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Effects of Chemotherapeutic Agents on Expression of Somatostatin Receptors in Pancreatic Tumor Cells

Departments of Nuclear Medicine, Internal Medicine I, and Oncology, University of Vienna, Vienna; Ludwig Boltzmann Institute of Clinical Oncology and Department of Nuclear Medicine, Hospital Lainz, Vienna; and Department of Radiochemistry, Seibersdorf Research Center, Seibersdorf, Austria

Specific tumors express high amounts of receptors for somatostatin (SST), providing the basis for imaging and treatment using radiolabeled SST analogs. However, little is known about the potential influence of cytotoxic drugs on SST receptor (SSTR) expression in malignant cells. Methods: To study the interaction between cytotoxic drugs and SSTR expression, the pancreatic cancer–derived tumor cell lines BxPC-3, Panc-1, Capan-1, and ASPC-1 were exposed to a range of cytotoxic drugs in vitro: Gemcitabine, 5-fluorouracil, cisplatin (cis-diaminedichloroplatinum [II]), camptothecin, mitomycin C, and doxorubicin were checked for changes in binding characteristics of the SSTR ligand ¹¹¹In-1,4,7,10-tetraazacyclododecane- N,N',N'',N'''-tetraacetic acid-lanreotide (DOTA-LAN). Chemosensitivity was quantitated by measurements of reduction in cell numbers, changes in cell cycle distribution, and appearance of apoptotic subG1 (subG1/0 cell DNA content) cells. Results: Cells were treated with gemcitabine (1.0 or 2.0 µg/mL), 5-fluorouracil (65–520 µg/mL), camptothecin (1.5 or 3 µg/mL), mitomycin C (0.1 or 0.2 µg/mL), and doxorubicin (1.0 or 2.0 µg/mL). Each of the chemotherapeutic agents induced a loss of high-affinity receptors. In addition, gemcitabine caused a reduction of low-affinity receptors in BxPC-3, Panc-1, and ASPC-1 cells. Mitomycin C, camptothecin, and 5-fluorouracil also induced an overexpression of low-affinity receptors. In cells pretreated with cisplatin (2–10 µg/mL), binding of DOTA-LAN was increased. Excluding gemcitabine, the increase in low-affinity binding sites exhibits a weak correlation with apoptosis (r² = 0.62). For gemcitabine, these effects were reversed after 4 d of recovery of the cell lines, eventually revealing overexpression of low- and high-affinity sites for BxPC-3 and Panc-1 cells and low-affinity sites for ASPC-1 cells. Conclusion: Our results clearly show that the pancreatic tumor lines reduce the expression of high-affinity DOTA-LAN binding sites during application of chemotherapeutic drugs, which is accompanied by variable overexpression of low-affinity binding sites. In the case of gemcitabine, SSTRs are overexpressed during recovery from drug exposure within 4 d. These findings may have implications on the interpretation of scintigraphic results obtained by receptor ligands.

Key Words: somatostatin receptors • DOTA-lanreotide • chemotherapy • gemcitabine