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Successful receptor-mediated radiation therapy of xenografted human midgut carcinoid tumour.

Kölby L, Bernhardt P, Johanson V, Schmitt A, Ahlman H, Forssell-Aronsson E, Mäcke H, Nilsson O - Br. J. Cancer (2005)

Bottom Line: The diagnostic amount (0.5 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) did not influence tumour growth and was rapidly excreted.In contrast, the therapeutic amount (30 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) induced rapid tumour regression and entrapment of (177)Lu so that the activity concentration of (177)Lu remained high, 7 and 13 days after injection.In conclusion, human midgut carcinoid xenografts can be cured by receptor-mediated radiation therapy by optimising the uptake of radioligand and taking advantage of the favourable change in biokinetics induced by entrapment of radionuclide in the tumours.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Lundberg Laboratory for Cancer Research, Institute for Surgical Sciences, Göteborg University, Sahlgrenska University Hospital, Sweden. lars.kolby@surgery.gu.se

ABSTRACT
Somatostatin receptor (sstr)-mediated radiation therapy is a new therapeutic modality for neuroendocrine (NE) tumours. High expression of sstr in NE tumours leads to tumour-specific uptake of radiolabelled somatostatin analogues and high absorbed doses. In this study, we present the first optimised radiation therapy via sstr using [(177)Lu-DOTA(0)-Tyr(3)]-octreotate given to nude mice xenografted with the human midgut carcinoid GOT1. The tumours in 22 out of 23 animals given therapeutic amounts showed dose-dependent, rapid complete remission. The diagnostic amount (0.5 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) did not influence tumour growth and was rapidly excreted. In contrast, the therapeutic amount (30 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) induced rapid tumour regression and entrapment of (177)Lu so that the activity concentration of (177)Lu remained high, 7 and 13 days after injection. The entrapment phenomenon increased the absorbed dose to tumours from 1.6 to 4.0 Gy MBq(-1) and the tumours in animals treated with 30 MBq received 120 Gy. Therapeutic amounts of [(177)Lu-DOTA(0)-Tyr(3)]-octreotate rapidly induced apoptosis and gradual development of fibrosis in grafted tumours. In conclusion, human midgut carcinoid xenografts can be cured by receptor-mediated radiation therapy by optimising the uptake of radioligand and taking advantage of the favourable change in biokinetics induced by entrapment of radionuclide in the tumours.

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Typical morphological appearance of GOT1 tumours 1 day (B), 3 days (C), 7 days (D) and 13 day (E) after treatment with 30 MBq [177Lu-DOTA0-Tyr3]-octreotate compared to an untreated tumour (A). After injection of [177Lu-DOTA0-Tyr3]-octreotate, significant increases in the apoptotic cell count vs controls could be seen both 1 day p.i. (P=0.0000030) and 3 day p.i. (P=0.00000059). At 3 days p.i., all five tumours presented with large confluent necroses and oedema. At 7 and 13 days p.i., the apoptotic cell count decreased and the oedema and necroses were gradually replaced by fibrosis. The apoptotic cell count was 1.9±0.29 (mean±s.e.m.) for control animals and 26±4.3, 29±3.1, 1.2±0.65 and 0±0 at 1, 3, 7 and 13 days p.i., respectively (F). Typically, apoptotic cells (condensed and fragmented nuclei and eosinophilic cytoplasma) are indicated by arrows. Scale bar equals 20 μm.
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fig5: Typical morphological appearance of GOT1 tumours 1 day (B), 3 days (C), 7 days (D) and 13 day (E) after treatment with 30 MBq [177Lu-DOTA0-Tyr3]-octreotate compared to an untreated tumour (A). After injection of [177Lu-DOTA0-Tyr3]-octreotate, significant increases in the apoptotic cell count vs controls could be seen both 1 day p.i. (P=0.0000030) and 3 day p.i. (P=0.00000059). At 3 days p.i., all five tumours presented with large confluent necroses and oedema. At 7 and 13 days p.i., the apoptotic cell count decreased and the oedema and necroses were gradually replaced by fibrosis. The apoptotic cell count was 1.9±0.29 (mean±s.e.m.) for control animals and 26±4.3, 29±3.1, 1.2±0.65 and 0±0 at 1, 3, 7 and 13 days p.i., respectively (F). Typically, apoptotic cells (condensed and fragmented nuclei and eosinophilic cytoplasma) are indicated by arrows. Scale bar equals 20 μm.

Mentions: In untreated controls, tumour cells grew in solid sheets with small variation in nuclear size and without necroses. The tumour cells were positive for the general NE-marker CgA, serotonin (5-HT) and Vesicular Mono Amine Transporters (VMAT1 and 2). In animals treated with 30 MBq [177Lu-DOTA0-Tyr3]-octreotate, a significant increase in apoptotic cell count, compared to controls, was observed both at 1 day p.i. (P=0.0000030) and 3 days p.i. (P=0.00000059). In animals killed 3 days p.i., all five tumours had large confluent necroses and intercellular oedema. In animals, killed 7 and 13 days p.i., the number of tumour cells was clearly reduced as was the apoptotic cell count and the oedema and necroses were replaced by fibrosis. The typical appearance of a tumour 13 days p.i. was that of almost complete fibrosis and absence of tumour cells (Figure 5). The apoptotic cell count at each time point is presented in Figure 5F.


Successful receptor-mediated radiation therapy of xenografted human midgut carcinoid tumour.

Kölby L, Bernhardt P, Johanson V, Schmitt A, Ahlman H, Forssell-Aronsson E, Mäcke H, Nilsson O - Br. J. Cancer (2005)

Typical morphological appearance of GOT1 tumours 1 day (B), 3 days (C), 7 days (D) and 13 day (E) after treatment with 30 MBq [177Lu-DOTA0-Tyr3]-octreotate compared to an untreated tumour (A). After injection of [177Lu-DOTA0-Tyr3]-octreotate, significant increases in the apoptotic cell count vs controls could be seen both 1 day p.i. (P=0.0000030) and 3 day p.i. (P=0.00000059). At 3 days p.i., all five tumours presented with large confluent necroses and oedema. At 7 and 13 days p.i., the apoptotic cell count decreased and the oedema and necroses were gradually replaced by fibrosis. The apoptotic cell count was 1.9±0.29 (mean±s.e.m.) for control animals and 26±4.3, 29±3.1, 1.2±0.65 and 0±0 at 1, 3, 7 and 13 days p.i., respectively (F). Typically, apoptotic cells (condensed and fragmented nuclei and eosinophilic cytoplasma) are indicated by arrows. Scale bar equals 20 μm.
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Related In: Results  -  Collection

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fig5: Typical morphological appearance of GOT1 tumours 1 day (B), 3 days (C), 7 days (D) and 13 day (E) after treatment with 30 MBq [177Lu-DOTA0-Tyr3]-octreotate compared to an untreated tumour (A). After injection of [177Lu-DOTA0-Tyr3]-octreotate, significant increases in the apoptotic cell count vs controls could be seen both 1 day p.i. (P=0.0000030) and 3 day p.i. (P=0.00000059). At 3 days p.i., all five tumours presented with large confluent necroses and oedema. At 7 and 13 days p.i., the apoptotic cell count decreased and the oedema and necroses were gradually replaced by fibrosis. The apoptotic cell count was 1.9±0.29 (mean±s.e.m.) for control animals and 26±4.3, 29±3.1, 1.2±0.65 and 0±0 at 1, 3, 7 and 13 days p.i., respectively (F). Typically, apoptotic cells (condensed and fragmented nuclei and eosinophilic cytoplasma) are indicated by arrows. Scale bar equals 20 μm.
Mentions: In untreated controls, tumour cells grew in solid sheets with small variation in nuclear size and without necroses. The tumour cells were positive for the general NE-marker CgA, serotonin (5-HT) and Vesicular Mono Amine Transporters (VMAT1 and 2). In animals treated with 30 MBq [177Lu-DOTA0-Tyr3]-octreotate, a significant increase in apoptotic cell count, compared to controls, was observed both at 1 day p.i. (P=0.0000030) and 3 days p.i. (P=0.00000059). In animals killed 3 days p.i., all five tumours had large confluent necroses and intercellular oedema. In animals, killed 7 and 13 days p.i., the number of tumour cells was clearly reduced as was the apoptotic cell count and the oedema and necroses were replaced by fibrosis. The typical appearance of a tumour 13 days p.i. was that of almost complete fibrosis and absence of tumour cells (Figure 5). The apoptotic cell count at each time point is presented in Figure 5F.

Bottom Line: The diagnostic amount (0.5 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) did not influence tumour growth and was rapidly excreted.In contrast, the therapeutic amount (30 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) induced rapid tumour regression and entrapment of (177)Lu so that the activity concentration of (177)Lu remained high, 7 and 13 days after injection.In conclusion, human midgut carcinoid xenografts can be cured by receptor-mediated radiation therapy by optimising the uptake of radioligand and taking advantage of the favourable change in biokinetics induced by entrapment of radionuclide in the tumours.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Lundberg Laboratory for Cancer Research, Institute for Surgical Sciences, Göteborg University, Sahlgrenska University Hospital, Sweden. lars.kolby@surgery.gu.se

ABSTRACT
Somatostatin receptor (sstr)-mediated radiation therapy is a new therapeutic modality for neuroendocrine (NE) tumours. High expression of sstr in NE tumours leads to tumour-specific uptake of radiolabelled somatostatin analogues and high absorbed doses. In this study, we present the first optimised radiation therapy via sstr using [(177)Lu-DOTA(0)-Tyr(3)]-octreotate given to nude mice xenografted with the human midgut carcinoid GOT1. The tumours in 22 out of 23 animals given therapeutic amounts showed dose-dependent, rapid complete remission. The diagnostic amount (0.5 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) did not influence tumour growth and was rapidly excreted. In contrast, the therapeutic amount (30 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) induced rapid tumour regression and entrapment of (177)Lu so that the activity concentration of (177)Lu remained high, 7 and 13 days after injection. The entrapment phenomenon increased the absorbed dose to tumours from 1.6 to 4.0 Gy MBq(-1) and the tumours in animals treated with 30 MBq received 120 Gy. Therapeutic amounts of [(177)Lu-DOTA(0)-Tyr(3)]-octreotate rapidly induced apoptosis and gradual development of fibrosis in grafted tumours. In conclusion, human midgut carcinoid xenografts can be cured by receptor-mediated radiation therapy by optimising the uptake of radioligand and taking advantage of the favourable change in biokinetics induced by entrapment of radionuclide in the tumours.

Show MeSH
Related in: MedlinePlus