Optimisation of radionuclide therapy by reduction of normal tissue damage

Abstract

Background:177Lu-octreotate is used to treat patients with neuroendocrine tumours (NETs) often resulting in prolonged life and better quality of life, but is today seldom a cure for these patients. Optimisation of 177Lu-octreotate therapy can be achieved by reducing the risk of side effects on the main dose limiting organs, kidneys and bone marrow, enabling higher administered activity. One proposed option is co-administration with the antioxidant α1-microglobulin (A1M).

Aims: 1) to investigate if co-administration with A1M results in a negative (protective) effect on the tumour response to 177Lu-octreotate 2) to study the normal tissue response in mice following 177Lu-octreotate administration with or without A1M and A1M alone, 3) and to propose biomarkers for 177Lu-octreotate induced kidney damage.

Methods: Biodistribution of 177Lu was investigated in mice bearing human GOT2 NET after injection of 177Lu-octreotate with or without A1M. Tumour volume and regulation of apoptosis related genes were studied on human GOT1 NET in mice after injection of 177Lu-octreotate with or without A1M and A1M alone. Effects on normal tissues were studied in mice injected with 177Lu-octreotate with or without A1M and A1M alone. Early proteomic responses were investigated in kidney tissues and bone marrow. Regulation of apoptosis related genes was investigated in kidney tissues. Late effects on kidneys were studied based on expression of proposed markers for kidney damage.

Results and conclusions: No negative impact of A1M were observed on the therapeutic effects of 177Lu-octreotate in NET. A tissue-dependent early proteomic response was observed in kidney tissue, including regulation of previously observed radiation responsive proteins. No clear changes in regulation of these radiation-induced proteins was observed after co-administration of A1M. Regulation of pro- and anti-apoptotic genes was observed in kidney cortex and kidney medulla following 177Lu-octreotate exposure. Indication of an A1M initiated pro-survival response was observed in kidney medulla when 177Lu-octreotate was combined with A1M. Promising results were found for KIM-1, CDKN1A and S100A6 as biomarkers for 177Lu-octreotate induced late kidney injury, and RBP4 as an early responding urinary biomarker. No clear protective effect of A1M on late radiation induced effects on kidneys were observed.