Μελέτη παραμέτρων σχετιζόμενων με την αντικαρκινική δράση της σωματοστατίνης επί ηπατωμάτων

Abstract

Somatostatin (sst) is a hormone - regulatory peptide with multiple and diverse role in the central nervous system, the gastrointestinal tract and other peripheral tissues. SST has inhibitory actions on various secretory and growth processes. Its actions are implemented via G-protein bound receptor family. The receptors (sstr1-5) bound with high afinity with natural sst, whereas synthetic analogues (created to overcome the limitation of short half-life of the natural sst) bound mainly to sstr 2, 3, and 5. Somatostatin receptors’ expression in human tumours in vivo & in vitro, in non-tumoural tissues and in vessels, provided the ground for intense research and important applications in the diagnosis and treatment, most characteristically in neuroendocrine tumours. The identification of somatostatin receptors in the liver experimentally (sinusoidal cells, Kupffer cells), in chronic liver diseases and in hepatocellular carcinoma – HCC) together with the clear value of sst in the treatment of portal hypertension, gave the evidence for the use of sst in the treatment of HCC. HCC is an important neoplasm as it represents the third cause of death from cancer. Its incidence rises worldwide. The radical therapeutic options (liver transplantation, resection or radiofrequency ablation in small HCC) are possible for a minority of HCC patients as screening is far from ideal. Palliative treatments (radiofrequency ablation, transarterial chemoembolisation) can prolong life in selected patients. Nevertheless many people are not candidates for any of the abovementioned treatments. The experience from the experimental models, the identification of sstr in liver strctures and the success of somatostatin analogues in neuroendocrine tumours gave the evidence to treat inoperable HCC with these regimens and study the factors related to the response and the outcome. After the original randomised study of octreotide in HCC, we conducted an open prospective study of long acting somatostatin analogues (octreotide, lanreotide) in 32 patients with inoperable HCC. The study showed better survival in the study group versus historic controls (median 15 months vs. 8, p<0.01) with relative risk for death in untreated patients 2.7. There has been a stabilisaton or reduction of the tumour in 40% of patients, almost all with good or improving quality of life (Karnofsky Performance Scale). The percentage of patients that responded was remarkably analogous with the percentage of HCCs that express sstr. Additionally, the positive effect of the treatment regimen was identified after 6 months treatment. The majority of HCC patients of the previous clinical study, together with a group of 30 cirrhotics and 48 healthy controls were studied regarding a significant clinical parameter, the thrombotic complications. We studied the role of acquired and genetic risk factors. In serum of patients with cirrhosis and HCC, low levels of protein C, S, antithrombin and lipoprotein (a) has been found. HCC patients had statistically higher homocystein levels compared to the other two groups. On the contrary the prevalence of APC resistance, factor V Leiden, G20210GA mutation in prothrombin gene and C677T polymorphism of methylentrahydrofolate reuctase had no statistical significant differences. We further studied comparativelly all the clinical reports of somatostatin analogues’ treatment for HCC, either randomised trials, case control studies, or case reports. Various problems and significant heterogeneity in the design of such trials was identified. Major clinical trials included moribund patients, frequently receiving 1 month treatment at most, thus failing to subject the patients into the critical 6 months therapeutic period, as shown in our studies. Thus, despite the good tolerance of the regimen and the excellent quality of life, the results vary significantly from impressive to poor. The “rule” of 40% of patients who benefit from such treatment is again confirmed, implying the relation with sstr. On the other hand this might reveals the insufficient targeting of implicated sstr from the available sst analogues. We analyze the potential mechanisms of action and resistance of HCC in this drug. Furthermore, the poor results of somatostatin analogues on HCC in studies including big numbers of alcoholics were confirmed in an analysis of the patients in our clinical study. Thus, patients with non alcoholic aetiology had mean survival 12 months vs. 5 months of patients with alcoholic aetiology. Trying to explore further this phenomenon, we studied experimentally in HepG2 cell line the effect of ethanol and its metabolite (acetaldehyde) in the expression of sstr2 and sstr5. SSTR induction was identified from octreotide, ethanol and acetaldehyde separately. When octreotide and ethanol were incubated together, as well as acetaldehyde and octreotide, we found suppression of the expression of sstr. We propose that this mechanism has important role in the clinical result of alcoholic patients treated with long acting somatostatin analogues.