Despite the improvement in the operative results for patients with gastric cancer, the prognosis of those with liver metastasis remains dismal. Multimodal therapy has attracted considerable attention as a breakthrough in the strategy for treating cases of highly advanced gastric cancer. We report the case of a 62-year-old female with gastric cancer accompanied by multiple liver metastases successfully treated by TS-1, a novel oral fluoropyrimidine derivative. One treatment course consisted of 4 weeks of TS-1 administration (100 mg daily) followed by a 2-week break. After 3 courses of treatment, an abdominal CT scan showed no evidence of liver metastases and gastroscopy revealed that the primary gastric lesion was reduced. Grade 1 toxicity (nausea and diarrhea) was seen but 6 days rest improved the condition. Distal gastrectomy was subsequently performed without any finding of residual tumor. TS-1 may have a promising role in neoadjuvant chemotherapy for gastric cancer.

Toremifene is an anti-estrogenic drug like tamoxifen. We assessed the body distributions after administration of toremifene and tamoxifen in order to evaluate their treatment regimens by measuring the concentrations in tissues. It is known that, after toremifene (TOR) or tamoxifen (TAM) is consecutively administered to breast cancer patients, TOR or TAM and their main active N-desmethyl-metabolites (TOR-1 or TAM-1) are detected in sera, tumor tissues, and lymph nodes. Accordingly, after we administered toremifene or tamoxifen to primary breast cancer patients previous to surgery, we measured the concentrations of TOR, TOR-1, TAM, TAM-1 in sera, tumor tissues, and lymph nodes. We found that the concentrations of TOR and TOR-1 in sera, tumors, and lymph nodes reached a peak about 2 weeks after administration of toremifene 40 mg. Likewise, the concentrations of TAM and TAM-1 in sera, tumors, and lymph nodes reached a peak about 2 weeks after administration of tamoxifen, although the peak levels were lower than those of TOR or TOR-1. The concentrations of TAM-1 in lymph nodes were significantly and positively correlated to the duration of administration of TAM, and it was predicted that the concentration of TAM-1 in lymph nodes would reach a steady state at more than 4 weeks after administration of tamoxifen. The concentrations of TOR and TOR-1 were higher in tumors and lymph nodes than in sera. Furthermore, the concentrations of TOR and TOR-1 were significantly higher than those of TAM and TAM-1 in sera and tumors, respectively. Moreover, the concentration in tissue increased in a dose-dependent manner with administration of toremifene 120 mg. There were no significant differences between breast cancers positive and negative for estrogen receptors, with regard to the concentrations of TOR and TOR-1 in either sera, tumors, or lymph nodes. In conclusion, it would be expected that treatment with toremifene might be more effective for breast cancer than that with tamoxifen.

Although the pathogeneses of interstitial pneumonia are not well understood, it has been reported that inflammatory cells, especially neutrophils, and their injurious substances play important roles in the progression of interstitial pneumonia. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to inhibit chronic airway inflammation by mechanisms of anti-neutrophil and several other anti-inflammatory activities. The present study was undertaken to investigate the effects and mechanisms of 14-MRMLs (erythromycin: EM; clarithromycin: CAM; roxithromycin: RXM) on an experimental model of bleomycin (BLM) -induced acute lung injury in mice.

The HER 2/neu protein is thought to be a unique and useful molecular target for antibody therapy of cancers overexpressing the HER 2/neu gene. The recombinant humanized anti-HER 2 monoclonal antibody trastuzumab (Herceptin) has been available for clinical use in metastatic breast cancer in Japan since June 2001. Some breast cancer patients have responded to trastuzumab alone. A phase III study showed significant efficacy of combination use with paclitaxel compared with paclitaxel alone. Trastuzumab has some toxicities including infusion reaction and cardiotoxicity. It is very rare that infusion reaction manifests lethally. Although trastuzumab should not be concurrently used with an anthracycline, cardiotoxicity was also identified in patients treated with trastuzumab alone. The cumulative dose of anthracycline has not yet been identified as a risk factor, but patients who have received a high cumulative dose should be treated with special caution. In this article, the details of this novel biologic agent are reviewed from basic and clinical studies.

A 36-year-old woman was referred to our hospital because of a right breast lump. Chest computed tomography revealed pulmonary metastases with lymphangitis carcinomatosa. Additional examination revealed liver metastases and axillary and cervical lymph node metastases. The patient was started on CA therapy (cyclophosphamide 900 mg, adriamycin 90 mg). A minor response was observed in the pulmonary metastases after two courses but new brain metastases were detected. We then tried paclitaxel administration (260 mg). A partial response was observed in the brain and pulmonary metastases. Thus, paclitaxel administration was continued on a weekly basis (120 mg) and the brain and pulmonary metastases continued to diminish. The primary breast cancer, liver metastases and axillary and cervical lymph node metastases were disappeared. Whole brain radiation was done with weekly paclitaxel administration and the brain metastases were diminished even more. Paclitaxel is as a radiosensitizer and seems to have a strong antineoplastic effect with concurrent radiation.

Myalgia/arthralgia is a crucial side effect of paclitaxel, and may become the major dose-limiting side effect. However, this is a situation where there is little effective preventive treatment. L-Glutamine was reported as a neuroprotective agent for vincristine-induced neurotoxicity. In Japan, there have been reports on steroid and Shakuyaku-Kanzou-to (a herbal medicine) for paclitaxel-induced myalgia/arthralgia. This study aimed to compare the effect of L-Glutamine and Shakuyaku-Kanzou-to, and to discuss the validity of these agents for the paclitaxel-induced myalgia/arthralgia. Our results suggested that Shakuyaku-Kanzou-to showed no remarkable effects against paclitaxel-induced myalgia/arthralgia as had been reported before; however, both L-Glutamine and Shakuyaku-Kanzou-to decreased the duration of grade 2 toxicity (CALGB Expanded Common Toxicity Criteria) in comparison with those who were not treated. L-Glutamine and Shakuyaku-Kanzou-to might therefore a preventive effect against moderate or severer myalgia/arthralgia during paclitaxel-treated chemotherapy. Further trials are needed to confirm the value of these drugs.

Gene expression of human ovarian carcinoma cell lines and epithelial ovarian tumors was examined by oligonucleotide microarray for about 6000 human cDNAs. (1) Comparison of gene expression between CDDP-sensitive human ovarian serous adenocarcinoma cell lines and CDDP-resistant cell lines revealed that gamma-glutamylcysteine synthetase, glutathione peroxidase-like protein, dehydrogenase (UGDH), NAD(P)H: quinoneoxireductase, glucose-6-phosphatase, ornithine decarboxylase and dihydrodiol dehydrogenase were associated with a mechanism of CDDP-resistance. Comparison of gene expression between taxol-sensitive human ovarian cell lines and taxol-resistant cell lines showed that up-regulation of 30 kinds of gene expression including MDR and semaphorin E in taxol-resistant cell lines. (2) Comparison of gene expression among serous adenocarcinomas, clear cell adenocarcinomas and non-cancerous ovarian tissues by hierarchical clustering demonstrated that clear difference between carcinomas and non-cancerous ovarian tissues but not obvious difference between serous and clear adenocarcinomas. Genes that were up- and down-regulated specifically in these two types of ovarian carcinomas were further selected by the criteria that difference in the mRNA level by more than 4-fold between tumors and non-cancerous tissues. Tissue type specific alterations of gene expression are likely to play important roles in the carcinogenesis of epithelial ovarian tumors. cDNA microarray is a powerful and high-throughput tool to analyze gene expression of cancer development.

Subacute transient cerebral dysfunction following high-dose methotrexate occurred during neo-adjuvant chemotherapy for an eighteen-year-old male with osteosarcoma in his right femur. The variety of symptoms including hemiparesis and hesitancy of speech occurred 8 days after an administration of high-dose methotrexate (10 g/m2). Evaluations including CT scan of the brain, hemogram and blood chemistry revealed no abnormal findings. The patient found it difficult to sit, speak and eat, but was not confused. He improved in a few days without any specific treatment or residual sequelae. This syndrome was transient and did not recur when he had two additional HD-MTX treatments. The cause of this syndrome remains unknown and does not seem to be predictable. It is, thus, necessary for oncologists to take due care with regard to this syndrome in HD-MTX chemotherapy.

We performed PMC-CPT-11 therapy (modified pharmacokinetic modulating chemotherapy plus irinotecan, or modified PMC) in a case of sigmoid colon cancer with local invasion and multiple hepatic metastases. This regimen combined PMC therapy which includes Hartmann's operation, simple hysterectomy and postoperative 5-fluorouracil (5-FU), with intravenous irinotecan, or CPT-11. The multiple hepatic metastatic lesions disappeared after surgery and no local recurrence has been found since. These results indicate that PMC-CPT-11 (modified PMC) therapy could be an effective regimen for cases of progressive colon cancer in the future.

In order to develop a new therapeutic intervention for pancreatic cancer, we have examined the effect of gene therapy for pancreatic disease. The transfection of the gene for UPRT, a 5-FU-converting enzyme, resulted in a significant change in the sensitivity of pancreatic cancer cells against 5-FU, resulting in the decrease of the tumor volume disseminated in the abdominal cavity of mice. Although the production levels of vascular endothelial growth factor (VEGF) in pancreatic cancer cell lines are different, anti-angiogenesis gene therapy using a soluble form of VEGF receptor (flt-1) has been demonstrated to be a promising strategy for pancreatic cancer. The transfection efficacy is the crucial point for the success of gene therapy; therefore, it is necessary to develop a vector system for solid tumors. It has been revealed that replication-competent adenoviruses are not only a strong weapon themselves, but are also useful carriers of genes possessing anti-tumor activities as virus vectors specific to tumors without normal p53 function or intact Rb pathway. Determining whether these experimental results are universally true will require clinical trials in the future.

We have previously reported that cisplatin induces caspase-9 activation in head and neck squamous cell carcinoma cells (HNSCCs) in vitro, and the use of a specific inhibitor of caspase-9 blocks cisplatin-induced apoptosis in HNSCCs. Our purpose here was to determine whether HNSCCs selected for resistance to cisplatin fail to exhibit caspase-9 activation in response to cisplatin. Cisplatin-resistant HNSCCs (CRHNSCCs) were selected for growth in the presence of cisplatin. Following cisplatin treatment, no protelyzed caspase-9 subunits were detected in the CRHNSCCs, whereas proteolytic degradation of procaspase-9 was observed in parental cisplatin-sensitive HNSCCs (CSHNSCCs). Using a direct enzymatic assay measuring cleavage of the synthetic peptide substrate (LEHD-AFC), caspase-9 activity in cisplatin-treated CRHNSCCs was less than that in cisplatin-treated CSHNSCCs. Because caspase-9 activation requires the release of mitochondorial cytochrome c (Cyt c) into the cytoplasm, we determined the level of cytoplasmic Cyt c in response to cisplatin treatment. Interestingly, following cisplatin treatment, the same extent of increase in cytoplasmic Cyt c was evident and the expression of Bcl-2 family proteins (Bcl-2 and Bcl-XL) remained unchanged in both CRHNSCCs and CSHNSCCs. These results suggest that in certain HNSCC cell types, inhibition of caspase-9 activity represents another mechanism of acquired cisplatin resistance. This inhibition mechanism may be independent of the release of Cyt c into the cytoplasm.

Research in tumor angiogenesis is making rapid progress. It was recently confirmed that tumors utilize both vasculogenesis and existing blood vessels for angiogenesis, and angiogenesis has become a molecular target of new cancer therapies. Numerous inhibitors of angiogenesis have been developed and clinical trials conducted. However, problems such as side effects and the appropriate design of clinical trials have been noted, and the development of some inhibitors has stalled. Therefore more time and study will be required before clinical application of angiogenesis inhibitors is feasible. Trials combining existing chemotherapeutic regimens with angiogenesis inhibitors is feasible. Trials combining existing chemotherapeutic regimens with angiogenesis inhibitors, i.e., antiangiogenic chemotherapy, are underway in which low-dose anticancer and antiangiogenic agents are administered daily over the long term, and the results are awaited.

Based on recent progress in cancer biology, numerous molecules that contribute to proliferation, invasion, and metastasis of cancer cells have been identified. The epidermal growth factor receptor (EGFR), a member of cell membrane receptors, is overexpressed by many tumors, and EGFR overexpression correlates with poor prognosis and disease progression. The EGFR is an attractive target for novel anticancer therapy. ZD1839 and OSI-774, highly specific EGFR tyrosine kinase inhibitors, have shown promising antitumor activity against cisplatin-resistant non-small cell lung cancer in phase I and phase II trials. IMC-C225, a monoclonal antibody against EGFR, has achieved significant disease control in head and neck cancer and colorectal cancer in combination with anticancer agents. These agents are under evaluation in phase III trials. In conclusion, it is expected that EGFR-directed therapies will soon be established as an effective novel treatment for many cancer patients.