Growth inhibition of experimental non-Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN-238.
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.
Keller
Gunhild
G
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70112-1262, USA.
Engel
Jörg B
JB
Schally
Andrew V
AV
Nagy
Attila
A
Hammann
Brian
B
Halmos
Gabor
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001835:Body Weight; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000737:chemistry; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin / Q000494:pharmacology*; D013997:Time Factors
C110845:AN 238; D000970:Antineoplastic Agents; D010455:Peptides; D011758:Pyrroles; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C098751:AN 204; D013004:Somatostatin; D004317:Doxorubicin