Der Einfluss neoadjuvanter Chemotherapie auf Leberintegrität und Ischämietoleranz

Zusammenfassung

Im Zuge neuer Therapiestrategien, Lebermetastasen kolorektaler Karzinome neoadjuvant zu behandeln, ist die Gewebeintegrität und Ischämietoleranz der Leber während und nach einer Operation von besonderer Bedeutung. Ziel dieser Arbeit war es daher, in einem Tiermodell zu untersuchen, ob eine Chemotherapie in Kombination mit einer Ischämie die Organintegrität beeinflusst. Männliche Wistar-Ratten erhielten entweder eine Chemotherapie mit 5-FU, FA und Oxaliplatin oder Placebo. Während einer folgenden Operation wurde für 30 min ein Pringle-Manöver durchgeführt. Die Reperfusion dauerte entweder 1 h oder 24 h. Perioperativ erfolgte die Messung von Gallefluss und Gewebeperfusion. Bei der Bestimmung blutchemischer Parameter zeigten sich zwischen Chemo- und Placebogruppe keine Unterschiede, lediglich der Gallefluss war bei Verknüpfung von Chemotherapie und Ischämie signifikant vermindert. Demgegenüber kam es durch die Kombination von Placebogabe und Ischämie zu einer Aufregulierung von PUMA und Caspase3-Spaltprodukten. Im Vergleich dazu konnten wir einen Anstieg des kontraapoptotischen Chaperones GRP78 in den Chemotherapiegruppen verzeichnen. Aus diesen Ergebnissen schlussfolgern wir, dass Chemotherapie in unserem Modell eine Präkonditionierung der Leber bewirkt, welche vor zellulärer Apoptoseinduktion schützt und allgemein die Organtoleranz gegenüber Ischämie zu fördern scheint.

Abstract

The increasing interest in neoadjuvant chemotherapy of liver metastasis after colorectal carcinoma prior to resection has focussed surgical concerns to the influence of oncological chemotherapy on hepatic tolerance to intraoperative ischaemia. The present study was thus undertaken in order to produce first experimental data on liver function and morphology after neoadjuvant chemotherapy and subsequent ischaemic challenge in a rat model. Male Wistar rats were randomised to receive an intraperitoneal chemotherapy (CH) or placebo (PL) according to the same protocol. Afterwards the animals were subjected to 30 min of total hepatic ischaemia induced by Pringle’s manoeuvre and subsequent reperfusion for 1 h or 24 h. Serum activities of hepatic enzymes showed no differences between CH and PL at any time. Bile flow, however, was found to be significantly reduced in CH. In contrast, post-ischaemic up-regulation of PUMA and cleavage of caspase3 was found to be more prominent in PL than in CH, while the antiapoptotic chaperone GRP78 revealed a higher expression in the latter. It is concluded that chemotherapy did not affect ischaemic tolerance of the liver in our model, but promoted a kind of preconditioning, that is likely to counteract cellular induction of apoptosis upon ischaemic challenge.

Schlüsselwörter

Lebermetastasen - Chemotherapie - Ischämie

Key words

liver metastases - Chemotherapy - ischaemia

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