Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has recently been demonstrated in various clinical experiments that native somatostatin and its long-acting analogues increase circulating levels of insulin-like growth factor-binding protein-1 (IGFBP-1) within 1-2 h, independent of effects on circulating insulin or glucose levels. Using human hepatoma cells in vitro the somatostatin analogue, octreotide, has been shown to increase IGFBP-1 mRNA within 24 h indicative of a direct stimulatory effect of octreotide on IGFBP-1 synthesis. In order to ascertain whether octreotide acutely stimulates IGFBP-1 mRNA in vivo, placebo or two doses of octreotide were injected subcutaneously into three groups of rats. One hour after saline or octreotide administration, liver, kidney and serum were obtained for the measurement of IGFBPs-1 to -6 mRNA in tissue and IGFBPs and IGF-I in serum. Octreotide increased liver IGFBP-1 (562%) and IGFBP-3 (23%) mRNA expression with a concomitant rise in the circulating 30 kDa (106%) and 38-42 kDa (23%) IGFBPs. No detectable changes were seen in other liver IGFBP transcripts, other circulating IGFBPs or in any of the kidney IGFBP transcripts. Serum IGF-I increased by 37% in the animals receiving the high octreotide dose. No concomitant changes were observed in glucose or insulin levels. These data show that octreotide acutely stimulates hepatic IGFBP-1 and -3 mRNA in vivo in rats. The stimulating effect on IGFBP-3 presents a possible hitherto unknown form of regulation of IGFBP-3 whilst the effect on IGFBP-1 indicates that the stimulatory effect of octreotide on circulating IGFBP-1 described in clinical trials may be due to increased hepatic production. The present findings may be of importance in the clinical use of octreotide.
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PMID:Stimulation of hepatic insulin-like growth factor-binding protein-1 and -3 gene expression by octreotide in rats. 854 25

Clinical resistance to chemotherapeutic drugs is an important problem in the treatment of cancer; the circumvention of resistance has become one of the basic goals of cancer therapy. The most frequent form of primary liver cancer is hepatocellular carcinoma, which is essentially refractory to chemotherapy. We earlier showed that TT-232, a new somatostatin analogue developed in our laboratory, exerted a strong antiproliferative effect both in vitro and in vivo, but no growth hormone release inhibitory or antisecretory activity. Here we report that TT-232 has a pronounced antiproliferative effect on differentiated and dedifferentiated, drug-sensitive and multidrug-resistant hepatocellular carcinoma cell lines. TT-232 induces apoptosis at comparable levels in all these hepatoma variants demonstrating that the multidrug resistance of hepatomas does not correlate with a reduced susceptibility to apoptosis induction. These results clearly reveal that the machinery involved in apoptosis is functional in both drug-sensitive and resistant hepatoma variants and can be activated by the somatostatin analogue TT-232.
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PMID:Apoptosis is induced in both drug-sensitive and multidrug-resistant hepatoma cells by somatostatin analogue TT-232. 1037 72

Hepatocellular carcinoma is responsible in France for approximately 5,500 deaths per year. Incidence rates are growing and the general status of patients is improving mainly because of earlier diagnosis and improvement in the treatment of complications of liver cirrhosis. In most of the cases the severity of the underlying liver disease is the prominent prognostic factor. Its treatment remains a difficult challenge for oncologists. Unfortunately surgery is usually contraindicated. Most trials of systemic chemotherapy are disappointing with poor response rates and severe side effects; new drugs and direct delivery in the hepatic artery appear to be of interest. Results with interferon are interesting but requires more studies. The lack of efficacy of antiandrogenic and antiestrogenic treatments were recently demonstrated; a recent randomized study showing the interest of somatostatin requires confirmation. Reports on radiotherapy are anecdotals. A lot of studies using liver directed therapies were conducted worldwide. Percutaneous ethanol injections (PEI) are well tolerated and are highly effective in small solitary tumors (> 70% of complete necrosis) but less in larger tumors; recurrences are frequent. No randomized trial have been performed concerning PEI but survival rates seem similar to those of surgery. A randomized controlled trial recently demonstrates that injection of acetic acid is more effective than injection of ethanol. Chemoembolization was extensively studied because of the demonstration of objective responses but all trials failed to demonstrate an improvement in survival. Intraarterial injection of radioactive Lipiodol achieves the same response rate and the same survival than chemoembolization but is significantly best tolerated. This treatment is superior to best supportive cares in patients with portal vein thrombosis. In conclusion, despite the fact that this disease is very frequent we have currently too many treatment options and are lacking of simple rules. The best treatment remains prevention, and the efficacy of hepatitis B vaccination was recently demonstrated in Taiwan.
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PMID:[Nonsurgical treatment of hepatocellular carcinoma]. 1041 27

Based on the fact that somatostatin (SST) analogs have given promising results for treatment of hepatocellular cancer, we performed both in vitro and in vivo investigations to define the role of a depot formulation of the long acting SST-analog lanreotide (LAN). A decrease of cells in the S-phase as compared to controls (p<0.03) followed by a significant, dose-dependent induction of apoptosis could be demonstrated in Hep G2 cells along with a dose-dependent influence of the peptide on cellular proliferation. Northern blotting demonstrated the presence of mRNA for SSTR subtypes 2, 3 and 4 in Hep G2 cells, but only slight SSTR expression in normal liver tissue. In addition, 21 untreated patients with advanced HCC not amenable to surgery were administered 30 mg of LAN by deep intramuscular injection every 14 days until documented disease progression. Fifteen of these patients also underwent scanning with commercially available 111In-DTPA-D-Phe1-Octreotide (111In-OCT) to define the in vivo expression of SSTR. No positive 111In-OCT scans were obtained, indicating the absence of relevant amounts of functional SSTR2 in HCC. One patient (5%) showed a partial response to treatment, 8 patients had stable disease (38%), while the remaining patients progressed during treatment. The median survival was 4.2 months (range 1.2-13+), and the median time to progression was 2.5 months (range, 1.5-7+). However, 4 patients (19%) had an increase in WHO performance status lasting between 2.5 and 6 months, 5 patients (24%) had an increase in body weight, while pain markedly improved in 1 additional patient (5%). In total, 5 patients (24%) had a decrease in serum-AFP levels by at least 30%. Our results clearly indicate the ability of LAN to decrease the S-phase fraction along with induction of apoptosis in Hep G2 cells in a dose-dependent manner. Our data suggest clinical potential of SST-analogs in HCC and indicate that suboptimal doses of the peptide might have been administered in our series.
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PMID:Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide in vitro and in vivo. 1081 95

Inoperable liver tumors have an unfavorable natural course despite various therapeutic modalities. Octreotide, a somatostatin analog, has shown considerable antitumor activity on animal models of various hepatic tumors and on isolated cell culture lines. In this paper, a review of the experimental evidence is presented. Moreover clinical papers of case reports of uncontrolled studies of patients are also reviewed. The majority of clinical studies provide evidence of a clinical and biochemical response of liver endocrine tumors while regression of tumor size is a rare event. A randomized controlled trial of octreotide in the treatment of advanced hepatocellular carcinoma has shown a significant survival benefit in the treated patients. Literature reports indicate a stimulatory effect of octreotide on Kupffer cells as a possible antitumor mechanism, but other antiproliferative actions of octreotide have been suggested but not proved. Finally the question of the presence and affinity of somatostatin receptors on liver tumor tissue is discussed. In conclusion, according to our experience, octreotide administration is the best available treatment for advanced inoperable hepatocellular carcinoma and future better patient selection, based on receptor subtypes, might further improve the results.
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PMID:Octreotide for cancer of the liver and biliary tree. 1127 8

[carbohydrate structure--see text] Resistance to chemotherapy has become a major problem in cancer therapy. The new sugar amino acid (SAA) containing somatostatin analogues presented possess antiproliferative and apoptotic activity against both multidrug-resistant and drug-sensitive hepatoma carcinoma cells. Synthesis, design, and biological evaluation of the cyclic analogues and of the furanoid SAA used will be discussed. Four analogues have IC(50) values in the low microM range, making them promising leads for chemotherapeutic drugs against multidrug-resistant carcinoma.
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PMID:Sugar amino acid containing somatostatin analogues that induce apoptosis in both drug-sensitive and multidrug-resistant tumor cells. 1170 Jan 22

An earlier report has shown that subcutaneous short acting octreotide significantly improves survival of patients with inoperable hepatocellular carcinoma (HCC). The aim of this study was to compare survival of the patients with inoperable HCC treated with long acting somatostatin analogues (LASA) to a historical control group of untreated patients. The survival of 32 patients with inoperable HCC who received LASA treatment was compared to those of 27 untreated patients. The Karnofsky scale was used for assessing quality of life. An improved overall survival was found in the treated group (median survival 15 months, 95% CI 6-24 months for the treated group and 8 months, 95% CI 5-11 months for the controls). The survival benefit remains even after removal of the most advanced cases from the control group. The relative risk of death of the untreated patients is 2.7 (95% CI 1.4-5.3) compared to the treated patients. The tumor remained stable or regressed in 40% of the treated patients. A superior quality of life was found in the treated group. In conclusion long acting somatostatin analogues appear to be beneficial, improving survival and performance status in inoperable HCC cases. Further studies are required to define a subgroup of patients that may benefit to a greater extent than others.
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PMID:Treatment of hepatocellular carcinoma with long acting somatostatin analogues. 1206 29

Although various types of treatment of hepatocellular carcinoma (HCC) have been tried, the prognosis remains dismal, especially in patients with advanced stage of the disease. Somatostatin analogues exert antitumor effects. HCC have been shown to exhibit somatostatin receptors. The present randomized placebo-controlled study aimed at examining the efficacy of long-acting octreotide (Sandostatin LAR) for the treatment of advanced HCC. Seventy patients were randomized to receive a 2-week course of 250 microg short-acting octreotide twice daily followed by Sandostatin LAR 30 mg injection once every 4 weeks for 6 doses (n = 35) or placebo (control group) (n = 35). The clinical and laboratory parameters were monitored. There was no difference in the cumulative survival between the Sandostatin LAR-treated group compared with the control group [median survival 1.93 months vs. 1.97 months, respectively, P = NS (log-rank test)]. There was no tumor regression and no reduction of alpha-fetoprotein (AFP) levels in patients receiving Sandostatin LAR treatment. There was no improvement of quality of life assessed by Karnofsky performance score. In conclusion, Sandostatin LAR monotherapy did not have survival benefit in our selected group of patients with advanced HCC. Further studies should be performed in patients with less advanced disease and/or different etiology to evaluate its benefit.
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PMID:A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. 1257 12

Long-acting octapeptide somatostatin analogs can effectively control symptoms resulting from excessive hormone release in patients with endocrine tumors of the gastrointestinal tract, provided that these tumors and metastases show a high expression of the somatostatin receptor subtype 2. The presence of this receptor subtype on these tumors can be demonstrated by in vitro studies, but also in vivo using 111In-pentetreotide scintigraphy. In a few studies, significant antiproliferative effects of these drugs on these tumors have also been demonstrated. The effectiveness of octapeptide somatostatin analogs in the management of chemotherapy- related and AIDS-related diarrhea and in reducing postoperative complications of pancreatic surgery have also been demonstrated. These drugs have been used to decrease the output of enterocutaneous pancreatic fistulas and are prophylactically used to prevent the development of these fistulas. Octapeptide somatostatin analog therapy is widely accepted for the initial management of acute variceal bleeding in cirrhotic patients. These drugs are currently also being evaluated for the treatment of advanced hepatocellular carcinoma and malignant intestinal obstruction. Radiotherapy with octapeptide somatostatin analogs coupled to radionuclides such as indium-111, yttrium-90, and lutetium- 177 is currently being studied in phase I-III trials.
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PMID:Somatostatin analog therapy in treatment of gastrointestinal disorders and tumors. 1272 9

TT-232 (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) has been developed as an antitumor somatostatin analog. TT-232 has no growth hormone release inhibitory effect and does not inhibit the secretion of gastric acid. This analog induces apoptosis in and exerts pronounced antiproliferative effects on various human tumors (colon, pancreas, lymphoma, leukemia, melanoma, hepatoma) cell lines. The growth of human xenografts (prostate, breast carcinoma, lymphoma, melanoma) and animal tumors (colon-26, P-388, S-180, B16, MXT) was inhibited by TT-232 (dose range: 30-750 microg/kg/day) in 54-98% of cases. Continuous long-term infusion proved to be the most effective way of administration. TT-232 combined with decarbazine or etoposide treatment enhanced the antitumor activity of these drugs on human melanoma and lymphoma xenografts, respectively. Regarding the mode of action, TT-232 activates cell cycle inhibitors via SSTR receptors, inhibits tyrosine kinases through interfering with the proliferative signaling cascades, and interacts with an intracellular receptor and an enzyme involved in glycolysis causing translocation of this enzyme to the nucleus, thus inducing apoptosis. TT-232 may be a promising candidate in the therapy of human malignancies.
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PMID:TT-232: a somatostatin structural derivative as a potent antitumor drug candidate. 1450 79


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