Many malignant tumors including non-small cell lung cancer (NSCLC) express or over-express EGFR that have shown correlations with rapid growth, metastases, resistance to conventional chemotherapy or radiotherapy, and poor prognosis. Gefitinib is a potent and selective inhibitor of EGFR tyrosine kinase (EGFRTK). Gefitinib specifically inhibited EGF-stimulated cell proliferation in vitro and it also exhibited a broad anti-tumor spectrum against NSCLC, prostate, colorectal, and ovarian cancers in vivo. Gefitinib showed dose-dependent and reversible reduction of c-fos mRNA level and decreased Ki67 significantly in tumors in vivo. In in vitro studies, gefitinib arrested the cell cycle at G1 phase by inducing intrinsic cyclin-dependent kinase (cdk) inhibitors and following inhibition of cdk2. Apoptosis was also seen in gefitinib-treated tumor cells and skin biopsy samples from clinical study. Gefitinib inhibited VEGF production in tumor cells through inhibition of EGFR signaling, leading to suppression of angiogenesis. In clinical studies, gefitinib demonstrated therapeutic benefit in patients who failed conventional chemotherapy. No correlation has been established between the anti-tumor activity of gefitinib and EGFR expression level, whilst sensitivity factors to gefitinib are yet to be elucidated. Identification of sensitivity factors will be a key for effective use of EGFRTK inhibitors including gefitinib for cancer treatment.

The Philadelphia chromosome found in leukemia cells of chronic myelogenous leukemia (CML) patients is produced by translocation between chromosomes 9 and 22, resulting in expression of a chimera protein of Bcr and Abl kinase in the cytoplasm. Bcr-Abl kinase attracted oncology researchers as a molecular target for CML therapy, and a variety of small Abl kinase inhibitors were synthesized. STI571 (imatinib mesylate) was produced by modification of 2-phenylaminopyrimidine, a core structure of protein kinase C inhibitor, to improve selectivity, stability, solubility, and bioavailability. STI571 competitively binds to the ATP binding site of Bcr-Abl kinase and inhibits Abl tyrosine kinase activity. STI571 showed significant efficacy in the clinical study with CML patients at all stages: chronic phase, accelerated phase, and blast crisis. More than 90% of the patients showed good hematologic response to STI571. STI571 is also a potent inhibitor of a receptor-type c-Kit tyrosine kinase. Therefore, STI571 was examined for therapeutic efficacy against malignant Gastro-Intestinal Stromal Tumors (GIST), which are mainly caused by aberrant expression of a mutated c-Kit that is constitutively active without binding of a ligand, stem cell factor (SCF). More than a half of the metastatic GIST patients enrolled in the clinical study responded to STI571. Thus, STI571 is now used as a therapeutic drug for both CML and GIST in more than 80 countries worldwide. Certain point mutations in the ATP binding site were found to be a cause of resistance to STI571 in both Bcr-Abl and c-Kit kinases. Therefore, it would be better to make a precise therapeutic strategy with STI571 based on the gene analysis data. It is also expected that it will be possible to design an inhibitor to overcome such resistance by using the structural information on the mutants.

Tyrosine kinase (TK) plays an important role in a variety of biological circumstances including growth, apoptosis, differentiation, immune system, angiogenesis, development, and so forth. Some inhibitors for TK have been successful in clinical applications in malignant disorders. Due to its physiological participation in cells exposed to many stimuli and to structural homology of high degree, true molecular targeting requires complete understanding of signal transduction pathways in all of the cells in which the targeted TK is involved.

The relation between p53 expression of human colon cancer cell lines and induction of apoptosis by anticancer drugs was examined experimentally. HCT116 had wild-type p53 expression and 5-fluorouracil (5-FU) in combination with cisplatinum (CDDP) increased both Sub G1 DNA content and the proportion of apoptotic cells. However, solitary administration of these drugs altered neither. Alternatively, for SW480 with mutant-type p53 expression, both combined administration and solitary administration of anticancer drugs showed minimal effect on Sub G1 DNA content and proportion of apoptotic cells. These results indicate that the type of p53 expression might play an important role in the determination of response to low-dose CDDP + 5-FU therapy in colon cancer patients.

We investigated the effect of PSK on Th1/Th2 balance in tumor-bearing mice. PSK was intraperitoneally administered to Meth A-bearing BALB/c mice, and PSK caused regression of the Meth A tumor. The results of Winn assay suggested that the effect of PSK was dependent on CD4+T cells. Furthermore, spleen cells were cultured with mitomycin C-treated Meth A, after which the cytokine concentration was measured by ELISA. IFN-gamma production was increased and IL-4 showed almost no change in PSK-administered mice. In another experiment, PSK was orally administered to colon 26-bearing mice in which tumors were inoculated into the subserosal space of the cecum. Mesenteric lymph nodes cells were cultured with mitomycin C-treated colon 26 cells. IFN-gamma production was increased, but not so much as to be statistically significant, and IL-4 was significantly decreased in PSK-administered mice. PSK increased IFN-gamma and IL-12 p70 production and decreased IL-4 production when spleen cells were stimulated with Con A together with PSK in vitro. As suggested from these results, PSK might induce cytokine production that works for Th1 differentiation, and suppress cytokine production that works for Th2 differentiation, and shift the Th1/Th2 balance toward Th1 dominance in tumor-bearing mice.

The effects on esophageal cancer of monoclonal antibody trastuzumab, directed against the HER2 protein, were evaluated in this study. Immunohistochemical study showed that 90% (45/50) of esophageal cancer specimens expressed HER2 protein, and flow cytometric analysis showed that 4 kinds of human esophageal cancer cells (TT, TE2, TE6, TE10) expressed high levels of HER2 protein. Trastuzumab treatment (100-500 ng/ml) was not able to inhibit the growth of the all kinds of cancer cells, but the combination treatment of trastuzumab and peripheral mononuclear cells resulted in antibody dependent cell-mediated cytotoxicity (ADCC) against the cancer cells TE6 and TE10 in a dose dependent manner. Intraperitoneal injection of trastuzumab at 1 mg/body twice a week for 5 weeks significantly inhibited the growth of mice-bearing xenografts of TE6 and TE10. Our results suggest that trastuzumab therapy is useful in the treatment of human esophageal cancer.

A 65-year-old male underwent iliocecal excision and hepatic posterior segmentectomy for cecum cancer and synchronous liver hepatic metastasis in September and October 2001, respectively. A reservoir was implanted by the GDA-coil method from the right femoral artery in November, and WHF (5-FU 1,000 mg/m2) was administered 8 times. Because of the remnant liver recurrence, WHF was restarted in April 2002. Left leg paralysis appeared suddenly after the 3rd administration. Heparin and urokinase were administrated continuously after hospitalization. Also, liver function tests showed a worsening condition. The bile duct necrosis in the liver was examined with abdominal CT scan. The anti-coagulation therapy was changed to an oral drug on the 7th day after hospitalization. The liver function tests normalized gradually. Although the rehabilitation for leg paralysis performed during hospitalization was continued after discharge from the hospital, the patient is unable to walk and uses a wheelchair. Hepatic arterial infusion chemotherapy is considered safe for blood and non-blood toxicity compared with systemic chemotherapy. However, there are also complications as in this case, where QOL is reduced remarkably, and caution is required.

The patient was a 74-year-old woman with gastric cancer with multiple liver metastasis. She was treated with daily oral administration of TS-1 100 mg/day (day 1-21) and systemic administration of CDDP 90 mg (day 8) as neoadjuvant chemotherapy for 2 courses. As metastatic lesions became smaller, we performed distal gastrectomy. TS-1 was started for the residual cancer lesion. However, liver metastatic lesions increased in size, so we carried out intraarterial chemotherapy (IAC), Nausea appeared at 9 days, pancytopenia at 28 days and ARDS at 78 days after IAC. She died due to ARDS.

Hepatic artery infusion chemotherapy (HAI) using 5-FU is a good method of treating patients with liver metastases from colorectal cancer. We investigated the toxicity and the response in relation to the concentration of 5-FU after HAI, and examined various factors that would have an effect on the 5-FU concentration.

Two cases of radiation myositis following gemcitabine-based chemotherapy for advanced non-small cell lung cancer are presented. In the two cases, myositis appeared 3 and 5.5 months after the completion of radiation therapy and 2 and 2.5 months after the beginning of chemotherapy, respectively. The affected areas, the upper back and right thigh, appeared as areas of increased signal intensity on T2-weighted MR imaging and were enhanced by the administration of Gd-DTPA in the skeletal muscles. These coincided with the previously irradiated area. Although radiation myositis is a rare complication, it is important to be careful of radiation recall induced by chemotherapeutic agents.

We measured paclitaxel (PTX) concentrations in blood and ascites in a patient with advanced gastric cancer treated with weekly paclitaxel (80 mg/m2). After 180 minutes from infusion of PTX, the concentration of PTX in ascites was 13 ng/ml, which was more than the reported cytotoxic dose of PTX (8.5 ng/ml). The concentration of PTX in ascites was retained, and rose rather slowly during a 24-hour period. The patient died soon after the measurement, meaning this measurement was taken at a time when the antitumor effect was ineffective and under poor general conditions. The result suggested, however, that the desired concentration of PTX in ascites can be obtained with a smaller dose of PTX in a regimen of weekly PTX.

The patients were a 57-year-old and a 38-year-old woman who had supraclavicular lymph node and multiple lung metastases from breast cancer. They were given 3 and 4 courses of paclitaxel (TXL) weekly therapy (80 mg/m2, day 1, 8, 15, repeated every 4 weeks). One patient had received docetaxel (TXT) and CEF therapy previously. There were no severe adverse effects except leukopenia, neutropenia and alopecia. The weekly TXL therapy brought complete remission against the supraclavicular lymph node and multiple lung metastases. The durations of the response to this weekly therapy were 15 and 5 months, respectively, and their effects have continued to the present. We believe that the weekly TXL therapy is a well-tolerated, feasible and safe administration schedule on an outpatient basis, and improves the patient's quality of life. Furthermore, we suggest the possibility of TXL being effective against both TXT and anthracycline-resistant breast cancer.

Irinotecan hydrochloride has been administered to patients with breast cancer resistant to anthracyclines and/or taxanes in our department. A retrospective analysis of the efficacy and toxicity of irinotecan therapy was conducted to clarify its clinical usefulness. A total of 35 consecutive patients with advanced or recurrent breast cancer were treated with irinotecan between June 1996 and March 2002. The patients ranged in age from 37 to 66 years old (median, 52). The most frequent metastatic lesion was in the liver. The number of previous chemotherapy was 2 to 7 regimens (median, 3). Ninety-one percent and 97% of the tumors were anthracycline- and taxane-resistant, respectively. The weekly dose of irinotecan was 40-160 mg/body (median, 100), and the total dose was 40-6, 110 mg/body (median, 840). An objective response rate of 6% and a clinical benefit rate of 23% were obtained. The median time-to-progression and overall survival were 3 months and 8 months, respectively. Severe toxicity (grade 3 or 4) was observed in 34% of the patients for a decrease in the white blood count, in 26% for neutropenia, in 17% for nausea/vomiting and in 6% for diarrhea. Although this study suggests that irinotecan is a clinically useful treatment of anthracycline- and/or taxane-resistant breast cancer, its anti-tumor effect was not satisfactory. The activity of first-line irinotecan therapy or the combined use of irinotecan with other agents should be investigated in clinical studies.

Anthracycline antibiotics, including adriamycin (ADM), are widely used to treat various human cancers, but their clinical use has been limited because of their cardiotoxicity. ADM is especially toxic to heart tissue. The mechanisms responsible for the cardiotoxic effect of ADM have been very/extremely controversial. This review focuses on the participation of free radicals generated by ADM in the cardiotoxic effect. ADM is reduced to a semiquinone radical species by microsomal NADPH-P450 reductase and mitochondrial NADH dehydrogenase. In the presence of oxygen, the reductive semiquinone radical species produces superoxide and hydroxyl radicals. Generally, lipid peroxidation proceeds by mediating the redox of iron. ADM extracts iron from ferritin to form ADM-Fe3+, which causes lipid peroxidation of membranes. These events may lead to disturbance of the membrane structure and dysfunction of mitochondria. However, superoxide dismutase and hydroxyl radical scavengers have little effect on lipid peroxidation induced by ADM-Fe3+. Alternatively, ADM is oxidatively activated by peroxidases to convert to an oxidative semiquinone radical, which participates in inactivation of mitochondrial enzymes or including succinate dehydrogenase and creatine kinase. Here, we discuss the activation of ADM and the role of reductive and oxidative ADM semiquinone radicals in the cardiotoxic effect of this antibiotic.

A 6-year-old girl with chronic myeloid leukemia (CML) was treated with imatinib 230 mg/m2/day and its pharmacokinetics were investigated. The patient had a complete hematologic response on day 21, but had a minor cytogenetic response and the CML progressed to a blast crisis on day 133. At present, she has maintained complete cytogenetic remission with allogenetic peripheral blood stem cell transplantation. The pharmacokinetics revealed that the maximum concentration (1.4 micrograms/ml); time to maximum concentration (5.1 h); half-life (11.0 h); trough concentration (0.4 microgram/ml); and, area under the concentration-time curve (28.1 micrograms.h/ml) were inferior to those for adult patients in the 400 mg/day group. This observation suggests that a suboptimal plasma concentration might be related to resistance to imatinib and/or blast crisis.

There are few clinical investigations on the hot flushes that develop during endocrine therapy for prostate cancer in Japan, although there are many reports in the Western countries. Therefore, we evaluated the incidence of hot flushes and the association between hot flushes and clinical characteristics of prostate cancer patients receiving endocrine therapy.

Most anticancer agents frequently cause mucositis, such as stomatitis and gastrointestinal mucosal injury, which is closely associated with decrease in quality of life, infections and discontinuation of chemotherapy in patients with malignancy. We retrospectively evaluated the preventive effect of oral administration of oren-gedoku-to on stomatitis and diarrhea induced by cytotoxic drugs in 40 patients with acute leukemia. Incidence of stomatitis was 27.9% in the group given oren-gedoku-to, which was significantly lower compared with 71.6% in those who received a gargle consisting of allopurinol, sodium gualenate, and povidone-iodine. Drug-induced diarrhea was observed in 9.3% of the oren-gedoku-to group compared with 31.7% of the control group. These observations indicate a significant preventive effect of oren-gedoku-to on mucositis caused by anticancer agents.