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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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Uptake of [177Lu-DOTA0-Tyr3]-octreotate was studied in tumours as well as in several organs 24 h p.i. In the tumours, the maximum uptake was 17±3.3%IA g−1 (mean±s.e.m. n=5 for all groups) and was seen in animals receiving 15 MBq (0.5 μg) and 7.5 MBq (0.25 μg) [177Lu-DOTA0-Tyr3]-octreotate. Decreasing uptake for higher administered doses indicated saturation of sstr in tumour tissue. For the critical organs kidney and liver, no signs of saturation was seen. P-values reflect the difference vs 7.5 MBq.
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fig1: Uptake of [177Lu-DOTA0-Tyr3]-octreotate was studied in tumours as well as in several organs 24 h p.i. In the tumours, the maximum uptake was 17±3.3%IA g−1 (mean±s.e.m. n=5 for all groups) and was seen in animals receiving 15 MBq (0.5 μg) and 7.5 MBq (0.25 μg) [177Lu-DOTA0-Tyr3]-octreotate. Decreasing uptake for higher administered doses indicated saturation of sstr in tumour tissue. For the critical organs kidney and liver, no signs of saturation was seen. P-values reflect the difference vs 7.5 MBq.

Mentions: In normal tissues, the uptake was generally lower than in tumours. The highest uptake was found in the kidneys (6.1–7.7%IA g−1) (Figure 1). For all other organs (liver, spleen, small intestine, blood, skeletal muscle, heart, brain, lungs, pancreas and adrenals), the uptake was very low (0.01–1.7) %IA g−1. For kidneys, liver, blood, skeletal muscle, heart and brain, the uptake was independent of the amount of activity administered, which indicates no saturation, or nonspecific distribution in the tissues. However, in the spleen, small intestine, lungs, pancreas and adrenals, the uptake was highest for 7.5 MBq [177Lu-DOTA0-Tyr3]-octreotate and declined with increasing amounts of [177Lu-DOTA0-Tyr3]-octreotate, which indicates saturation of receptor-mediated binding.


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)

Uptake of [177Lu-DOTA0-Tyr3]-octreotate was studied in tumours as well as in several organs 24 h p.i. In the tumours, the maximum uptake was 17±3.3%IA g−1 (mean±s.e.m. n=5 for all groups) and was seen in animals receiving 15 MBq (0.5 μg) and 7.5 MBq (0.25 μg) [177Lu-DOTA0-Tyr3]-octreotate. Decreasing uptake for higher administered doses indicated saturation of sstr in tumour tissue. For the critical organs kidney and liver, no signs of saturation was seen. P-values reflect the difference vs 7.5 MBq.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Uptake of [177Lu-DOTA0-Tyr3]-octreotate was studied in tumours as well as in several organs 24 h p.i. In the tumours, the maximum uptake was 17±3.3%IA g−1 (mean±s.e.m. n=5 for all groups) and was seen in animals receiving 15 MBq (0.5 μg) and 7.5 MBq (0.25 μg) [177Lu-DOTA0-Tyr3]-octreotate. Decreasing uptake for higher administered doses indicated saturation of sstr in tumour tissue. For the critical organs kidney and liver, no signs of saturation was seen. P-values reflect the difference vs 7.5 MBq.
Mentions: In normal tissues, the uptake was generally lower than in tumours. The highest uptake was found in the kidneys (6.1–7.7%IA g−1) (Figure 1). For all other organs (liver, spleen, small intestine, blood, skeletal muscle, heart, brain, lungs, pancreas and adrenals), the uptake was very low (0.01–1.7) %IA g−1. For kidneys, liver, blood, skeletal muscle, heart and brain, the uptake was independent of the amount of activity administered, which indicates no saturation, or nonspecific distribution in the tissues. However, in the spleen, small intestine, lungs, pancreas and adrenals, the uptake was highest for 7.5 MBq [177Lu-DOTA0-Tyr3]-octreotate and declined with increasing amounts of [177Lu-DOTA0-Tyr3]-octreotate, which indicates saturation of receptor-mediated binding.

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