Low density lipoprotein modified silica nanoparticles loaded with docetaxel and thalidomide for effective chemotherapy of liver cancer

In the present study, we successfully developed a docetaxel (DTX) and thalidomide (TDD) co-delivery system based on low density lipoprotein (LDL) modified silica nanoparticles (LDL/SLN/DTX/TDD). By employing the tumor homing property of LDL and the drug-loading capability of silica nanoparticles, the prepared LDL/SLN/DTX/TDD was expected to locate and specifically deliver the loaded drugs (DTX and TDD) to achieve effective chemotherapy of liver cancer. In vitro analysis revealed that nano-sized LDL/SLN/DTX/TDD with decent drug loading capabilities was able to increase the delivery efficiency by targeting the low density lipoprotein receptors, which were overexpressed on HepG2 human hepatocellular liver carcinoma cell line, which exerted better cytotoxicity than unmodified silica nanoparticles and free drugs. In vivo imaging and anti-cancer assays also confirmed the preferable tumor-homing and synergetic anti-cancer effects of LDL/SLN/DTX/TDD.

Polydatin inhibits cell proliferation, invasion and migration, and induces cell apoptosis in hepatocellular carcinoma

Polydatin, a small molecule from Polygonum cuspidatum, has many biological functions, particularly anti-cancer effects. However, the anti-cancer effects of polydatin in hepatocellular carcinoma (HCC) have not been examined yet. In the present study, MTT assay, BrdU assay, transwell invasion assay, and wound healing assay were performed to determine cell proliferation, invasion and migration. Flow cytometry and TUNEL assay were used to measure cell apoptosis. Quantitative real-time PCR and western blotting assays were used to determine mRNA and protein expression levels. Xenograft experiment was performed to determine the in vivo anti-tumor effect of polydatin. Immunostaining was performed to analyze the expression of caspase-3 and Ki-67. Our results showed that polydatin inhibited cell proliferation in a concentration-dependent and time-dependent manner in the HCC cell lines. Polydatin also induced cell apoptosis in a concentration-dependent manner possibly via increasing the caspase-3 activity, and up-regulating the protein expression of caspase-3, caspase-9, Bax, and down-regulating the protein expression of Bcl-2. In addition, polydatin treatment had an inhibitory effect on cell proliferation, invasion and migration in HCC cell lines. Polydatin treatment also suppressed the Wnt/beta-catenin signaling activities in HCC cells. Polydatin treatment significantly reduced tumor growth in nude mice inoculated with HepG2 cells, suppressed the expression of Ki-67, and increased caspase-3 expression and TUNEL activity. Our data indicated the important role of polydatin for the suppression of HCC progression.

Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice

ABSTRACT PURPOSE: To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. METHODS: Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. RESULTS: 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. CONCLUSION: 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

Effects of Arsenic Trioxide on Radiofrequency Ablation of VX2 Liver Tumor: Intraarterial versus Intravenous Administration

OBJECTIVE: Arsenic trioxide (As2O3) can be used as a possible pharmaceutical alternative that augments radiofrequency (RF) ablation by reducing tumor blood flow. The aim of this study was to assess the effect of intraarterial and intravenous administration of As2O3 on RF-induced ablation in an experimentally induced liver tumor. MATERIALS AND METHODS: VX2 carcinoma was grown in the livers of 30 rabbits. As2O3 (1 mg/kg) was administered through the hepatic artery (n = 10, group A) or ear vein (n = 10, group B), 30 minutes before RF ablation (125 mA +/- 35; 90 +/- 5degrees C). As a control group, 10 rabbits were treated with RF ablation alone (group C). RF was intentionally applied to the peripheral margin of the tumor so that ablation can cover the tumor and adjacent hepatic parenchyma. Ablation areas of the tumor and adjacent parenchymal changes among three groups were compared by the Kruskal-Wallis and Mann-Whitney U test. RESULTS: The overall ablation areas were 156 +/- 28.9 mm2 (group A), 119 +/- 31.7 (group B), and 92 +/- 17.4 (group C, p < 0.04). The ablation area of the tumor was significantly larger in group A (73 +/- 19.7 mm2) than both group B (50 +/- 19.4, p = 0.02) and group C (28 +/- 2.2, p < 0.01). The ratios of the tumoral ablation area to the overall ablation area were larger in group A (47 +/- 10.5%) than that of the other groups (42 +/- 7.3% in group B and 32 +/- 5.6% in group C) (p < 0.03). CONCLUSION: Radiofrequency-induced ablation area can be increased with intraarterial or intravenous administration of As2O3. The intraarterial administration of As2O3 seems to be helpful for the selective ablation of the tumor.

Construction of three different recombinant scorpion fusion proteins with bifunctional activity.

This is the first report of three different fusion proteins with an antitumor-analgesic peptide obtained from Chinese scorpion Buthus martensii Karsch (BmKAGAP). The fusion proteins were constructed in the form of chimeric toxins, aiming to obtain bifunctional analgesic and antitumor activity. The fusion proteins consisted of luteinizing hormone-releasing hormone (LHRH), three different types of flexible linkers (L1, Ser-Ser-His-His-His-His-His-His-Ser-Ser-Gly-Leu-Val-Pro-Arg-Gly-Ser-His-Met; L2, Gly-Gly-Gly-Ser-Gly-Gly-Gly-Ser; L3, Ser-Gly-Gly-Ser-Gly-Gly-Ser-Gly-Gly-Gly-Ser-Ser-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser), and BmKAGAP. The genes coding three fusion proteins were cloned and expressed in E. coli in soluble form. Following two successive column chromatographic separations, purified fusion proteins were obtained. These fusion proteins exhibited analgesic activity in mice and were cytotoxic to a hepatocellular carcinoma cell line Hep3B.

In vivo effects of adenosine 5´-triphosphate on rat preneoplastic liver / Efecto in vivo de adenosina 5´-trifosfato sobre el hígado preneoplásico de la rata

The utilization of adenosine 5´-triphosphate (ATP ) infusions to inhibit the growth of some human and animals tumors was based on the anticancer activity observed in in vitro and in vivo experiments, but contradictory results make the use of ATP in clinical practice rather controversial. Moreover, there is no literature regarding the use of ATP infusions to treat hepatocarcinomas. The purpose of this study was to investigate whether ATP prevents in vivo oncogenesis in very-early-stage cancer cells in a well characterized two-stage model of hepatocarcinogenesis in the rat. As we could not preclude the possible effect due to the intrinsic properties of adenosine, a known tumorigenic product of ATP hydrolysis, the effect of the administration of adenosine was also studied. Animals were divided in groups: rats submitted to the two stage preneoplasia initiation/promotion model of hepatocarcinogenesis, rats treated with intraperitoneal ATP or adenosine during the two phases of the model and appropriate control groups. The number and volume of preneoplastic foci per liver identified by the expression of glutathione S-transferase placental type and the number of proliferating nuclear antigen positive cells significantly increased in ATP and adenosine treated groups. Taken together, these results indicate that in this preneoplastic liver model, ATP as well as adenosine disturb the balance between apoptosis and proliferation contributing to malignant transformation.

La utilización de adenosina 5´-trifosfato (ATP ) para inhibir el crecimiento de algunos tumores en humanos y en animales se basa en la actividad anticancerígena observada en experimentos in vitro e in vivo. El uso del ATP en la práctica clínica es discutido debido a resultados contradictorios. Por otra parte, no existen antecedentes del uso de ATP en el tratamiento de hepatocarcinomas. El objetivo del presente estudio fue determinar si el ATP previene la oncogénesis in vivo en un modelo de preneoplasia hepática murina de dos etapas. Para determinar la probable contribución de la adenosina, producto de la hidrólisis de ATP y descrita como tumorigénica, se estudió también el efecto del nucleósido exógeno sobre los focos preneoplásicos. Los animales se dividieron en grupos: ratas sometidas al modelo de preneoplasia de iniciación/promoción, ratas tratadas con ATP o adenosina intraperitonealmente durante las dos fases del modelo y los correspondientes grupos controles. El número y el volumen de focos preneoplásicos por hígado, identificados por la expresión de la forma placentaria de la glutation S- transferasa de rata y el número de células positivas para el antígeno nuclear proliferante, aumentaron significativamente en los grupos tratados con ATP y adenosina. Los resultados en su conjunto indican que en este modelo preneoplásico, el ATP y la adenosina alteran el balance entre apoptosis y proliferación, contribuyendo a la transformación maligna.

The Antitumor Effect and Hepatotoxicity of a Hexokinase II Inhibitor 3-Bromopyruvate: In Vivo Investigation of Intraarterial Administration in a Rabbit VX2 Hepatoma Model

OBJECTIVE: The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. MATERIALS AND METHODS: This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3-BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/ 0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. RESULTS: The tumor necrosis rate was significantly higher in the high dose group (93% +/- 7.6 [mean +/- SD]) than that in the control group (48% +/- 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% +/- 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% +/- 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. CONCLUSION: Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method.

Atividade quimiopreventiva da tributirina quando administrada isoladamente ou em associação com vitamina A na etapa de promoção da hepatocarcinogênese em ratos / Chemopreventive activity of tributyrin when administrated isolated or in association with vitamin A in promotion phase of hepatocarcinogenesis to rats

No presente estudo avaliou-se a atividade quimiopreventiva da vitamina A (VA), tributirina (TB) e/ou 5-azacitidina (5-AzC) quando administradas isoladamente ou em associação na etapa de promoção do modelo de hepatocarcinogênese. Para tanto, ratos Wistar foram submetidos ao modelo do "hepatócito resistente" (HR), que consistiu na aplicação intraperitoneal de uma dose do agente iniciante dietilnitrosamina (DEN, 20 mg/100 g de p.c.), seguida, 2 semanas após, da aplicação de 4 doses consecutivas de 2- acetilaminofluoreno (2-AAF; 2 mg/100 g de p.c.) e de hepatectomia parcial (HP) a 70 ’POR CENTO’, acrescida de 1 dose de AAF (0,5 mg/100 g de p.c.) 4 dias após a cirurgia. Logo após a aplicação do modelo, os animais receberam VA (1 mg/ 100 g de p.c.) em dias alternados, TB (200 mg/ 100 g de p.c.) todos os dias e /ou 5-AzC (0,25 mg/ 100g de p.c.) duas vezes por semana ou, ainda, óleo de milho, maltodextrina e solução salina (grupo controle) durante cinco semanas. De acordo com a análise macroscópica do fígado, e em comparação ao grupo controle, verificou-se que o grupo tratado com TB isoladamente e o grupo tratado com VA e TB em associação apresentaram menor (p < 0,05) incidência e menor (p < 0,05) número médio de nódulos hepáticos. Em relação à análise morfométrica das lesões pré-neoplásicas (LPN) hepáticas positivas para a enzima glutationa S-transferase forma placentária (GST-P), observou-se que em comparação ao grupo controle os grupos experimentais que receberam 5-AzC apresentaram maior (p < 0,05) número de LPN hepáticas totais (persistentes + remodelação), LPN persistentes e LPN em remodelação, indicando que a 5-AzC teve ação potencializadora da iniciação nesse modelo de hepatocarcinogênese. Além disso, quando comparado ao grupo controle, observou-se que o grupo que recebeu TB isoladamente e o grupo que recebeu TB e nos tamanhos das LPN persistentes. Em comparação aos animais do grupo controle, não...

Chemopreventive activity of vitamin A (VA), tributyrin (TB) and/or 5-azacitidine (5-AzC) when administrated isolated or in association, was evaluated during the promotion phase of the "Resistant Hepatocyte"(RH) model of hepatocarcinogenisis. Rats received one dose of diethylnitrosamine (DEN; 20 mg/100g body weigh [b.w.]) for initiation and two weeks later, the animals received five doses of 2-acetylaminofluorene (AAF, 2 mg/100g b.w.), 4 consecutive doses before partial (2/3) hepatectomy and the remaining one four days after surgery. After 3 days, the animals received vitamin A (1mg/100 g.w.), TB (200 mg/ 100g de b.w.) and /or 5-AzC (0,25 mg/ 100 g de b. w.) or corn oil, maltrodextrin and saline (control goup) during five consecutive weeks. Incidence area of visible hepatocyte nodules/animal were smaller (p < 0,05) in goups that received TB and VA +TB than control group. Number of total (persistant + remodeling), persistent and remodeling hepatic placental glutathione S-transferase (GST-P) positive preneoplastic lesions (PNL) were higher (p < 0,05) in groups that received 5-AzC, indicating that 5-AzC potentiates initiation induced by carcinogens in rat liver. Moreover, the groups that received TB isolated or in association with VA presented mean area of persistent hepatic GST-p positive PNL smaller (p < 0,09) than control group. The animals treated with 5-AzC showed higher (p < 0,05) growth index in PNL than control group. The treatment with VA and TB isolated or in association increased (p < 0,05) the number of apoptotic bodies in PNL when compared to control group. Compared to normal group lower (p < 0,05) hepatic concentrations of retinyl palmitate were observed in control group, indicating that VA metabolism is altered in initial phases of hepatocarcinogenesis. The experimental groups that received VA showed higher concentrations of retinol and retinyl palmitate than control group. Moreover, the animals that received TB showed higher concentration...

Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-induced hepatoma rats

OBJECTIVE: To evaluate the effect of ginger extract on the expression of NFêB and TNF-á in liver cancer-induced rats. METHODS: Male Wistar rats were randomly divided into 5 groups based on diet: i) control (given normal rat chow), ii) olive oil, iii) ginger extract (100mg/kg body weight), iv) choline-deficient diet + 0.1 percent ethionine to induce liver cancer and v) choline-deficient diet + ginger extract (100mg/kg body weight). Tissue samples obtained at eight weeks were fixed with formalin and embedded in paraffin wax, followed by immunohistochemistry staining for NFêB and TNF-á. RESULTS: The expression of NFêB was detected in the choline-deficient diet group, with 88.3 ± 1.83 percent of samples showing positive staining, while in the choline-deficient diet supplemented with ginger group, the expression of NFêB was significantly reduced, to 32.35 ± 1.34 percent (p<0.05). In the choline-deficient diet group, 83.3 ± 4.52 percent of samples showed positive staining of TNF-á, which was significantly reduced to 7.94 ± 1.32 percent (p<0.05) when treated with ginger. There was a significant correlation demonstrated between NFêB and TNF-á in the choline-deficient diet group but not in the choline-deficient diet treated with ginger extract group. CONCLUSION: In conclusion, ginger extract significantly reduced the elevated expression of NFêB and TNF-á in rats with liver cancer. Ginger may act as an anti-cancer and anti-inflammatory agent by inactivating NFêB through the suppression of the pro-inflammatory TNF-á.

Effects of phenol, glycerin and acetic acid on the liver of guinea pigs

PURPOSE: To investigate the histolytic action of a solution composed of phenol, glycerin and acetic acid for irresectable hepatic metastasis. METHODS: Thirty-two (n=32) guinea pigs were randomly distributed into two groups of 16 animals. The animals in group 1 (experimental) and group 2 (control) were redistributed in two subgroups of eight animals each, according to the day of sacrifice (24 hours and four weeks after injection). All the animals were submitted to median laparotomy, which was followed by the injection of solution E and saline into the livers of subjects in both the experimental and control groups, respectively. The animals were evaluated for biochemical and anatomopathological (liver) alterations after 24 hours and four weeks of the experiment. RESULTS: It was observed that solution E produced necrosis limited to the injected area and that hepatic tissue recovery occurred after four weeks with the formation of a small necrosis area. No biochemical parameters were altered either in the experimental or in the control group. CONCLUSION: In view of the obtained results, the possibility of using the proposed solution can be considered in cases of irresectable metastasis.

OBJETIVO: Investigar a ação histolítica da solução composta de fenol, glicerina e ácido acético para os casos de metástases hepáticas não ressecáveis. MÉTODOS: Foram utilizadas 32 cobaias, distribuídas, por sorteio, em quatro grupos: experimental (24 horas e quatro semanas) e controle (24 horas e quatro semanas); todos os animais foram submetidos a laparotomia mediana e realizada a injeção da solução E (grupo experimental) ou solução fisiológica (grupo controle). Foram estudadas as alterações bioquímicas e anatomopatológicas (fígado) com 24 horas e quatro semanas de evolução. RESULTADOS: Verificou-se que a solução E produz necrose delimitada à área infiltrada apos 24 horas e que ao final de quatro semanas ocorreu regeneração do tecido hepático com formação de discreta área de fibrose. Não foram observadas quaisquer alterações bioquímicas tanto no grupo experimental como controle. CONCLUSÃO: Frente aos resultados obtidos, é válido considerar-se a possibilidade do emprego da solução proposta, nos casos de metástases hepáticas não ressecáveis.

Effects of acetylsalicylic acid and acetic acid solutions on VX2 liver carcinoma in rabbits: in vivo analysis

PURPOSE: To analyze, in vitro, the effects of acetylsalicylic acid (aspirin) and acetic acid solutions on VX2 carcinoma cells in the liver of rabbits with VX2 hepatic tumors; to determine the histolytic and anatomopathological characteristics of the solutions; and to evaluate the eventual biochemical and hepatic changes. METHODS: A total of 48 rabbits were evaluated. The animals were randomized into two groups, protocol 3 (study group) and protocol 4 (controls), and each group was then subdivided into 3 subgroups. Four days after implantation of the tumor in the liver, median laparotomy was performed with a 0.4-ml injection of a solution of either aspirin (5.0 percent), acetic acid (5.0 percent) or saline. The animals were sacrificed after 24 hours (protocol 3) or after 11 days (protocol 4). Body weight, clinical evolution and biochemical levels, as well as the abdominal and thoracic cavities, were evaluated, and liver microscopy was performed. RESULTS: No changes in clinical evolution, body weight or biochemical levels were reported. However, an increase in alkaline phosphatase was observed in protocol 4 (controls). The tumor was eliminated in both protocols. CONCLUSION: Acetylsalicylic acid and acetic acid solutions cause the destruction of experimental hepatic tumors.

OBJETIVO: Analisar os efeitos das soluções de aspirina e de ácido acético, in vivo, em fígado de coelhos portadores de tumor hepático VX2, verificando o efeito histolítico e anatomo-patológico das soluções e eventuais alterações bioquímicas hepáticas. MÉTODOS: Utilizou-se 48 coelhos, divididos em 2 protocolos experimentais(3 e 4), subdivididos em 3 grupos cada. Após 4 dias da implantação do tumor no fígado, procedeu-se a laparotomia mediana, com injeção de 0,4 ml da solução de aspirina (5,0 por cento), de ácido acético (5,0 por cento) e solução salina; o sacrifício ocorreu apos 24 horas (protocolo 3) e 11 dias (protocolo 4); avaliou-se o peso, evolução clinica, dosagens bioquímicas, cavidade abdominal e torácica e microscopia do fígado. RESULTADOS: Não foram observadas alterações na evolução clinica, peso e nas dosagens bioquímicas, apenas elevação da fosfatase alcalina no grupo controle do protocolo 4. Observamos desaparecimento do tumor em ambos os protocolos. CONCLUSÃO: As soluções de ácido acético e ácido acetilsalicílico acarretam destruição do tumor hepático experimental.

FDG-PET for Evaluating the Antitumor Effect of Intraarterial 3-Bromopyruvate Administration in a Rabbit VX2 Liver Tumor Model

OBJECTIVE: We wanted to investigate the feasibility of using FDG-PET for evaluating the antitumor effect of intraarterial administration of a hexokinase II inhibitor, 3-bromopyruvate (3-BrPA), in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: VX2 carcinoma was grown in the livers of ten rabbits. Two weeks later, liver CT was performed to confirm appropriate tumor growth for the experiment. After tumor volume-matched grouping of the rabbits, transcatheter intraarterial administration of 3-BrPA was performed (1 mM and 5 mM in five animals each, respectively). FDG-PET scan was performed the day before, immediately after and a week after 3-BrPA administration. FDG uptake was semiquantified by measuring the standardized uptake value (SUV). A week after treatment, the experimental animals were sacrificed and the necrosis rates of the tumors were calculated based on the histopathology. RESULTS: The SUV of the VX2 tumors before treatment (3.87+/-1.51[mean+/-SD]) was significantly higher than that of nontumorous liver parenchyma (1.72+/-0.34) (p < 0.0001, Mann-Whitney U test). The SUV was significantly decreased immediately after 3-BrPA administration (2.05+/-1.21) (p = 0.002, Wilcoxon signed rank test). On the one-week follow up PET scan, the FDG uptake remained significantly lower (SUV 1.41+/-0.73) than that before treatment (p = 0.002), although three out of ten animals showed a slightly increasing tendency for the FDG uptake. The tumor necrosis rate ranged from 50.00% to 99.90% (85.48%+/-15.87). There was no significant correlation between the SUV or the SUV decrease rate and the tumor necrosis rate in that range. CONCLUSION: Even though FDG-PET cannot exactly reflect the tumor necrosis rate, FDG-PET is a useful modality for the early assessment of the antitumor effect of intraarterial administration of 3-BrPA in VX2 liver tumor.

Chemoprevention by Butea monosperma of hepatic carcinogenesis and oxidative damage in male wistar rats.

In this communication, we document chemopreventive effects of Butea monosperma extract on hepatic carcinogenesis and on tumor promoter induced markers and oxidative stress in male Wistar rats. Treatment of male Wistar rats for five consecutive days with 2-AAF i.p. induced significant hepatic toxicity, oxidative stress and hyperproliferation. Pretreatment of B.monosperma extract (100 and 200 mg/kg body weight) prevented oxidative stress by restoring the levels of antioxidant enzymes and also prevented toxicity at both doses. The promotion parameters induced (ornithine decarboxylase activity and DNA synthesis) by 2-AAF administration in diet with partial hepatectomy (PH) were also significantly suppressed dose dependently by B. monosperma. Thereafter, we proceeded with studies on rat liver carcinogenesis. After fourteen days of DEN treatment, dietary administration of 2-AAF with PH resulted in a 100% incidence of tumors in the animals. However, B.monosperma caused reduction in the number of tumors/ rat and percentage of tumor bearing rats at the end of the study, as confirmed histologically. Thus, our data suggest that B.monosperma extract is a potent chemopreventive agent which suppresses 2-AAF-induced hepatic carcinogenesis and oxidative damage in Wistar rats. The protective activity of the plant might be due to the two major constituents (butrin and isobutrin).

Effects of high dose ascorbate administration on L-10 tumor growth in guinea pigs

Sodium ascorbate is preferentially toxic to tumor cells at high concentrations. It has not been established, however, whether sufficient intra-tumor ascorbate concentrations are safely achievable in vivo. We administered sodium ascorbate subcutaneously or orally for eighteen days to Sewall-Wright strain-2 guinea pigs bearing intradermal L-10 hepatocarcinoma tumors. Tumor masses and intra-tumor ascorbate concentrations were determined at necropsy. L-10 cells formed tumors that metastasized to the lymph nodes, with tumor burdens reaching nearly 50 grams in untreated animals. Subcutaneous injections of ascorbate (500 mg/kg/day) inhibited tumor growth by as much as sixty-five percent, with oral supplementation reducing it by roughly fifty percent. Tumor growth correlated inversely with intra-tumor ascorbate concentration, the latter exceeding 2 mM in some cases. Ascorbate concentrations sufficient to kill tumor cells can be safely achieved in solid tumors in vivo, suggesting a possible role for high dose intravenous ascorbate in treating cancer.

Intracellular signalling: phosphatidylinositol lipid metabolism in cancer cells.

Evidence for heightened capacity for signal transduction in rat hepatoma as well as in human breast and ovarian carcinoma cells as reflected by coordinate increases in PI kinase and PIP kinase in the PI phosphorylation sequence leading to the production of second messengers IP3 and DAG is shown. The linkage of signal transduction enzymes with malignant growth is also seen as MDA-MB- 435 human breast carcinoma or ovarian OVCAR-5 cells express their proliferative capacity in tissue culture in the log phase. In both cases, quercetin inhibit cell proliferation with a decline in PI kinase activity and IP3 levels preceding the growth inhibition seen with quercetin. The elevated steady state activities of PI and PIP kinase indicate a metabolic up-regulation in signal transduction capacity of cancer cells which is down-regulated by quercetin. Since the gain in function manifested in the over-expressed capacity for signal transduction confers selective growth advantage to cancer cells, increased activities of PI and PIP kinases may be considered as sensitive targets for cancer chemotherapy. The potential of quercetin as an interceptor of intracellular signal transduction mechanisms needs to be explored.

Anticancer effect of liposome incorporated with methotrexate and antibody against tumor specific surface antigen of rat hepatoma

antibody against tumor specific surface membrane protein was produced by immunizing a New Zealand White rabbit with antigen (66 kDa) prepared from the plasma membrane of rat hepatoma induced by feeding a diet containing 3'-methyl-4-dimethylaminoazobenzene, and was purified by protein A-Sepharose 6MB affinity chromatography. The purified antibody was incorporated into liposomes by a reverse phase evaporation vesicle method in order to prepare a tumor specific anticancer drug carrier. The effect of the antibody against tumor specific antigen was evaluated by comparing the inhibition of DNA synthesis in hepatoma cells with different preparations of methotrexate. Methotrexate encapsulated into liposome showed a stronger inhibitory effect on DNA synthesis (1.4-1.7 times) than free methotrexate. Liposomes having the antibody showed stronger inhibitory effect (3.1 times) on DNA synthesis than free methotrexate group in hepatic nodular area. From these results, it is concluded that tumor specific antibody inserted into liposomal membrane would be recognized by surface antigens which were expressed on the plasma surface membrane of rat hepatoma cells and thereby increase the carrying efficiency of drugs to the target cells. This could be useful in cancer chemotherapy.

Anticancer effect of liposome incorporated with methotrexate and antibody against tumor specific surface antigen of rat hepatoma

antibody against tumor specific surface membrane protein was produced by immunizing a New Zealand White rabbit with antigen (66 kDa) prepared from the plasma membrane of rat hepatoma induced by feeding a diet containing 3'-methyl-4-dimethylaminoazobenzene, and was purified by protein A-Sepharose 6MB affinity chromatography. The purified antibody was incorporated into liposomes by a reverse phase evaporation vesicle method in order to prepare a tumor specific anticancer drug carrier. The effect of the antibody against tumor specific antigen was evaluated by comparing the inhibition of DNA synthesis in hepatoma cells with different preparations of methotrexate. Methotrexate encapsulated into liposome showed a stronger inhibitory effect on DNA synthesis (1.4-1.7 times) than free methotrexate. Liposomes having the antibody showed stronger inhibitory effect (3.1 times) on DNA synthesis than free methotrexate group in hepatic nodular area. From these results, it is concluded that tumor specific antibody inserted into liposomal membrane would be recognized by surface antigens which were expressed on the plasma surface membrane of rat hepatoma cells and thereby increase the carrying efficiency of drugs to the target cells. This could be useful in cancer chemotherapy.

Possibilidade de tratamento de algumas neoplasias hepáticas mediante injeçäo de álcool etílico: provas de exeqüibilidade no animal de experimentaçäo / Treatment of some liver neoplasms with the injection of ethilic alcohol: efficiency tests in experimental animals

O objetivo deste trabalho foi verificar preliminarmente os efeitos locais e sistêmicos provocados pela injeçäo de álcool etílico no parênquima hepático do animal de experimentaçäo para, depois, possibilitar sua utilizaçäo no tratamento de algumas neoplasias hepáticas humanas. O estudo foi realizado em 51 coelhos e os resultados obtidos demonstraram uma boa tolerância do álcool etílico, com uma resposta local e sistêmica que é dose-dependente. Localmente e ao nível hepático, a injeçäo produz uma zona de necrose que em breve lapso de tempo torna-se delimitada e circunscrita a um tecido de granulaçäo. Decorrido um mês nem sempre era possível reconhecer a área de necrose na superfície do fígado e somente as secçöes seriadas do parênquima hepático permitiam reconhecer a lesäo