Role of immunosuppression in recurrence after liver transplantation for diethylnitrosamine-induced tumors in rats

Abstract

Hepatocellular carcinoma is one of the world's most common malignant diseases, with an increasing incidence related to liver cirrhosis. The purpose of the study was to evaluate the role of immunosuppression in recurrence in rats transplanted after liver tumor induction by diethylnitrosamine (DENA), which has proved to be a reliable carcinogen. In 14-week-old Lewis rats weighing 200 g, tumors were induced by the oral administration (5 mg/100 ml in drinking water ad libitum) of DENA for 13 weeks. Orthotopic liver transplantation (OLT) was performed after 4 weeks' latency. In the Lewis/Lewis rats weighing 200 g, tumors sporin A (CsA) treatment, median survival was 199-days with no recurrence or metastasis. In the BN/Lewis group with no CsA (5 ats) median survival was 144 days. All rats died due to rejection. In the other BN/Lewis group (10 rats), OLT was followed by CsA administration (7.5 mg/kg). Median survival was 161 days. In three rats (218 days), there was liver tumor recurrence; in two rats (137.5 days), kidney and lung metastases were found. The remaining rats died of septic complications. In the Lewis/Lewis + CsA group (10 rats), median survival was 131 days with 5 recurrencies and/or metastases. Two rats are still surviving at 84 and 88 days. Our results suggest that the DENA model is reliable; it proved to have a similar carcinologic pattern to HCC in man. Moreover, immunosuppression seems to play an important role in determining recurrence. Further studies are needed to investigate the efficacy of chemotherapy agents pre- and post-transplantation.

mTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation?

“…Similar findings have been reported by other researchers [20,21]. Preclinical data relating to an effect of CNI therapy per se on HCC growth, however, are conflicting [22][23][24][25]. Lowering the intensity of immunosuppression to the minimum level compatible with effective rejection prophylaxis is advisable, but it remains unclear whether class-specific effects of immunosuppressant agents also exist.…”

Decreased hepatocyte membrane potential differences and GABAa-β3 expression in human hepatocellular carcinoma

“…38 Conversely, GABA A receptor antagonists such as fluoroquinolone antibiotics and calcineurin inhibitors could theoretically enhance tumor growth and might therefore be avoided in patients with HCC. [39][40][41] The discrepancy between HCC and adjacent nontumor tissue PDs could also be exploited in terms of developing charged compounds that would serve as the basis for new imaging modalities when the diagnosis of HCC is being considered. 42 In conclusion, relative to adjacent nontumor tissues, HCC tissues are depolarized and have decreased GABA A -␤ 3 receptor expression.…”

Sorafenib delays recurrence and metastasis after liver transplantation in a rat model of hepatocellular carcinoma with high expression of phosphorylated extracellular signal-regulated kinase

“…Moreover, we performed arterial reconstruction in our LT model because Morris hepatoma is a hypervascular tumor and has angiographic features similar to those of human HCC with an increase in the tumoral arterial blood flow . The findings of previous studies performed with nonarterialized grafts do not reflect the clinical setting of orthotopic HCC because hepatic artery reconstruction contributes to intrahepatic recurrence after LT for HCC . As shown in Figs.…”