Enhancement of somatostatin-receptor-targeted 177Lu-[DOTA0-Tyr3]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation

Nayak, Tapan K.; Atcher, Robert W.; Prossnitz, Eric R.; Norenberg, Jeffrey P.

doi:10.1016/j.nucmedbio.2008.05.003

« Previous Next »Nuclear Medicine and Biology
Volume 35, Issue 6 , Pages 673-678, August 2008

Enhancement of somatostatin-receptor-targeted ¹⁷⁷Lu-[DOTA⁰-Tyr³]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation

Tapan K. Nayak
- College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA
- Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
- Current address: Radiation Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
Robert W. Atcher
- College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA
- Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
Eric R. Prossnitz
- Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
- Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA
Jeffrey P. Norenberg
- College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA
- Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA
- Corresponding author. College of Pharmacy, University of New Mexico, Albuquerque, NM 87131 0001, USA.

Received 27 February 2008; received in revised form 30 April 2008; accepted 9 May 2008.

Abstract

Introduction

Clinical studies of patients treated with somatostatin-receptor (sstr)-targeted [DOTA⁰-Tyr³]-octreotide (DOTATOC) labeled with ¹⁷⁷Lu and ⁹⁰Y 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 μg/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 ¹⁷⁷Lu-DOTATOC after the total 8-day treatment as described. Cell viability and apoptosis experiments were performed to study the effects of gemcitabine pretreatment and ¹⁷⁷Lu-DOTATOC radionuclide therapy. Parallel control studies were performed with receptor-non-targeted ¹⁷⁷Lu-DOTA and DOTATOC.

Results

Cells treated with gemcitabine for 4 days showed a down-regulation of sstr expression as determined by ¹⁷⁷Lu-DOTATOC uptake. However, after 4 days of additional growth in absence of gemcitabine, the uptake of ¹⁷⁷Lu-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 G₂M 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. ¹⁷⁷Lu-DOTATOC resulted in two to three times greater apoptosis in gemcitabine-pretreated Capan-2 cells compared to the untreated cells.

Conclusion

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.

Keywords: Somatostatin receptors, Combination therapy, Gemcitabine, Radionuclide therapy, DOTATOC