptors, LHRH
• AN 207
• Gonadotropin-Releasing Hormone
• Doxorubicin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Breast Neoplasms (chemistry, drug therapy, pathology)
• Doxorubicin (analogs & derivatives, pharmacology, therapeutic use)
• Female
• Gonadotropin-Releasing Hormone (analogs & derivatives, pharmacology, therapeutic use)
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• RNA, Messenger (biosynthesis)
• Receptors, LHRH (drug effects)
• Transplantation, Heterologous