Administration of a targeted cytotoxic analog of luteinizing hormone-releasing hormone inhibits growth of estrogen-independent MDA-MB-231 human breast cancers in nude mice.

Abstract

Receptor targeted chemotherapy is less toxic and more effective than conventional chemotherapy. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast cancers. Highly potent cytotoxic radical 2-pyrrolinodoxorubicin (AN-201) was linked to the agonistic analog [D-Lys6]LH-RH to form cytotoxic LH-RH analog AN-207. We evaluated whether AN-207 could be targeted to the hormone-independent MDA-MB-231 human breast cancers. Nude mice bearing MDA-MB-231 tumors were injected i.v. with 250 nmol/kg doses of cytotoxic radical AN-201, cytotoxic LH-RH analog AN-207, the unconjugated mixture of AN-201 and carrier [D-Lys6]LH-RH, [D-Lys6]LH-RH alone and vehicle (control). The growth of MDA-MB-231 tumors in animals given a single dose of AN-207 was inhibited significantly (p = 0.01) for 3 weeks after injection, whereas tumors in all the other groups grew steadily. All cytotoxic compounds produced leukopenia, but the strongest lymphocyte suppression was caused by cytotoxic radical AN-201. Three weeks after treatment, the presence of mRNA for LH-RH receptors was demonstrated by RT-PCR in all the groups and radioreceptor assays demonstrated high-affinity binding sites for LH-RH on tumor cell membranes of control animals and those treated with AN-201, the carrier peptide alone or in combination with AN-201. At this time point binding assays did not reveal the expression of membrane proteins in tumors treated with AN-207, but 60 days after administration of AN-207, high affinity LH-RH binding sites were found again in MDA-MB-231 tumors. These results indicate that cytotoxic LH-RH analog AN-207 could be utilized for receptor targeted chemotherapy of breast cancers expressing receptors for LH-RH.

• Authors: Z Kahán, A Nagy, A V Schally, G Halmos, J M Arencibia, K Groot
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 59 Issue 3 Pg. 255-62 (Feb 2000) ISSN: 0167-6806 [Print] Netherlands
• PMID: 10832595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Antineoplastic Agents
• DNA Primers
• Pyrroles
• RNA, Messenger
• Receptors, LHRH
• AN 204
• AN 207
• Gonadotropin-Releasing Hormone
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Breast Neoplasms (prevention & control)
• DNA Primers
• Disease Models, Animal
• Doxorubicin (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Drug Delivery Systems
• Female
• Gonadotropin-Releasing Hormone (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Humans
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Pyrroles (pharmacology)
• RNA, Messenger (isolation & purification)
• Radioligand Assay
• Receptors, LHRH (drug effects, genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Specific Pathogen-Free Organisms
• Tumor Cells, Cultured