A 49-year-old woman was diagnosed with local recurrence and cervical lymph node and bone metastases 55 months after surgery for breast cancer. She was treated with goserelin acetate and tamoxifen but the disease was assessed as progressive after 8 months. Five courses of CMF therapy were performed but lung, pleural and mediastinal lymph node metastases were detected. Then, five courses of CAF therapy were carried out, but a contralateral breast metastasis was detected and the patient complained of shortness of breath. The CAF therapy was assessed as PD. We attempted administration of doxifluridine (5'-DFUR) and mitomycin C (MMC) on an outpatient basis. After 6 months, no progressive disease was detected and she was relieved of her shortness of breath. The combination therapy was assessed as long NC. Combination therapy with 5'-DFUR and MMC is thus a useful treatment for adriamycin- and methotrexate-resistant breast cancer, especially in terms of quality of life.

Granisetron has been used widely for the prevention and treatment of nausea and vomiting associated with anticancer drugs in adult patients with cancer. This multi-center open study was conducted to study the efficacy, safety and usefulness of granisetron in children with cancer. Among 166 evaluable patients, the efficacy rate (percentage of "remarkably effective" or "effective") was 84.9% and the usefulness rate (percentage of "extremely useful" or "useful") was 87.3%. No serious adverse effects were observed. As granisetron 40 micrograms/kg had an excellent antiemetic effect and a high degree of safety against nausea and vomiting associated with anticancer drugs, it was shown to be useful for children with cancer.

A lot of anticancer agents have been isolated from natural sources, especially from microorganisms and plants. However, there is no special type of compounds for cancer therapy. Various types of substances are effective for various types of cancers and tumors: for instance, alkaloids, lignans, terpenes and steroids, etc. In this report, the authors will describe especially about higher plants.

Cisplatin (CDDP) is an effective antineoplastic agent in the treatment of solid malignant tumors. Its clinical use, however, is limited because of various side effects including sensorineural hearing loss. Several agents have been proposed to reduce these side effects. GBE has recently been reported to scavenge superoxide and hydroxyl radicals, resulting in a reduction of lipid peroxidation. GBE is expected to protect against CDDP-induced toxicity because its generative mechanism is thought to be associated with free-radical formation. The purpose of the present study was to evaluate GBE's efficacy as a protective agent against cisplatin-induced ototoxicity. Fisher rats were used in this study and were divided into three treatment groups: 1) animals administered 1.0 mg of CDDP per kg for 10 days (Group I), 2) animals receiving 100 mg of GBE per kg 90 min before administration 1.0 mg of CDDP per kg (Group II) and 3) a vehicle control (Group III). First, the protective effect of GBE on CDDP-induced ototoxicity was investigated. The auditory threshold was evaluated by means of the compound action potential (CAP) recording. After CAP recordings, cochlear sensory epithelia were observed throughout the cochlea by scanning electron microscopy. In Group II, the elevation of CAP thresholds at 12 kHz, 16 kHz, 20 kHz and the missing rate for the outer hair cells were significantly reduced as compared to those in Group I. These data suggest that GBE is effective for otoprotection against CDDP. Second, the protective effect of GBE on CDDP-induced nephrotoxicity was evaluated. Nephrotoxicity was evaluated by means of measurement of serum BUN and creatinine and histopathological examination of the kidney. These were significant differences in serum BUN and creatinine levels between Group I and Group II. Third, the influence of GBE against the antitumor effect of CDDP was researched in the rats inoculated subcutaneously with SCC-158 squamous cell carcinoma cells. There was no difference in tumor growth rate (TGR) between Group I and Group II. The result suggested that the combined administration had no influence on the antitumor activity of CDDP. In conclusion, the co-administration of CDDP with GBE is beneficial to ameliorate CDDP-induced toxicity without attenuation of CDDP antitumor activity.

In order to define the roles of p53 in acquisition of drug resistance in ATL cell lines, we prepared several ATL cell lines which differed in sensitivity to adriamycin (ADM), and examined their functional p53 statuses, expressions of p53, p21, Bcl-2, Bax, and cell cycles. Our findings demonstrated: (1) Regardless of sensitivity to ADM, most of the cell lines, including ADM-resistant cell lines, carried wild-type p53. (2) Only one cell line, ED-S, which was the most sensitive to ADM carried non-functional mutated-type p53. (3) In the ATL cells carrying wild-type p53, regardless of sensitivity to ADM, ADM-treatment led to an elevation of p53 protein level with concomitant elevations of p21 and Bax protein levels. (4) In the cell line expressing mutated-type p53, ADM-treatment at the concentration of IC50 induced elevations of p53, and Bax protein levels but did not p21 protein level. (5) Expression of Bcl-2 protein did not change in any of the cell lines by treatment with ADM at their respective IC50 levels, but increased in the ADM-resistant cell line when it was treated with ADM at IC50 of its parent cell line. (6) In the cell cycle analysis, ADM-treatment induced G1- and G2-arrest and then apoptosis in the cell lines with wild-type p53, whereas it induced only G2-arrest and then apoptosis in the cell line with mutated-type p53 at the same time course as in those with wild-type p53. These findings suggest that p53 does not play a leading part either in the apoptosis induced by ADM, or in the acquisition of resistance to ADM in ATL cells, and that ADM-induced apoptosis is mediated by multiple pathways leading to the activation of effector molecules.

The resistance of head and neck squamous carcinoma cells (HNSCCs) to cis-Diamminedichloroplatinum(II) (CDDP), which is widely used for the treatment of many malignancies, is a serious problem in the clinic. The mechanism by which cancer cells get resistant to this compound has not been completely understood. To elucidate the mechanism, we compared gene expression in the cells sensitive to CDDP with that in the resistant variants using fluorescent differential display technique. Side-by-side comparison on a sequence gel demonstrated that 105 genes were differentially expressed between KB, a human oral SCC line, and KB/cDDP, which was developed from KB and shows 2.5-fold increases in resistance to CDDP, as well as between HEp2, a human laryngeal SCC line, and its cDDP-resistant variants. Several candidates for the CDDP resistance related genes have been cloned by the following re-amplifications. Northern blot analysis revealed that human chorionic gonadotropin alpha subunit gene and human mitochondrial cytochrome c oxidase subunit II gene were expressed higher in KB/cDDP than in KB parental cells. Our results suggest that these two genes are associated with CDDP resistance and that human chorionic gonadotropin alpha subunit gene product is potentially a clinical biomarker for the resistance to CDDP.

Over 25 years ago survival was the sole aim in the management of cancer patients. However, over the past 25 years quality of life (QOL) as well as survival has become increasingly important in the treatment of cancer. In other words, treatment modalities without good QOL are no longer accepted. Thus, supportive therapies for cancer patients are very important. These supportive therapies fall into two categories. One is the management of adverse events induced by cancer therapies such as surgery, radiotherapy or chemotherapy. Adverse events induced by the administration of anti-cancer drugs in particular must be managed to maintain QOL. The second category is the management of pain, cachexia, metabolic disorders or mental depression induced by the existence of cancer. Over these 25 years major advances have been observed in the supportive therapy for cancer patients. These include the development of colony-stimulating factor (CSF) agents and the anti emetic agents such as serotonin-receptor inhibitors. These two agents have contributed to the relief of drug-induced adverse events. Opioids have been frequently used to relieve cancer pain. Hypercalcemia accompanying cancer are very easily treated with bisphosphonate agents. In the present paper, the advances in supportive therapy for cancer patients that have been made during these 25 years will be reviewed.

From the middle of the 20th Century, many anticancer drugs have been developed, and about 40 kinds of anticancer drugs are currently have been used for cancer treatment. From the past pre-clinical and clinical studies, it was found that combination of two or more drugs was sometimes more effective than the single use, resulting the increase of cure-rates in some-type of human malignancies. Recently, new treatment regimens based on the concept of biochemical modulation have been used for the treatment of cancer of the digestive organs. Also, currently, supportive therapies against the adverse-drug reactions (side effects) became available, and sometimes improvement of QOL of the cancer patients has been expected with the use of these therapies. In facing to the 21st Century, studies of new type of drugs such as those to novel molecular targets have been progressing.

The prevention of nausea, vomiting and appetite loss induced by remission induction chemotherapy for acute myeloid leukemia was compared by randomization between granisetron alone and combination with granisetron plus methylprednisolone. Granisetron was administered at 40 micrograms/kg during chemotherapy, and methylprednisolone was administered concomitantly at 125 mg/body for 3 days or more in the combination group. The single and combination groups comprised 14 and 13 patients, respectively, and there was no significant difference between the background of both groups. To evaluate the effect they were scored according to 4 grades, and evaluated every 24 hours from the start of chemotherapy to 5 days after its completion. The complete inhibition rate of vomiting was as high as 71.4% and 92.3% in the single and combination groups, respectively, showing no significant difference. The grade of vomiting was mild in both groups. Nausea was noted in 71.4% and 46.2%, respectively, and the inhibitory effect tended to be higher in the combination group. Appetite loss developed in 92.9% and 41.7%, respectively, and the prevention effect was clearly higher in the combination group. The prevention effects on nausea 7, 8 and 10 days after the start of chemotherapy, on appetite loss 2-10 days after it, and 2-5 days after its completion, were higher in the combination group. Granisetron revealed an excellent inhibitory effect on vomiting induced by remission induction chemotherapy for acute myeloid leukemia, but combination with granisetron and methylprednisolone was considered useful for nausea in the latter half of the treatment period and for appetite loss during the whole period.

MX2, a new lipophilic morpholino anthracycline, has been reported to have chemotherapeutic effects superior to those of adriamycin against murine and human glioma cells in vitro and in vivo. To assess the combination effect of MX2 and hyperthermia in vitro, the thermo-chemosensitivities of cultured human (U251MG and KC) and rat (C6 and 9L) glioma cell lines were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The number of viable cells in each cell line was markedly and dose-dependently decreased by MX2 treatment, but the sensitivity of U251MG to MX2 was less than that of the other cell lines. The survival of each cell line was decreased with the hyperthermic treatment at 43 degrees C for 60 minutes. Combined treatment with MX2 and hyperthermia had an additive effect on cultured glioma cells when MX2 was added to the medium at a dose below 50 ng/ml. However, combined treatment indicated neither an additive nor a synergistic effect when the dose of MX2 was above 50 ng/ml. We conclude that MX2 may be clinically useful against malignant gliomas when administered alone or in combination with hyperthermia.

To evaluate the efficacy of docetaxel therapy against anthracycline-resistant breast cancer, twenty patients were treated with docetaxel. Of the 20 patients pretreated with anthracycline, 17 were clinically anthracycline-resistant and the remaining three were refractory to anthracycline on histoculture drug response assay. Nine patients had loco-regional recurrence and 11 had distant +/- loco-regional recurrence. Docetaxel (49-60 mg/m2) was administered every 4 weeks, and was infused 1-13 times (median; 3 times). Of the 19 evaluable patients, eight (42%) showed partial response with the docetaxel therapy. Durations of the response ranged from 1 to 8 months (median; 4 months). Major adverse effects of the therapy were alopecia, neutropenia, and leucocytopenia. Hypersensitivity reaction was observed in one case. In addition, severe adverse effects such as grade 2 pneumonia and grade 4 diarrhea were found in one patient each. In conclusion, although the adverse effects are not negligible, docetaxel therapy is effective against anthracycline-resistant breast cancer.