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Transcriptional effects of 177Lu-octreotate therapy on GOT1 tumor in nude mice using conventional and priming treatment schedules

Konferensbidrag (offentliggjort, men ej förlagsutgivet)
Författare Johan Spetz
Johanna Dalmo
Nils Rudqvist
Britta Langen
Toshima Z Parris
Bo Wängberg
Ola Nilsson
Khalil Helou
Eva Forssell-Aronsson
Publicerad i 15th International Congress of Radiation Research, Kyoto, Japan, May 25-29
Publiceringsår 2015
Publicerad vid Institutionen för kliniska vetenskaper, Avdelningen för radiofysik
Institutionen för kliniska vetenskaper, Avdelningen för kirurgi
Institutionen för kliniska vetenskaper, Avdelningen för onkologi
Sahlgrenska Cancer Center
Institutionen för biomedicin, avdelningen för patologi
Språk en
Ämneskategorier Cell- och molekylärbiologi, Medicinsk cellbiologi, Tumörbiologi, Molekylärbiologi, Cancer och onkologi, Radiofysik, Strålningsbiologi

Sammanfattning

Introduction: 177Lu-octreotate can be used for therapy of somatostatin receptor expressing neuroendocrine tumors (NET). In GOT1 human small intestine NET transplanted to nude mice 177Lu-octreotate therapy has been successful with high cure rate. In clinical studies, on the other hand, the results have been moderate, and complete tumor remission is rarely seen. Previous studies have shown that a priming injection of 177Lu-octreotate 24 h before the main injection of 177Lu-octreotate resulted in higher SSTR expression, and increased absorbed dose, volume reduction and time to regrowth in GOT1 tumors in vivo. To our knowledge, the cellular effects of a priming treatment schedule have not yet been studied using a high throughput approach. Aim: To identify transcriptional changes responsible for the therapeutic differences in 177Lu-octreotate therapy of GOT1 tumors in nude mice with or without priming. Methods: GOT1 bearing BALB/c nude mice were treated with 15 MBq i.v. injected 177Lu-octreotate or 5 MBq of 177Lu-octreotate followed by additional 10 MBq of 177Lu-octreotate after 24 h. Animals were killed after 1, 3, 7 and 41 d and total RNA was extracted from excised tumor samples. Microarray analysis was performed on RNA from treated animals and untreated controls and differentially regulated transcripts were identified (change≥1.5-fold; adjusted P-value <0.01) using Nexus Expression 3.0. Results: Priming gave significantly greater treatment effects than without. Microarray analysis showed clear differences in transcriptional response, both with regard to treatment schedule and time-of-response. Higher influence on cell cycle arrest and physico-chemical environment was found 3 d after priming treatment compared to conventional treatment. Inhibition of apoptosis was found after 41 d without priming, but not after priming. Conclusions: Priming may be a promising method to optimize 177Lu-octreotate therapy in human malignant NET. Larger impact on cell cycle arrest and physico-chemical environment at earlier time points might influence the tumor volume reduction after priming. The prolonged time to tumor regrowth after priming may be explained by a lack of anti-apoptotic regulation at later time points.

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