Growth inhibition of experimental non-Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN-238.

Abstract

The cytotoxic analogue of somatostatin, AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201), a superactive derivative of doxorubicin (DOX), linked to somatostatin analogue carrier RC-121 binds with high affinity to receptors for somatostatin and can be targeted to tumors that express these receptors. Because somatostatin receptors are found in a high percentage of human non-Hodgkin's lymphomas (NHLs), we evaluated the antitumor effect of AN-238 in 2 human NHL cell lines in vivo. Nude mice bearing xenografts of RL and HT human NHL were treated with AN-238 or its components at equimolar doses, and antitumor effects were determined. Expression of mRNA for somatostatin receptor subtypes was measured by RT-PCR, and the presence of somatostatin receptors was determined by radioligand binding. Toxicity was evaluated by following white blood cell count (WBC) and body weight. AN-238 significantly (p < 0.05) inhibited growth of RL and HT xenografts and prolonged the tumor doubling time. Cytotoxic radical AN-201, the unconjugated mixture of somatostatin analogue RC-121 and AN-201 or RC-121 alone had no significant effects. Blockade of somatostatin receptors by excess RC-121 abolished the effect of AN-238, demonstrating targeting. Expression of somatostatin receptors was not changed after repeated treatment with AN-238. AN-201, but not AN-238, significantly lowered the WBC and caused a greater decrease in body weight than AN-238. Our findings demonstrate that targeted chemotherapy with AN-238 can strongly inhibit the growth of NHL cells, which express somatostatin receptors. AN-238 could be considered for the treatment for patients with NHL.

• Authors: Gunhild Keller, Jörg B Engel, Andrew V Schally, Attila Nagy, Brian Hammann, Gabor Halmos
• Journal: International journal of cancer (Int J Cancer) Vol. 114 Issue 5 Pg. 831-5 (May 01 2005) ISSN: 0020-7136 [Print] United States
• PMID: 15609311 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: 2004 Wiley-Liss, Inc.

Chemical References

• AN 238
• Antineoplastic Agents
• Peptides
• Pyrroles
• RNA, Messenger
• Receptors, Somatostatin
• AN 204
• Somatostatin
• Doxorubicin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Body Weight
• Doxorubicin (analogs & derivatives, pharmacology)
• Humans
• Kinetics
• Leukocytes (metabolism)
• Lymphoma, Non-Hodgkin (drug therapy, pathology)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy, pathology)
• Peptides (chemistry)
• Pyrroles (pharmacology)
• RNA, Messenger (metabolism)
• Receptors, Somatostatin (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Somatostatin (pharmacology)
• Time Factors