ABSTRACT
BACKGROUND: Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine tumours (NET) comprise somatostatin-analogue lutetium-177-labelled octreotate ((177)Lu-TATE) treatment, also referred to as peptide receptor radionuclide therapy (PRRT), and temozolomide (TMZ) treatment. Their combination might result in additive effects. Using MRI and SPECT/CT, we studied tumour characteristics and therapeutic responses after different (combined) administration schemes in a murine tumour model in order to identify the optimal treatment schedule for PRRT plus TMZ. METHODS: We performed molecular imaging studies in mice bearing SSTR-expressing H69 (humane small cell lung cancer) tumours after single intravenous (i.v.) administration of 30 MBq (177)Lu-TATE or TMZ (oral 50 mg/kg daily for 14 days). Tumour perfusion was evaluated weekly by dynamic contrast-enhanced MRI (DCE-MRI), whereas tumour uptake of (111)In-octreotide was quantified using SPECT/CT until day 39 after treatment. Based on these results, seven different (177)Lu-octreotate and TMZ combination schemes were evaluated for therapy response, varying the order and time interval of the two therapies and compared with single treatments. RESULTS: PRRT and TMZ both resulted in tumour size reduction, accompanied by significant changes in MRI characteristics such as an enhanced tumour perfusion. Moreover, TMZ treatment also resulted in increased uptake of the SST analogue (111)In-octreotide until day 13. In the subsequent therapy study, 90 % of animals receiving (177)Lu-TATE at day 14 after TMZ treatment showed complete response, being the best anti-tumour results among groups. CONCLUSIONS: Molecular imaging studies indicated that PRRT after TMZ treatment could induce optimal therapeutic effects because of enhanced tumour uptake of radioactivity after TMZ, which was confirmed by therapy responses. Therefore, clinical translation of TMZ treatment prior to PRRT might increase tumour responses in NET patients as well.
ABSTRACT
Osteoarthritis (OA) is a non-rheumatoid joint disease characterized by progressive degeneration of extra-cellular cartilage matrix (ECM), enhanced subchondral bone remodeling, osteophyte formation and synovial thickening. Alendronate (ALN) is a potent inhibitor of osteoclastic bone resorption and results in reduced bone remodeling. This study investigated the effects of pre-emptive use of ALN on OA related osteoclastic subchondral bone resorption in an in vivo rat model for severe OA. Using multi-modality imaging we measured effects of ALN treatment within cartilage and synovium. Severe osteoarthritis was induced in left rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with subcutaneous ALN injections and compared to twenty untreated controls. Animals were longitudinally monitored for 12weeks with in vivo µCT to measure subchondral bone changes and SPECT/CT to determine synovial macrophage activation using a folate-based radiotracer. Articular cartilage was analyzed at 6 and 12weeks with ex vivo contrast enhanced µCT and histology to measure sulfated-glycosaminoglycan (sGAG) content and cartilage thickness. ALN treatment successfully inhibited subchondral bone remodeling. As a result we found less subchondral plate porosity and reduced osteophytosis. ALN treatment did not reduce subchondral sclerosis. However, after the OA induction phase, ALN treatment protected cartilage ECM from degradation and reduced synovial macrophage activation. Surprisingly, ALN treatment also improved sGAG content of tibia cartilage in healthy joints. Our data was consistent with the hypothesis that osteoclastic bone resorption might play an important role in OA and may be a driving force for progression of the disease. However, our study suggest that this effect might not solely be effects on osteoclastic activity, since ALN treatment also influenced macrophage functioning. Additionally, ALN treatment and physical activity exercised a positive effect in healthy control joints, which increased cartilage sGAG content. More research on this topic might lead to novel insights as to improve cartilage quality.
