[Efficacy of combined local therapy especially with hepatic arterial infusion for liver metastasis from gastric cancer].

Herein, we report four cases of a single liver metastasis after gastric cancer resection. Initially, we chose to perform hepatic arterial infusion( HAI) with high-dose 5-fluorouracil( 5-FU)( 6,000 mg/week) or weekly 500-750 mg of 5-FU. Three patients showed a partial response (PR) and one patient showed no change (NC). Therefore, we performed hepatectomy or radiofrequency ablation( RFA) 300-350 days after HAI. All four patients received postoperative HAI. Two patients survived without recurrence for 12 and 21 months. One patient developed prostate cancer but survived for 22 months as an outpatient. Finally, one patient experienced recurrence in the residual liver, but at a site not supplied by the hepatic artery. This patient survived for 36 months as an outpatient. In conclusion, HAI, liver resection, and RFA are effective in the management of single liver metastasis from gastric cancer.

[Combination therapy for inoperable cholangiocellular carcinoma-systemic chemotherapy and hepatic arterial injection].

We report the case of a 52-year-old woman with cholangiocellular carcinoma (CCC) involving the lymph node and lung metastases who was admitted to our hospital because of right abdominal pain and anorexia. We started systemic chemotherapy(SCT) comprising 5-fluorouracil(5-FU; 1 g) and gemcitabine(GEM; 1 g) biweekly. After 1 course of SCT, we treated her with high-dose hepatic arterial injection (6 g 5-FU/1 week). This chemotherapy regimen improved her symptoms. After placing an arterial port into the right femoral artery, we continued SCT comprising GEM biweekly and hepatic arterial injection(HAI) of 5-FU weekly. Finally, we opted for weekly HAI and simultaneous SCT of 5-FU and GEM biweekly. The SCT dose of 5-FU was 1,000 mg and the dose of GEM ranged from 800 to 1,000 mg. For HAI, the dose of 5-FU was changed to between 250 and 750 mg. Lymph node metastases disappeared and lung metastases were reduced by this treatment. Because the lung metastases had progressed after 10 months, we increased the SCT dose of 5-FU to 1,500 mg and the dose of GEM to 1,200 mg. We also added systemic mitomycin C and prolonged the injection time of systemic 5-FU from 3 hours to 3 days. The lung metastases were reduced by this treatment. Our patient is still alive and has worked for more than 1 year. We recommend combination therapy of SCT and HAI for CCC with metastases.

A new APE1/Ref-1-dependent pathway leading to reduction of NF-kappaB and AP-1, and activation of their DNA-binding activity.

APE1/Ref-1 is thought to be a multifunctional protein involved in reduction-oxidation (redox) regulation and base excision DNA repair, and is required for early embryonic development in mice. APE1/Ref-1 has redox activity and AP endonuclease activity, and is able to enhance DNA-binding activity of several transcription factors, including NF-kappaB, AP-1 and p53, through reduction of their critical cysteine residues. However, it remains elusive exactly how APE1/Ref-1 carries out its essential functions in vivo. Here, we show that APE1/Ref-1 not only reduces target transcription factors directly but also facilitates their reduction by other reducing molecules such as glutathione or thioredoxin. The new activity of APE1/Ref-1, termed redox chaperone activity, is exerted at concentration significantly lower than that required for its redox activity and is neither dependent on its redox activity nor on its AP endonuclease activity. We also show evidence that redox chaperone activity of APE1/Ref-1 is critical to NF-kappaB-mediated gene expression in human cells and is mediated through its physical association with target transcription factors. Thus, APE1/Ref-1 may play multiple roles in an antioxidative stress response pathway through its different biochemical activities. These findings also provide new insight into the mechanism of intracellular redox regulation.

Porphyrin accumulation in mitochondria is mediated by 2-oxoglutarate carrier.

Heme (Fe-protoporphyrin IX), an endogenous porphyrin derivative, is an essential molecule in living aerobic organisms and plays a role in a variety of physiological processes such as oxygen transport, respiration, and signal transduction. For the biosynthesis of heme or the mitochondrial heme proteins, heme or its biosynthetic precursor porphyrin must be transported into mitochondria from cytosol. The mechanism of porphyrin accumulation in the mitochondrial inner membrane is unclear. In the present study, we analyzed the mechanism of mitochondrial translocation of porphyrin derivatives. We showed that palladium meso-tetra(4-carboxyphenyl)porphyrin (PdTCPP), a phosphorescent porphyrin derivative, accumulated in the mitochondria of several cell lines. Using affinity latex beads, we showed that 2-oxoglutarate carrier (OGC), the mitochondrial transporter of 2-oxoglutarate, bound to PdTCPP, and in vitro PdTCPP inhibited 2-oxoglutarate uptake into mitochondria in a competitive manner (Ki = 15 microM). Interestingly, all types of porphyrin derivatives examined in this study competitively inhibited 2-oxoglutarate uptake into mitochondria, including protoporphyrin IX, coproporphyrin III, and hemin. Furthermore, mitochondrial accumulation of porphyrins was inhibited by 2-oxoglutarate or OGC inhibitor. These results suggested that porphyrin accumulation in mitochondria is mediated by OGC and that porphyrins are able to competitively inhibit 2-oxoglutarate uptake into mitochondria. This is the first report of a putative mechanism for accumulation of porphyrins in the mitochondrial inner membrane.

Redox regulation of NF-kappaB activation: distinct redox regulation between the cytoplasm and the nucleus.

Reduction/oxidation (redox) regulation mediates numerous cellular responses and contributes to several physiological diseases. The transcription factor nuclear factor kappaB (NF-kappaB) is known to be a redox-sensitive factor. NF-kappaB plays a central role in immune responses and inflammation, through regulation of the gene expression of a large number of cytokines and other immune response genes. NF-kappaB is trapped in the cytoplasm in stimulated cells and translocates into the nucleus in response to several stimuli, including oxidative stress. Reactive oxygen species enhance the signal transduction pathways for NF-kappaB activation in the cytoplasm and translocation into the nucleus. In contrast, the DNA binding activity of oxidized NF-kappaB is significantly diminished, and that activity is restored by reducing enzymes, such as thioredoxin or redox factor 1. This review describes the signal transduction pathways for NF-kappaB activation and redox regulation of NF-kB activation in the cytoplasm and nucleus.