Effect of Antioxidant rA1M on Expression of Apoptosis and Oxidative-Stress-Related Genes during 177Lu-Octreotate Treatment of GOT1 Neuroendocrine Tumours

• Kidney radiotoxicity during targeted radionuclide therapy with 177Lu-octreotate in patients with neuroendocrine tumours (NETs) limits the administered activity and thereby the therapeutic response. Reducing renal side effects of radiation could allow for higher activity amounts and better tumour control, increasing the cure rate. Co-treatment with the human recombinant antioxidant α1– microglobulin (rA1M) protects against short and long-termed radiation-induced renal damage in mice treated with 177Lu-octreotate. Furthermore, co-treatment with rA1M does not affect the therapeutic effects on tumour volume in human NET GOT1-bearing mice. Purpose: The aim of this work was to investigate transcriptional regulation of genes related to apoptosis and oxidative stress in GOT1 tumours in mice at one and seven days after administration of rA1M and after treatment with 177Lu-octreotate with or without co-administration with rA1M. Methods: Adult female Balb/c mice with s.c. GOT1 tumours were i.v. injected with either 177Luoctreotate (30 MBq, n=6), rA1M (5mg/kg, n=6) or co-treatment with both (n=6). A control group was sham-treated with NaCl (n=4). RNA was extracted from tumours sampled at one or seven days after injection. Gene expression of 84 apoptosis and 84 oxidative stress-related genes were evaluated using RNA array plates and RT-qPCR. Results: RT-qPCR analysis showed higher and similar expression of apoptotic genes in the irradiated groups than rA1M administration alone on day one after injection. Corresponding result after seven days was similar but less prominent. The most affected pro-and anti-apoptotic genes were GADD45A, TNFRS10B, FADD, FAS, CASP4,6,3, BAX and BAG3, BIRC2, BIRC3, BIRC5, XIAP, NAIP, BCL2L10, BCL2L2, IGF-1R, IL-10, CFLAR, respectively. Overall, most oxidative stress genes were not significantly regulated. APOE, DUOX1, HMOX and FOXM1 were some of the most regulated genes in the oxidative stress array. The results were more similar between the irradiated groups than those in the A1M group. CYBG and MB, related to oxygen transportation, were significantly upregulated after 177Lu-octreotate and coadministration, but not after rA1M alone. Conclusions: The transcriptional regulation of the analyzed apoptosis-related genes may suggest a similar apoptotic response in irradiated and co-treated groups compared to administration of rA1M alone. Antioxidant genes were generally downregulated, indicating that antioxidant defense mechanisms were less prioritized in damaged cells.

Ämnesord

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

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

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

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

Nyckelord

α1-microglobulin

transcriptional response

GOT1

177Lu-octreotate

NET

gene regulation

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