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 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.
Kahán
Z
Z
Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70112-1262, USA.
Nagy
A
A
Schally
A V
AV
Halmos
G
G
Arencibia
J M
JM
Groot
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000096:biosynthesis; D011966:Receptors, LHRH / Q000187:drug effects; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D011966:Receptors, LHRH; C104648:AN 207; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin