Enhancement of somatostatin-receptor-targeted (177)Lu-[DOTA(0)-Tyr(3)]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation.
BACKGROUND
Clinical studies of patients treated with somatostatin-receptor (sstr)-targeted [DOTA(0)-Tyr(3)]-octreotide (DOTATOC) labeled with (177)Lu and (90)Y have shown overall response rates in the range of 9-33%. This study evaluates the potential for combination therapy with gemcitabine in an effort to improve clinical outcomes.


METHODS
Human pancreatic adenocarcinoma Capan-2, rat pancreatic cancer AR42J and human small cell lung cancer NCI-H69 cells were each treated with 1 microg/ml gemcitabine for 4 days followed by replacement of the medium alone for four additional days. Cell cycle and direct receptor-uptake studies were performed with (177)Lu-DOTATOC after the total 8-day treatment as described. Cell viability and apoptosis experiments were performed to study the effects of gemcitabine pretreatment and (177)Lu-DOTATOC radionuclide therapy. Parallel control studies were performed with receptor-non-targeted (177)Lu-DOTA and DOTATOC.


RESULTS
Cells treated with gemcitabine for 4 days showed a down-regulation of sstr expression as determined by (177)Lu-DOTATOC uptake. However, after 4 days of additional growth in absence of gemcitabine, the uptake of (177)Lu-DOTATOC was 1.5-3 times greater than that of the untreated control cells. In gemcitabine-pretreated Capan-2 cells, 84% of the cell population was in the G(2)M phase of the cell cycle. Due to sstr up-regulation and cell cycle modulations, synergistic effects of gemcitabine pretreatment were observed in cell viability and apoptosis assays. (177)Lu-DOTATOC resulted in two to three times greater apoptosis in gemcitabine-pretreated Capan-2 cells compared to the untreated cells.


CONCLUSIONS
Gemcitabine pretreatment up-regulates sstr expression and acts as a radiosensitizer through cell cycle modulation. The rational combination of gemcitabine and sstr-targeted radiopharmaceuticals represents a promising chemoradiation therapeutic tool with great potential to improve clinical outcomes and, thus, merits further study.
Nayak
Tapan K
TK
College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA.
Atcher
Robert W
RW
Prossnitz
Eric R
ER
Norenberg
Jeffrey P
JP
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D015282:Octreotide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000627:therapeutic use; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000528:radiation effects*; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects; D000093542:Gemcitabine
C504257:177Lu-octreotide, DOTA(0)-Tyr(3)-; D000964:Antimetabolites, Antineoplastic; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D003841:Deoxycytidine; D015282:Octreotide; D000093542:Gemcitabine