The effect of timing and sequence of gemcitabine administration and radiation for the treatment of medullary thyroid carcinoma.

• Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumour with sometimes high expression of somatostatin receptors. MTC originates from the thyroid C cell and occurs either sporadically (75%) or is caused by germline mutation of the RET proto-oncogene. At diagnosis, about 50% of the MTC patients have metastases, and low 10-year survival rate for metastatic disease has been reported, about 20%. We recently investigated the effect of gemcitabine, a nucleoside analogue, which inhibits DNA synthesis and repair, in combination with 177Lu-octreotate or external beam radiotherapy (EBRT) in a patient-derived MTC (GOT2) animal model and our results suggested additive and even synergistic cytotoxic effects. However, the ideal timing of gemcitabine administration with irradiation has not been studied. The aim of this study is 1) to investigate whether the time course and sequence between gemcitabine administration and irradiation is essential for achieving high anti-tumor effect, and 2) to study the molecular mechanisms involved in the interaction between gemcitabine and radiation in GOT2. EBRT was used instead of 177Lu-ocreotate to enable studies of timing. Materials and Methods: Balb/C-nu mice with GOT2 tumours were divided into groups with a similar mean tumor volume at the start of treatment. The mice were injected with 60 mg/kg gemcitabine, either 72h before (group 1), 0.25h before (group 2) or 72h after (group 3) irradiation with 3Gy. Tumor size was measured twice a week, using a digital caliper. Results: For all groups, tumor regression was observed during the first 11 days with a mean relative volume reduction related to the volume before treatment of 21%, 40% and 46% for groups 1, 2 and 3, respectively. A statistically significant difference was observed between group 1 and groups 2 or 3 (P=0.029 and 0.030, respectively). The lower tumour reduction in group 1 could be due to accumulation of cells in S-phase, which are relatively more resistant to radiation. The higher tumour volume reduction when gemcitabine was given concurrently with or after EBRT, suggests increased delivery of gemcitabine to the MTC tumours and/or enhanced effect of the combination. Conclusions: Our findings suggest that the combined effect of gemcitabine and EBRT is higher when gemcitabine is administrated simultaneously with or after EBRT. The optimal time schedule of the combined modalities is further investigated, together with translation of results to 177Lu-octreotate therapy.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)

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