Modified radiosensitivity of pancreatic cancer xenografts by farnesyl protein transferase inhibitor and MEK inhibitor

We investigated the effects of the farnesyl transferase inhibitor (FTI) manumycin and the MEK inhibitor PD98059 on growth of human pancreatic cancer, with mutant (SUIT2) or wild-type (BxPC-3) K-ras, xenografted into nude mice. Tumor growth was not reduced by either of the agents at a dose of 3 mg/kg without irradiation. Growth of SUIT2 irradiated at 15 Gy or 30 Gy was reduced by manumycin and PD98059: at 15 Gy, tumor volume doubling time (TVDT) increased from 18.6+/-3.8 to 36.3+/-14.2 days with PD98059 (p<0.05); at 30 Gy, TVDT increased from 32.8+/-6.8 to 70.5+/-10.5 days and 70.7+/-1.5 days, respectively. Manumycin tended to reduce growth of BxPC-3, but the difference in TVDT was not statistically significant. PD98059 significantly increased the TVDT of BxPC-3 at 30 Gy from 34.4+/-18 to 62.6+/-9.8 at 30 Gy. The present results suggest that Ras signaling pathways are potential targets for manipulation of radiosensitivity, and that induction of an alternative pathway may enhance radiosensitivity of pancreatic cancer.     

DJ-927, a novel oral taxane,overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo

DJ-927 is a novel taxane, which was selected for high solubility, non-neurotoxicity, oral bioavailability, and potent antitumor activity. In this study, we compared the in vitro and in vivo efficacy of DJ-927 with those of paclitaxel and docetaxel. DJ-927 exhibited stronger cytotoxicity than paclitaxel and docetaxel in various tumor cell lines, especially against P-glycoprotein (P-gp)-expressing cells. The cytotoxicity of DJ-927, unlike those of other taxanes, was not affected by the P-gp expression level in tumor cells, or by the co-presence of a P-gp modulator. When intracellular accumulation of the three compounds was compared, intracellular amounts of DJ-927 were much higher than those of paclitaxel or docetaxel, particularly in P-gp-positive cells. In vivo , DJ-927 showed potent antitumor effects against two human solid tumors in male BALB/c- nu/nu mice, and yielded significant life-prolongation in a murine liver metastasis model with male C57BL/6 mice, in which neither paclitaxel nor docetaxel was effective. The results demonstrate the superior efficacy of orally administered DJ-927 over intravenously administered paclitaxel or docetaxel against P-gp-expressing tumors, probably due to higher intracellular accumulation. A phase I clinical trials of DJ-927 is currently ongoing in the US. (Cancer Sci 2003; 94: 459–466)     

Carcinogenesis of the food mutagen PhIP in mice is independent of CYP1A2

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant of the heterocyclic amines found in cooked meat. Based on in vitro studies with rats and humans, CYP1A2 is believed to be the primary enzyme responsible for N(2)-hydroxylation, the initial step in the metabolic activation of PhIP. To determine whether CYP1A2 is the primary P450 responsible for metabolic activation of PhIP in mice that leads to tumor formation, neonatal Cyp1a2-null and wild-type mice were treated with approximately 11 (low dose) and approximately 22 (high dose) mg/kg PhIP at days 8 and 15, corresponding cumulatively to 600 and 1200 nmol PhIP, and analyzed at 19-21 months of age. Three major induced tumors were found; lymphomas and tumors in lung and liver. The incidence of lymphoma was higher in Cyp1a2-null females than wild-type females treated with low dose (600 nmol) PhIP whereas no significant differences were observed in other treatment groups of mice. Overall differences in incidences of lung adenoma/adenocarcinoma were in general not consistent among sexes, genotypes and PhIP doses used, although reduced incidences of lung tumors were found in Cyp1a2-null males with low dose (600 nmol) and null females with high dose (1200 nmol) PhIP. Higher incidences of hepatocellular adenoma were observed in Cyp1a2-null female and male mice as compared with wild-type mice. In vitro studies using Cyp1a2-null and wild-type mouse liver microsomes revealed that CYP1A2 is the major enzyme required for PhIP N2-hydroxylation in mouse, the initial metabolic activation of PhIP that is thought to lead to tumor formation. These in vivo and in vitro results suggest that although the metabolic activation of PhIP is carried out primarily by CYP1A2, an unknown pathway unrelated to CYP1A2 appears to be responsible for PhIP carcinogenesis in mouse when examined in the neonatal bioassay. In fact, CYP1A2 may even be protective against all transformation, especially in females.     

Significance of serial real-time PCR monitoring of EBV genome load in living donor liver transplantation

BACKGROUND: Quantitative analysis of the Epstein-Barr virus (EBV) genome has been recently reported to be helpful for early identification of EBV viremia which could reduce the risk of post-transplantation lymphoproliferative disorder (PTLD). AIM: To demonstrate the significance of serial monitoring of EBV genome load by real-time quantitative polymerase chain reaction (PCR) after living donor liver transplantation. METHODS: From March 1999 to April 2000, the EBV genome load in peripheral blood mononuclear cells (PBMNC) was measured serially in a total of 15 recipients of living donor liver transplantation (LDLT) who had a symptomatic EBV infection. RESULTS: In 15 patients, the mean values of the highest EBV DNA levels from the patients who had fever, URS, diarrhea, ascites, lymphadenopathy and PTLD were 36 232, 16 040, 15 968, 2485, 336 858 and 60 486 copies/microg DNA, respectively. Patients were treated by reduction or discontinuation of immunosuppressives and/or antiviral agents. The EBV DNA levels decreased in all these patients following the recovery from their symptoms. We encountered two cases of PTLD during this study period. One of them was referred to us after the onset of PTLD and one had been undergoing aggressive immunosuppression treatment for severe rejection. Both were successfully treated. CONCLUSIONS: Serial quantitative analysis of the EBV genome load by means of real-time PCR are thought to be useful for preventing PTLD through adjustment of the immunosuppression level in response to the viral genome load following symptomatic EBV infection.     

An oral history of Japanese nursing: voices of five senior nurses who have experienced nursing since the 1950s

The history of nursing cannot be considered separately from the history of women. In this study the public history of nursing and women was re-explored via the lived voices of five senior nurses in Japan. An oral history method using in-depth interviewing for data collection was used. Contemporary Japanese women's social position was constantly influenced by government policies from an historically androcentric society. Nursing, as a predominately female occupation, has also struggled with its position in society and in the hospital system. Data were categorised into five themes through the nurses' stories and analysed using feminist liberal theory. Findings from the current study showed that various elements of unequal opportunity to participate in society were an outcome of this history. Nursing in Japan appears to have been socialised without a relationship to feminism. Experiences of the participants in this study indicate a demand for the liberation of nurses as women. These participants wished nurses in Japan to focus on professionalism with an attitude which is independent of past androcentric policies and historical social inequities. With such an autonomous attitude, directions for nursing in Japan become constructive.     

Accumulation patterns of polychlorinated biphenyl congeners and organochlorine pesticides in Steller's sea eagles and white-tailed sea eagles, threatened species, in Hokkaido, Japan

Polychlorinated biphenyls (PCBs), including coplanar congeners, hexachlorocyclohexane isomers, chlordane-related compounds, and hexachlorobenzene, were found in the breast muscle of Steller's sea eagles (SSE) and white-tailed sea eagles (WSE) threatened species, collected in Hokkaido, Japan, during the two years from 1998 to 1999. Both PCBs and DDTs were the most notable compounds, with concentrations one to two orders of magnitude higher than the other compounds, that is, from 120 to 39,000 and from 68 to 15,000 ng/g wet weight, respectively. Non-ortho (International Union of Pure and Applied Chemistry [IUPAC] 77, 126, and 169) and mono-ortho (IUPAC 105, 118, and 156)-substituted coplanar PCB congeners amounted to 9.2 to 740 pg/g of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents derived from the World Health Organization, Paris, France (WHO), toxic equivalent factors. The atmospheric PCBs and DDTs in eastern Siberian cities, such as Khabarovsk and Magadan, have been reported to be much higher than Hokkaido and the North Pacific. Thus, we speculated that the eagles might have been contaminated in these areas, where they spend most of the year except winter, which they spend in eastern Siberia. Adult eagles accumulated more PCBs and DDTs than younger ones. The patterns of PCB congeners were also found to change, depending on the age of the eagle examined; adult eagles showed relatively higher proportions of highly chlorinated PCBs thanjuvenile eagles did. This difference would be related to the efficiency of the excretion and the metabolism of each PCB congener in the eagles.     

Suppression of solid tumor growth by a monoclonal antibody against tumor vasculature in rats: involvement of intravascular thrombosis and fibrinogenesis.

We have reported that immunization of rat tumor-derived endothelial cells (TEC) isolated from KMT-17 solid tumors results in the generation of several monoclonal antibodies (MAbs). TES-23, one of these MAbs, recognizes a naturally occurring 80-kDa antigen expressed on endothelial cells of tumor blood vessels. To determine whether such MAbs can suppress solid tumor growth in vivo by impairment of endothelial cells in tumors following direct binding, we tested the biodistribution of (125)I-labeled TES-23 in rats bearing KMT-17 solid tumors. We also examined the effect of treatment using unconjugated TES-23 on tumor growth and histo-pathological changes in tumor tissues. Biodistribution studies showed localization of TES-23 into tumor tissues 60 min after intravenous injection. TES-23 suppressed significantly the growth of KMT-17 solid tumors following administration for 5 days. Histo-pathological examination showed that TES-23 caused degeneration, apoptosis and/or necrosis and denudation of endothelial cells in viable tumor areas following local aggregation and adhesion of lymphocytes, with subsequent intravascular thrombus formation by platelets and fibrin. Our results indicate that TES-23, which recognizes TEC, can target endothelial cells of solid tumor vasculature directly, resulting in growth suppression in vivo by reduction of blood flow due to intravascular thrombosis. Our results also suggest that targeting tumor vasculature is a potentially attractive approach for the treatment of solid tumors.     

Fetal Heart Malformations in Experimental Hyperphenylalaninemia in Pregnant Rats

Abstract Sprague-Dawley rats were given L-phenylalanine intraperitoneally from the 8th to 11th day of pregnancy. The hearts of the fetuses were examined on the 21st day of pregnancy. We found that the group given the higher doses of L-phenylalanine had significantly more heart defects than the group given the lower dose and the controls. Ventricular septal defect was found in 80 % of the fetuses with congenital deformities of the heart. [¹⁴C] Leucine uptake by the embryos was significantly lower in the group loaded with L-phenylalanine than in the controls.
The activity of thymidine kinase, one of the rate-limiting enzymes in DNA synthesis, was significantly lower in the brain and heart tissues of the young rats loaded with L-phenylalanine than in the controls.
Thus, when blood levels of phenylalanine are high in early pregnancy, an amino acid imbalance in the embryo occurs during fetal organogenesis. Also, thymidine kinase decreases, which may hinder DNA synthesis. Both of these mechanisms seem to be involved in the higher incidence of fetal heart malformations in maternal phenylketonuria.