Fractionated 177Lu-octreotate therapy of human GOT1 tumors in nude mice increases treatment efficacy, possibly via SSTR up-regulation

• Introduction: The radiolabelled somatostatin analogue 177Lu-octreotate is a promising treatment option for malignant neuroendocrine tumors that overexpress somatostatin receptors. The human midgut carcinoid GOT1 cell line has shown promising treatment response to 177Lu-octreotate in xenografted mice. In clinical studies, however, only low cure rates have been achieved to date. In vitro and preclinical in vivo studies have shown that irradiation can up-regulate the expression of somatostatin receptors and thereby give an increased uptake of 177Lu-octreotate. The cellular processes that underlie positive treatment response to 177Lu-octreotate are otherwise largely unknown. Genome-wide analysis of tumor cell responses in this successful mouse model offers a venue to identify critical treatment parameters and to optimize clinical effectiveness of 177Lu-octreotate therapy. Aim: To investigate the genome-wide transcriptional response of xenografted GOT1 midgut carcinoid after fractionated treatment giving a priming administration before the main administration of 177Lu-octreotate. Methods: GOT1 bearing BALB/c nude mice were i.v. injected with 5, 10, 15 or 30 MBq 177Lu-octreotate. The groups receiving 5 and 10 MBq 177Lu-octreotate were given an additional 10 or 5 MBq 177Lu-octreotate 24 h after the first injection, respectively. Control animals were injected with NaCl. Animals were killed after 1, 3, 7 or 41 days for the 5+10, 10+5 and 15 MBq treatments and controls and after 41 days for the 30 MBq treatment. Tumor samples were excised and snap frozen in liquid nitrogen, followed by total RNA extraction. Microarray analysis was performed on samples from treated animals and untreated controls (Illumina HumanHT-12 Beadchips) and differentially regulated transcripts were identified (change, ≥1.5-fold; P-adjusted < 0.05). Associated biological functions and affected biological pathways (according to Gene Ontology terms, P-adjusted < 0.05) were analyzed using Nexus Expression and Ingenuity IPA. Results: The mean tumor volume was clearly reduced after 177Lu-octreotate treatment in all groups. The mean absorbed dose to the tumor tissue was almost 110 % higher for the 5+10 MBq than for the 15 MBq group. The best overall therapeutic effects were obtained in the 5+10 MBq group. Microarray analysis showed clear differences in transcriptional response between treated groups and time points. Affected associated biological processes were e.g. cell death and survival, and cell cycle regulation after 1, 3, and 7 days; cellular movement and cellular development were influenced after 41 days. Cellular growth and proliferation was affected after 1 day but not at later time points. Conclusions: Microarray analysis of 177Lu-octreotate-induced effects in xenografted GOT1 tumors showed distinct differences in transcriptional responses and associated cellular functions, both with regard to treatment fractionation and time-of-response. The use of priming activity offers a new venue for increasing clinical effectiveness of 177Lu-octreotate therapy of midgut carcinoid tumors, probably due to increased somatostatin receptor expression.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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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