In 1998, the Nobel Prize for Physiology and Medicine was awarded to three US pharmacologists studying the roles of nitric oxide in organisms. Nitric oxide and its metabolites such as peroxynitrite and nitric dioxide cause DNA damage and protein modifications. In addition, nitric oxide induces p53 accumulation. As part of a feedback loop, p53 mediates transcriptional transrepression of inducible nitric oxide synthase. Recent studies have suggested the interactive effects of nitric oxide and p53 on cellular sensitivity against cancer therapeutic agents. This review summarizes current knowledge of the roles of nitric oxide in cellular response to cancer therapeutic agents, in particular heat shock (hyperthermia) and the involvement of the p53 gene status in this regard.

View full abstract

We have performed interdisciplinary treatment consisting an operation, intraoperative irradiation (IOR), RF-Hyperthermia (RF-HT), and chemotherapy for patients with locally advanced pancreatic cancer. When a higher intra-tumor temperature was achieved during RF hyperthermia, a better tumor response was obtained. We could control the local disease and prolong the survival period of patients with locally unresectable pancreatic carcinomas. Heating by sufficient power of at least 1000W by Thermotron RF-8, and evaluating the treatment by monitoring the tumor temperature during treatment are important when heating pancreatic tumors successfully. Some means we contrived such as tumor exposure just below the abdominal wall by a by-pass operation, reduction of the subcutaneous fatty layer, chilling the body surface with use of crushed ice, anesthesia during the treatment were important for improving the efficiency and safety of this hyperthermia-centered multimodal treatment.

View full abstract

We demonstrated the effectiveness of inducible expression of the TNF-α gene. The TNF-α gene located under the heat-inducible promoter, gadd 153, was introduced into the human glioma cell line, U251-SP. Without heat treatment, no cytotoxicity for the transfected cells was observed. When the transfected cells were treated with hyperthermia at 43°C for 1 h or 45°C for 1 h, inducible expression of the TNF-α gene was observed. The pattern of enhancement of the gene expression varied with temperature. The TNF-α production per cell on treatment at 43°C reached 4.3 times the basal level at one day after the heat treatment while the maximum production on treatment at 45°C was observed at 4 days after the heating. The cytotoxicity of the transfected cells treated at 43°C and at 45°C was 81% at 3 days after the heating and 99.9% at 4 days after the heating, respectively.

View full abstract

Hyperthermia (HT) cancer treatments have been widely utilised, however, cancer cells develop thermotolerance following exposure to HT, and heat shock proteins (HSPs) are responsible for thermotolerance. A plant flavonoid, quercetin (QCT), has been reported to inhibit heat dependent expression of HSPs. In this study, therefore, the effects of prior exposure to QCT followed by HT on the cytotoxic and apoptotic activities were evaluated in FM3A, mouse breast cancer cells. Treatment of FM3A cells to 10 μM QCT and hyperthermia at 43°C for 1 h (HT) suppressed cell proliferation only in 34% and 55%, respectively and were relatively ineffective. Combination of the two treatments (QCT+HT) synergistically inhibited cell proliferation (90% inhibition). QCT+HT also suppressed clonogenicity (80%), compared to the results of QCT (56%) and HT (41%). Apoptotic cell death occurred after each treatment in a time-dependent manner. There was 4.9 ± 0.7%, 9.6 ± 1.5% and 18.1 ± 4.3% apoptosis after QCT+HT, and 3.2 ± 0.2%, 4.6 ± 0.5% and 8.6 ± 2.8% apoptosis after QCT, 3.4 ± 0.1%, 5.1 ± 0.3% and 10.1 ± 3.1% apoptosis after HT 1, 6 and 24 h post exposure compared to control of 2.0 ± 0.1%. HT or QCT proved ineffective in suppressing cell proliferation or inducing apoptosis. QCT+HT induced an accumulation of cells in G₂/M and S phases and a reduction in G₀/G₁phase. The increased FM3A cell killing by HT after prior exposure to QCT is probably due to suppressed HSPs expression and diminished cellular thermotolerance. QCT may play a useful adjunct role in the hyperthermic treatment of resistant tumor.

View full abstract

The effects of the p53 gene on synchronization of the cell phase with hydroxyurea (HU) and on cellular thermosensitivity in each cell phase were investigated using the murine transfectants with either wild-type p53 (wtp53) or mutatedp53 (mp53), or those with a p53-deficient genotype. The p53-deficient and the wtp53 cells were well synchronized in the early S phase by HU. A much lower quality of synchronization was obtained in the transfectants with mp53 than either those with a p53 -deficient or with wtp53. Cells in the S phase were the most thermosensitive among all the cell phases irrespective of the p53 status of the cells. However, among the cells bearing different status of p53 gene, there were differences in the cellular thermosensitivity in each phase. The cellular thermosensitivity was higher in the order of the wtp53, p53 -deficient and the mp53 cells in all cell phases. The p53 gene is therefore at least one of the factors to determine cellular thermosensitivity.

View full abstract