Inhibition of growth of MX-1, MCF-7-MIII and MDA-MB-231 human breast cancer xenografts after administration of a targeted cytotoxic analog of somatostatin, AN-238.
Since somatostatin (sst) receptors are expressed in a high percentage of human breast cancers, we studied the effects of a targeted cytotoxic somatostatin analog (AN-238) formed by linking the highly active doxorubicin (DOX) derivative 2-pyrrolino-DOX (AN-201) to octapeptide RC-121 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH(2)) in 3 human breast cancer models. The models included estrogen-independent MDA-MB-231 and MX-1 and estrogen-sensitive MCF-7-MIII tumors. Nude mice bearing xenografts of these cancers were injected i.v. with 250 nmol/kg doses of cytotoxic radical AN-201, cytotoxic analog AN-238 or the unconjugated mixture of AN-201 and sst analog RC-121. Significant inhibition of growth of MDA-MB-231, MX-1 and MCF-7-MIII tumors was observed 1 week after injection of a single dose of cytotoxic analog AN-238. The volume of MDA-MB-231 tumors remained significantly decreased 3 weeks after treatment. The volumes and weights of MCF-7-MIII tumors continued to be significantly reduced 60 days after therapy with AN-238. AN-238 also caused complete regression of MX-1 tumors in 5 of 10 animals, which remained tumor-free 60 days after treatment. In contrast, after treatment with cytotoxic radical AN-201, MDA-MB-231 and MCF-7-MIII tumors grew steadily and the regression of MX-1 tumors was only transitory in most animals. Toxicity of AN-201 was much greater than that of AN-238, as measured by animal deaths, loss of body weight and leukopenia. High-affinity sst receptors and mRNA for both sst(2) and sst(5) subtypes were found in all 3 tumor lines. Expression of sst receptors was not significantly affected by treatment with AN-238. Our results indicate that the cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast cancers expressing sst receptor subtypes 2 and 5.
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA, USA.
Z
Z
Kahán
A
A
Nagy
A V
AV
Schally
F
F
Hebert
B
B
Sun
K
K
Groot
G
G
Halmos
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood / Q000473:pathology / Q000628:therapy*; D002455:Cell Division; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000627:therapeutic use*; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use; D017481:Receptors, Somatostatin / Q000097:blood; D014183:Transplantation, Heterologous
C110845:AN 238; D000903:Antibiotics, Antineoplastic; D000922:Immunotoxins; D011758:Pyrroles; D017481:Receptors, Somatostatin; C098751:AN 204; D004317:Doxorubicin; D007986:Luteinizing Hormone; D013006:Growth Hormone