Therapy of malignant ascites in vivo by ²¹¹At-labelled microspheres

Summary

Aim: Determination of the biological effect of the alpha emitter ²¹¹At on cellular level as well as the assessment of dosimetric data in a tumour model in vivo. Methods: Transplantation of malignant ascitic cells in mice intraperitoneally and estimation of tumour characteristics (doubling time of the cells, mean survival of the animals following an i.p. application of a defined tumour cell number). ²¹¹At labelled human serum albumine microspheres B-20 (MSP) of variing activity were injected into tumour bearing mice intraperitoneally. The effectiveness of the therapy was evaluated by means of determination of the duration of cell cycle arrest as well as the microscopic analysis of the rate of abnormal mitotic cells due to radiation induced damage. Furthermore, dose dependence of survival was evaluated. Results: Three days following the intraperitoneally application of 8 x 10⁶ tumour cells, 50-600 kBq ²¹¹At-MSP were applied into the abdominal cavity. Considering the volume of ascites at this time and the administered activity, dose calculations were performed. An activity of 50 kBq caused a dose of 0.84 Gy. The increase of radiation induced effect on ascitic tumour cells was correlated with the dose. Between the duration of the cell cycle arrest and the administered activity, a directly proportional correlation was found. The mean survival of non-treated animals was 16.9 ± 3.7 days. The prolongation of the survival was proportional to the activity administered. Using a dosage of 10 Gy, five animals out of 16 survived. Conclusion: Therapy of malignant ascitic cells using ²¹¹At-MSP was effective in vivo. For tumour therapy, the ²¹¹At represents a highly effective alternative to usually applied beta emitters.

Zusammenfassung

Ziel: Beurteilung der biologischen Wirkung des Alpha-Strahlers ²¹¹At auf zellulärer Ebene an einem In-vivoTumormodell und Gewinnung dosimetrischer Angaben. Methoden: Intraperitoneale Übertragung maligner Aszitestumorzellen bei Mäusen und Bestimmung von Tumorcharakteristika (Generationszeit der Tumorzellen, mittlere Überlebenszeit nach i.p.-Applikation einer definierten Tumorzellzahl). Die Applikation ²¹¹At-markierter Humanserumalbumin-Mikrosphären B-20 (MSP) mit verschiedener Aktivität erfolgte bei tumortragenden Tieren intraperitoneal. Die Wirksamkeit der Therapie wurde anhand der Dauer der Zellzyklusblockade sowie der Häufigkeit abnormaler Mitosefiguren, als Maß für strahleninduzierte Schäden, lichtmikroskopisch ausgewertet. Außerdem wurde die Lebensverlängerung tumortragender Tiere dosisabhängig bestimmt. Ergebnisse: Drei Tage nach intraperitonealer Applikation von 8 x 10⁶ Tumorzellen wurden 50-600 kBq ²¹¹At-MSP ebenfalls intraperitoneal appliziert. Aus ermitteltem Aszitesvolumen und der Aktivität wurden Dosisabschätzungen vorgenommen. 50 kBq ²¹¹At-MSP führten in dem Tumormodell zu einer Dosis von 0,84 Gy. Die Zunahme strahleninduzierter Effekte an den Aszitestumorzellen korrelierte mit der Dosis. Die Dauer der Proliferationshemmung war direkt proportional der Radioaktivität. Unbehandelt betrug die mittlere Überlebenszeit der Tiere 16,9 ± 3,7 Tage. Die Verlängerung des Überlebens war direkt proportional zur Dosis. Bei einer Dosis von 10 Gy überlebten 5 von 16 Tieren im Beobachtungszeitraum von 90 Tagen. Schlussfolgerung: Die Therapie maligner Asziteszellen mit ²¹¹At-Mikrosphären erwies sich in vivo als effektiv. Für die Tumortherapie stellt ²¹¹At eine hoch wirksame Alternative zu den Betastrahlern dar.

Keywords

²¹¹Astatine - microspheres - Ehrlich mouse ascites carcionoma - radionuclide therapy

Schlüsselwörter

²¹¹Astat - Mikrosphären - Ehrlich-Mäuseasziteskarzinom - Radionuklidtherapie

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