Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer

PLoS One. 2019 Nov 14;14(11):e0225260. doi: 10.1371/journal.pone.0225260. eCollection 2019.

Abstract

Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Neuroendocrine / diagnosis
  • Carcinoma, Neuroendocrine / metabolism
  • Carcinoma, Neuroendocrine / therapy*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Gemcitabine
  • Humans
  • Immunohistochemistry
  • Mice
  • Octreotide / analogs & derivatives
  • Octreotide / pharmacology
  • Octreotide / therapeutic use
  • Radiation-Sensitizing Agents / pharmacology
  • Radiation-Sensitizing Agents / therapeutic use*
  • Radiometry
  • Radiotherapy
  • Thyroid Neoplasms / diagnosis
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / therapy*

Substances

  • 177Lu-octreotate
  • Radiation-Sensitizing Agents
  • Deoxycytidine
  • Octreotide
  • Gemcitabine

Supplementary concepts

  • Thyroid cancer, medullary

Grants and funding

This study was supported by grants from the Swedish Research Council (grant no. 21073), the Swedish Cancer Society (grant no. 3427), BioCARE – a National Strategic Research Program at the University of Gothenburg, the Swedish state under the agreement between the Swedish government and the county councils – the ALF-agreement (ALFGBG-725031), and the King Gustav V Jubilee Clinic Cancer Research Foundation to EFA, as well as grants from the Sahlgrenska University Hospital Research Funds, the Assar Gabrielsson Cancer Research Foundation, the Adlerbertska Research Foundation, the Herbert & Karin Jacobsson Foundation, the Royal Society of Arts and Sciences in Gothenburg (KVVS), and the Wilhelm and Martina Lundgren Research Foundation to VS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.