Expression of the somatostatin receptor subtype-2 gene predicts response of human pancreatic cancer to octreotide.
BACKGROUND
Somatostatin inhibits proliferation of many solid tumors. The current study examines whether inhibition of the growth of pancreatic cancer by the somatostatin analog, octreotide, requires tumor expression of somatostatin receptors.


METHODS
We studied five human pancreatic cancer cell lines, Capan-1, Capan-2, CAV, MIA PaCa-2, and Panc-1. Solid tumors were established in nude mice (n = 20/cell line) by flank injection of tumor cells. Subcutaneous octreotide (500 micrograms/kg/day) was administered by osmotic pumps to 10 of the animals in each group, and the other 10 received control infusions of saline solution. On day 36, the tumors were excised and weighed. Plasma levels of the putative trophic peptides cholecystokinin, epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and insulin were assessed by radioimmunoassay. Each of the five cell lines was assayed for the presence of cell surface somatostatin receptors by using whole cell competitive binding assays with 125I-somatostatin. Expression of the somatostatin receptor subtype-2 (SSR2) gene was determined with reverse transcriptase-polymerase chain reactions. Southern blot hybridization was used to assess the presence of the SSR2 gene.


RESULTS
Octreotide inhibited tumor growth in the MIA PaCa-2 group (512 +/- 75 mg control versus 285 +/- 71 mg treated; p < 0.05) but had no significant effect on tumor weight in the other four cell lines. Plasma levels of cholecystokinin, epidermal growth factor, insulin-like growth factor-1, and insulin were not altered by chronic octreotide infusion. Cell surface somatostatin receptors and SSR2 gene expression were detected only in the MIA PaCa-2 tumors. The gene for the SSR2 receptor was found in all five tumor lines.


CONCLUSIONS
Octreotide-mediated inhibition of pancreatic cancer growth is dependent on expression of somatostatin receptors. The expression of somatostatin receptors should be considered in the design and interpretation of clinical trials with somatostatin analogs for treatment of pancreatic cancer.
Fisher
W E
WE
Department of Surgery, Ohio State University, Columbus 43210, USA.
Muscarella
P
P
O'Dorisio
T M
TM
O'Dorisio
M S
MS
Kim
J A
JA
Doran
T A
TA
Sabourin
C L
CL
Schirmer
W J
WJ
D000230:Adenocarcinoma; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001483:Base Sequence; D001667:Binding, Competitive / Q000502:physiology; D015139:Blotting, Southern; D002455:Cell Division / Q000187:drug effects; D002766:Cholecystokinin / Q000097:blood; D004273:DNA, Neoplasm / Q000032:analysis; D004815:Epidermal Growth Factor / Q000097:blood; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D015282:Octreotide / Q000494:pharmacology*; D010190:Pancreatic Neoplasms; D010455:Peptides / Q000097:blood; D016133:Polymerase Chain Reaction; D017481:Receptors, Somatostatin / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000502:physiology
D018931:Antineoplastic Agents, Hormonal; D004273:DNA, Neoplasm; D007328:Insulin; D010455:Peptides; D017481:Receptors, Somatostatin; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D002766:Cholecystokinin; C093733:somatostatin receptor 2; D015282:Octreotide