Potential usage of liposomal 4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin (TOP-53) for cancer chemotherapy

To enhance the therapeutic efficacy as well as to reduce the side effect, we attempted to liposomalize 4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin (TOP-53), a novel and effective topoisomerase II inhibitor. More than 90% of TOP-53 was efficiently incorporated into the liposomes composed of dipalmitoylphosphatidylcholine and cholesterol by remote-loading method. Anti-tumor activity of liposomal TOP-53 against solid tumor was examined in vivo using colon26 NL-17 carcinoma model mice. Three doses of liposomal TOP-53 (12 mg/kg/dose) showed significant tumor growth suppression (97.5% reduction determined at day 25) and the increase in life span (33%) of tumor-bearing mice. Furthermore, one mouse out of 5 was completely cured after treatment. Since similar efficacy was observed in the free TOP-53 treated group, liposomalization does not contribute much to the enhancement of therapeutic efficacy. However, a slight but measurable damage at the injection site was observed when free TOP-53 was injected, and the damage was diminished by the liposomalization. Taken together, liposomalization reduces the side effect rather than enhancing the therapeutic efficacy when TOP-53 is used.     

Cancer chemotherapy by liposomal 6-[12-(dimethylamino)ethyl]aminol-3-hydroxy-7H-indeno[2,1-clquinolin-7-one dihydrochloride (TAS-103), a novel anti-cancer agent

A novel anti-tumor agent, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103), effectively inhibits both topoisomerase I and II activities. To enhance anti-tumor efficacy and to reduce the side effects of the agent, liposomalization of TAS-103 was performed. TAS-103 was effectively entrapped in liposomes by a remote-loading method, and was stable at 4 degrees C and in the presence of 50% serum. To evaluate the anti-tumor efficacy of liposomal TAS-103, the growth inhibition against Lewis lung carcinoma cells in vitro and the therapeutic efficacy against solid tumor-bearing mice in vivo were examined. Liposomal TAS-103 showed strong cytotoxic effect against Lewis lung carcinoma cells in a dose dependent manner and effectively suppressed solid tumor growth accompanying longer survival time of tumor-bearing mice in comparison with the mice treated with free TAS-103. These results suggest that liposomal TAS-103 is useful for cancer therapy.     

Preventive effects of Impatiens balsamina on the hen egg-white lysozyme (HEL)-induced decrease in blood flow

Monitoring the blood flow of unanesthesized mice was found to be a reliable and effective method for studying their anaphylactic responses, in addition to the known method of monitoring blood pressure. Hen egg-white lysozyme (HEL)-specific anaphylaxis in mice was estimated by monitoring the decrease in blood flow with a Doppler blood flow meter. This method is convenient for searching for both anaphylaxis and anti-anaphylactic substances from natural products. Using this system, we estimated the anti-anaphylactic effects of the 35% ethanol extract (IB) of petals of Impatiens balsamina L., as well as those of anti-allergic agents currently used. Kaempferol 3-rutinoside and lawsone from IB significantly inhibited the decrease of blood flow. We also found that platelet-activating factor (PAF) and serotonin participate in decreasing the blood flow, but histamine does not.     

Antipruritic effects of 1,4-naphthoquinones and related compounds

The antipruritic effects of orally administered 1,4-naphthoquinone derivatives and related compounds on compound 48/80-induced scratching behavior in mice were studied. 2-Hydroxy-3-(2-hydroxyethyl)-1,4-naphthoquinone, ferulic acid, 2,2'-methylenebis(3-hydroxy-1,4-naphthoquinone), and 2,2'-ethylidenebis(3-hydroxy-1,4-naphthoquinone) (impatienol) all exhibited significant antipruritic activity. However, 2-methoxy-3-(2-hydroxyethyl)-1,4-naphthoquinone (balsaquinone), which was isolated from a natural source for the first time, did not show any activity. The present results indicate that these compounds are promising for treating allergic diseases with chronic and severe pruritus.     

Effects of conjugated linoleic acid on anaphylaxis and allergic pruritus

The effects of conjugated linoleic acid (CLA) against anaphylaxis and allergic pruritus were investigated using a in vivo assay. Inhibitory effects of CLA were observed on the immediate (type 1) hypersensitivity reaction, with CLA significantly suppressing the decrease in blood pressure (BP) and blood flow (BF) induced by the hen egg-white lysozyme (HEL)-anaphylactic reaction in ddY mice. After oral administration, CLA showed antipruritic activity, with significant inhibition of scratching behavior induced by compound 48/80 (COM), a histamine-release agent. When painted onto the skin, CLA also inhibited COM, platelet-activating factor, and protease-induced scratching behavior, and COM-induced vasodilation of the skin. CLA offers promise as a drug for the treatment of allergic and inflammatory pruritus not only as an oral but also a topical agent. The present findings demonstrate that CLA can be effective for the prevention and treatment of allergic disease with severe pruritus.     

Alteration of zinc concentrations in the brain implanted with C6 glioma

The uptake of zinc, an essential element, is critical not only for cell proliferation but also cell functions. On the basis of the evidence suggesting that preferential uptake of 65Zn in brain tumors may be associated with avid cell proliferation, alteration of zinc concentrations in the brain implanted with C6 glioma was studied by brain autoradiography using 65Zn. After implantation of C6 glioma cells into the hippocampus, 65Zn concentrations in the brain were compared between 1 h and 6 days after intravenous injection of 65ZnCl(2). The 65Zn concentration in the tumor 1 h after the injection was approximately twice as high as that 6 days after the injection. However, the 65Zn concentration in the tumor 6 days after the injection was higher than in any other brain region. These results suggest that zinc taken up in the tumor may be utilized for tumor cell proliferation and that there is greater potential in the use of 69mZn, a short-half life gamma-emitter, for evaluation of the viability of brain tumors.     

How can we prevent alveolar echinococcosis? Ecosystem and risk management viewpoints

PURPOSE: This article focuses on understanding epidemiological features of alveolar echinococcosis and discussing its prevention and control, especially from a viewpoint of the ecosystem and risk management. METHOD: Publications on alveolar echinococcosis throughout the world were systematically reviewed with special reference to ecology, epidemiology and countermeasures. RESULTS: Alveolar echinococcosis, caused by accidental infection with larva of the parasite Echinococcus multilocularis is fatal to humans unless diagnosed at an early stage. No effective control measures have been identified so far because it is difficult to fully understand the ecology of the parasite and its intermediate and definitive hosts. It is also not easy to determine the precise infection route to humans mainly because of the long latent period. In Hokkaido, infection rates among red foxes have recently risen even in low endemic districts. Not only stray and domestic dogs but also some pigs in Hokkaido have been found to be infected. While the number of reported human cases is still small, around 10 cases per year, local residents seem to be threatened with the risk of infection. DISCUSSION AND CONCLUSIONS: We predict that the incidence of alveolar echinococcosis among humans in Japan will increase in the near future if no effective preventive measures are conducted. In addition, Echinococcus multilocularis infection has the potential to affect the economy of Hokkaido because of its impact on the agricultural and tourist industries. Well-designed epidemiological surveys are therefore urgently required, in the context of ecosystem and risk management prior to large outbreaks. International collaboration is also desired.     

A case of large-cell lung cancer with liver metastasis successfully treated using combination chemotherapy with CDDP and vinorelbine

A 38-year-old woman presented to our hospital with the chief complaint of dyspnea. A chest radiograph showed pleural effusion of the right lung and a CT scan revealed liver metastasis. A tumor biopsy done under bronchoscopy revealed large-cell carcinoma of the lungs. She was given 4 courses of a combination therapy consisting of CDDP (80 mg/m2) and vinorelbine (25 mg/m2). The primary tumor in the right lung and liver metastasis were markedly reduced in size and a partial response was obtained. The combination therapy of CDDP and vinorelbine may become a standard chemotherapy for advanced non-small cell lung cancer.     

Prominent matched hypoperfusion in an intact cerebellum after a solitary middle cerebellar peduncle infarct

We examined the cerebellar metabolism of a 61-year-old man with a small infarct in the left middle cerebellar peduncle and an intact cerebellum. Positron emission tomographic images obtained 28 days after onset showed prominent hypoperfusion and hypometabolism (almost 50% below the normal level) in the left cerebellar hemisphere. This case report shows that neural deafferentation may cause prominent hypometabolism without morphologic changes in the cerebellum. An arrest in synaptic activity may be the most important factor for the adaptive decrease in oxygen metabolism seen in ischemic brain.     

Growth-regulatory mechanism of two human esophageal-cancer cell lines in protein-free conditions

We investigated the growth-regulatory mechanism of 2 esophageal squamous-cancer cell lines, TE2-NS and TE3-OS cells, both of which can grow stably in protein-free conditions in vitro. Protein-free conditioned media from TE2-NS and TE3-OS cells stimulated the growth of these cells. Exogenous epidermal growth factor (EGF), transforming growth factor-alpha (TGF-α), insulin-like growth factor (IGF)-I and -II enhanced cell proliferation by 2.2- to 3.8-fold in protein-free conditions, as compared with an untreated control. Receptor-binding assays showed that both TE2-NS and TE3-OS cells possessed a single class of high-affinity binding sites for IGF-I and 2 classes of binding sites for TGF-α, as confirmed on the cell membrane by immunochemistry. These results suggest that EGF, TGF-α and IGFs are candidates for the autocrine growth factor in cancer cells. The addition of inhibitory monoclonal antibodies against TGF-a and EGFR, but not those against either EGF or IGF-IR, significantly inhibited growth of the cells. Immunocytochemical staining and ELISA of the conditioned media both confirmed the production of TGF-α protein, but not EGF protein, in these cell lines. The data for a protein-free culture system strongly suggested that TGF-α, but not EGF or IGF, is biologically important as an autocrine growth factor in the growth of these cell lines in vitro.