[A case of multiple liver metastases of sigmoid colon cancer responding well to UFT+Leucovorin therapy].

The subject was a 75-year-old female. For the treatment of multiple liver metastases from sigmoid colon cancer, the administration of UFT(300 mg/day)and oral Leucovorin(75 mg/day)was initiated after a resection of the sigmoid colon. A decrease in the liver metastases was observed in a CT scan 4 months after the start of this administration, and the disappearance of the metastatic focus in the liver was confirmed at 10 months thereafter. The administration of UFT and oral Leucovorin was continued for 2 months. Thereafter, at 12 months after the start of this administration, was continued with only the administration of UFT(300 mg/day)for 1 year. Now, 26 months have passed since the liver metastases disappeared and no recurrence has been found, even within the abdominal cavity. The condition of the patient has been excellent. The subject of this study was an elderly person, but an excellent QOL was secured without any adverse events, and the chemotherapy regimen could be maintained for 2 years. These findings suggest that UFT and oral Leucovorin can be expected to have an excellent therapeutic effect as an oral chemotherapeutic agent.

[Evaluation of hepatic artery infusion chemotherapy for liver metastasis of colorectal cancer using a side-hole catheter].

In our department forty cases of hepatic artery infusion chemotherapy using a side-hole catheter were analyzed with liver metastasis of colorectal cancer from December 2000 to December 2003. This easily placed catheter is able to inject the agent effectively from the side hole. The efficacy of high dose 5-FU (1,000 mg/m2/week) of hepatic artery injected chemotherapy was evaluated. The catheter was inserted from femoral or the left subclavian artery, and the side hole positioned at the base of proper hepatic artery or common hepatic artery. This method resulted in catheter trouble only 18% of the time. As for arterial infusion chemotherapy, system management and an evaluation of the drug distribution is essential. The one-year survival rate was 71.9%, the 50% survival time was 23.4 months, and the response rate was 71%. In conclusion, this therapy was effective and useful for hepatic metastasis.

Evidence that activation of nuclear factor-kappaB is essential for the cytotoxic effects of doxorubicin and its analogues.

Several reports within the last 5 years have suggested that nuclear factor (NF)-kappaB activation suppresses apoptosis through expression of anti-apoptotic genes. In the present report, we provide evidence from four independent lines that NF-kappaB activation is required for the cytotoxic effects of doxorubicin. We used doxorubicin and its structural analogues WP631 and WP744, to demonstrate that anthracyclines activate NF-kappaB, and this activation is essential for apoptosis in myeloid (KBM-5) and lymphoid (Jurkat) cells. All three anthracyclines had cytotoxic effects against KBM-5 cells; analogue WP744, was most potent, with an IC(50) of 0.5 microM, and doxorubicin was least active, with an IC(50) of 2 microM. We observed maximum NF-kappaB activation at 1 microM with WP744 and at 50 microM with doxorubicin and WP631, and this activation correlated with the IkappaBalpha degradation. Because the anthracycline analogue (WP744), most active as a cytotoxic agent, was also most active in inducing NF-kappaB activation and the latter preceded the cytotoxic effects, suggests that NF-kappaB activation may mediate cytotoxicity. Second, receptor-interacting protein-deficient cells, which did not respond to doxorubicin-induced NF-kappaB activation, were also protected from the cytotoxic effects of all the three anthracyclines. Third, suppression of NF-kappaB activation by pyrrolidine dithiocarbamate, also suppressed the cytotoxic effects of anthracyclines. Fourth, suppression of NF-kappaB activation by NEMO-binding domain peptide, also suppressed the cytotoxic effects of the drug. Overall our results clearly demonstrate that NF-kappaB activation and IkappaBalpha degradation are early events activated by doxorubicin and its analogues and that they play a critical pro-apoptotic role.

Piceatannol inhibits TNF-induced NF-kappaB activation and NF-kappaB-mediated gene expression through suppression of IkappaBalpha kinase and p65 phosphorylation.

Piceatannol is an anti-inflammatory, immunomodulatory, and anti-proliferative stilbene that has been shown to interfere with the cytokine signaling pathway. Previously, we have shown that resveratrol suppresses the activation of the nuclear transcription factor NF-kappaB. Piceatannol, previously reported as a selective inhibitor of protein tyrosine kinase Syk, is structurally homologous to resveratrol. Whether piceatannol can also suppress NF-kappaB activation was investigated. The treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-kappaB. In contrast, stilbene or rhaponticin (another analog of piceatannol) had no effect, suggesting the critical role of hydroxyl groups. The effect of piceatannol was not restricted to myeloid cells, as TNF-induced NF-kappaB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-kappaB activated by H(2)O(2), PMA, LPS, okadaic acid, and ceramide. Piceatannol abrogated the expression of TNF-induced NF-kappaB-dependent reporter gene and of matrix metalloprotease-9, cyclooxygenase-2, and cyclin D1. When examined for the mechanism, we found that piceatannol inhibited TNF-induced IkappaBalpha phosphorylation, p65 phosphorylation, p65 nuclear translocation, and IkappaBalpha kinase activation, but had no significant effect on IkappaBalpha degradation. Piceatannol inhibited NF-kappaB in cells with deleted Syk, indicating the lack of involvement of this kinase. Overall, our results clearly demonstrate that hydroxyl groups of stilbenes are critical and that piceatannol, a tetrahydroxystilbene, suppresses NF-kappaB activation induced by various inflammatory agents through inhibition of IkappaBalpha kinase and p65 phosphorylation.

The role of TNF and its family members in inflammation and cancer: lessons from gene deletion.

Almost two decades ago, tumor necrosis factor (TNF) was identified as a protein produced by the immune system that played a major role in suppression of tumor cell proliferation. Extensive research since then has revealed that TNF is a major mediator of inflammation, viral replication, tumor metastasis, transplant rejection, rheumatoid arthritis, and septic shock. As of today, 18 different members of the TNF superfamily have been identified, and most of them have been found to mediate a wide variety of diseases including cancer, arthritis, bone resorption, allergy, diabetes, atherosclerosis, myocardial infarction, graft versus host disease, and acquired immune deficiency disease. All the cytokines of the TNF superfamily mediate their effects through the activation of the transcription factor NF-kappaB, c-Jun N-terminal kinase, apoptosis, and proliferation. Thus, agents that can either suppress the production of these cytokines or block their action have therapeutic value for a wide variety of diseases. In this review, we have elucidated the signal transduction pathways used by the members of the TNF family and the effects of deletion of genes that mediate the pathways. Our current understanding of the signaling pathways for TNF and other family members could serve as a target for the development of therapeutics.