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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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Histopathological analysis of a small remnant of tumour tissue in an animal with CR 5 months after administration of 120 MBq [177Lu-DOTA0-Tyr3]-octreotate. The tumour residue consisted of a brownish nodule (2 mm in diameter). In the periphery, only a thin rim of fibroblasts was found. The dominant part of the nodule contained crystalline structures surrounded by inflammatory cells including macrophages and giant cells. Scale bar equals 1 mm.
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fig6: Histopathological analysis of a small remnant of tumour tissue in an animal with CR 5 months after administration of 120 MBq [177Lu-DOTA0-Tyr3]-octreotate. The tumour residue consisted of a brownish nodule (2 mm in diameter). In the periphery, only a thin rim of fibroblasts was found. The dominant part of the nodule contained crystalline structures surrounded by inflammatory cells including macrophages and giant cells. Scale bar equals 1 mm.

Mentions: In the therapy groups (7.5–120 MBq), all tumours, or tumour residues, were morphologically examined at the end of the observation period. Gross examination of the small residual tumour tissue, found in animals with CR in response to [177Lu-DOTA0-Tyr3]-octreotate, revealed brownish nodules, 1–2 mm in diameter. The microscopic analysis demonstrated a thin rim of fibroblasts in the periphery and a central part consisting of crystalline structures surrounded by inflammatory cells including macrophages and giant cells (Figure 6). Specific staining for fibrin (Ladewig) did not show any signs of thrombosis in treated tumours.


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)

Histopathological analysis of a small remnant of tumour tissue in an animal with CR 5 months after administration of 120 MBq [177Lu-DOTA0-Tyr3]-octreotate. The tumour residue consisted of a brownish nodule (2 mm in diameter). In the periphery, only a thin rim of fibroblasts was found. The dominant part of the nodule contained crystalline structures surrounded by inflammatory cells including macrophages and giant cells. Scale bar equals 1 mm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361494&req=5

fig6: Histopathological analysis of a small remnant of tumour tissue in an animal with CR 5 months after administration of 120 MBq [177Lu-DOTA0-Tyr3]-octreotate. The tumour residue consisted of a brownish nodule (2 mm in diameter). In the periphery, only a thin rim of fibroblasts was found. The dominant part of the nodule contained crystalline structures surrounded by inflammatory cells including macrophages and giant cells. Scale bar equals 1 mm.
Mentions: In the therapy groups (7.5–120 MBq), all tumours, or tumour residues, were morphologically examined at the end of the observation period. Gross examination of the small residual tumour tissue, found in animals with CR in response to [177Lu-DOTA0-Tyr3]-octreotate, revealed brownish nodules, 1–2 mm in diameter. The microscopic analysis demonstrated a thin rim of fibroblasts in the periphery and a central part consisting of crystalline structures surrounded by inflammatory cells including macrophages and giant cells (Figure 6). Specific staining for fibrin (Ladewig) did not show any signs of thrombosis in treated tumours.

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