Targeting of cytotoxic somatostatin analog AN-238 to somatostatin receptor subtypes 5 and/or 3 in experimental pancreatic cancers.
OBJECTIVE
The expression of somatostatin receptors (SSTRs) allows the localization and treatment of some tumors with radiolabeled SST analogues. We investigated whether SSTRs on human pancreatic cancer lines xenografted into nude mice can be used for targeting of cytotoxic somatostatin analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to octapeptide carrier RC-121.


METHODS
AN-238 and AN-201 were administered i.v. to nude mice bearing SW-1990 pancreatic cancers. Tumor growth reduction and survival were analyzed, and cell proliferation and apoptosis were determined with histological methods. The effects of repeated administration of AN-238 and AN-201 were also evaluated on xenografted Panc-1, MiaPaCa-2, CFPAC-1, Capan-1, and Capan-2 pancreatic cancers. The expression of mRNA for SSTR subtypes 2A, 3, and 5 in tumors was analyzed by reverse transcription-PCR, and binding assays were performed.


RESULTS
All of the cancer models except MiaPaCa-2 displayed functional receptors for SST. SW-1990 expressed mRNA for SSTR subtypes 3 and 5, whereas various patterns of subtypes 2A, 3, and 5 were found in other pancreatic cancers. Repeated administration of AN-238 at 150 nmol/kg significantly inhibited growth of SW-1990 cancers (93% after 45 days; P = 0.016) and other tumors but not MiaPaCa-2. AN-201 was toxic and less effective. The efficacy of AN-238 was consistent with SSTR expression.


CONCLUSIONS
Growth of experimental human pancreatic cancers that express SSTRs can be inhibited by cytotoxic somatostatin analogue AN-238.
Szepeshazi
K
K
Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, and Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Schally
A V
AV
Halmos
G
G
Sun
B
B
Hebert
F
F
Csernus
B
B
Nagy
A
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use*; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D013997:Time Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C110845:AN 238; D000903:Antibiotics, Antineoplastic; D011758:Pyrroles; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; D004317:Doxorubicin; C094573:somatostatin receptor 5