We performed a retrospective study that compared the efficacy and safety of dexamethasone (DEX) 8 mg with DEX 16 mg in cases of acute and delayed emesis induced by cisplatin (CDDP) chemotherapy in patients with lung cancer. Sixty-eight lung cancer patients treated with combination cisplatin, ifosfamide, and irinotecan therapy were studied. The DEX 8 mg group and the DEX 16 mg group received DEX intravenous injection 30 min prior to CDDP. All patients then received a 5-HT(3) antagonist intravenous injection 30 min before CDDP. Protection from acute nausea (day 1) was significantly superior in the DEX 16 mg group compared with the DEX 8 mg group (DEX 8 mg, 76.5%; DEX 16 mg, 100%). Protection from delayed emesis (day 1) was significantly superior in the DEX 16 mg group compared with the DEX 8 mg group. There was no reported severe nausea (grade 3) and vomiting (grade 2) in the DEX 16 mg group. Furthermore, perphenazine hydrochloride for use as rescue medication was required by significantly fewer patients in the DEX 16 mg group than in the DEX 8 mg group (DEX 8 mg, 41.2%; DEX 16 mg, 0%). Adverse effects were observed in 10 cases (nine reports of generalized fatigability, two of headache) in the DEX 8 mg group and in 16 cases (11 reports of generalized fatigability, one of pruritus) in the DEX 16 mg group. However, because the symptoms were all mild, we did not consider that there was any safety problem. In conclusion, DEX 16 mg is a clinically useful treatment for acute and delayed emesis induced by cisplatin-induced chemotherapy in patients with lung cancer.

We report a case in which 5-HT3 receptor antagonist, indisetron hydrochloride,was effective against CPT-11-induced diarrhea. When the patient, a 63-year-old male, developed lymph node metastases after resection for primary gastric cancer, 24-hour continuous administration of CPT-11 (125 mg/m2) was initiated. The following day he had diarrhea, possibly associated with the CPT-11. Hange-shashinto was administered but did not improve the condition. Thereafter, the diarrhea followed a protracted course (grade 1 to 2). His diarrhea improved when indisetron hydrochloride was administered with the fifth course of chemotherapy in place of the usual antiemetic drug. In this patient, indisetron hydrochloride, in addition to its role as an antiemetic, was considered to be effective against CPT-11-induced diarrhea.

The patient was a 72-year-old female. Under the supervision of her former doctor, this patient had an operation and adjuvant chemotherapy for progressive breast cancer. During the following period, local recurrence of breast cancer and pulmonary lymphopathia developed. Although medication with paclitaxel was attempted, the focus was resistant to this treatment, and metastasis to the brain was also observed. Due to the dyscrasia above, the patient had difficulty breathing and became bedridden. Subsequently, combination treatment of capecitabine and trastuzumab was attempted. As a result,metastasis in the brain and pulmonary lymphopathia were improved. The patient recovered enough to be discharged at one time. However, his condition took a turn for the worse after the interruption of the combination treatment by a side effect. In conclusion, the combination treatment of capecitabine and trastuzumab is thought to be effective for non-responders to paclitaxel.

Goserelin (GOS) therapy in an adjuvant setting for estrogen receptor(ER)-positive premenopausal patients with breast cancer was assessed in a randomised comparative study.

Capecitabine is a new oral fluoropyrimidine derivative. It is a prodrug that is activated to fluorouracil in three metabolic steps. Compared to 5'-deoxy-5-fluorouridine (doxifluridine) itself, capecitabine was designed to deliver more doxifluridine to cancer cells,where it is activated to fluorouracil. Based on differential distribution of the three metabolizing enzymes in different tissues, capecitabine is considered to yield more fluorouracil in cancer cells than bone marrow cells or gastro-intestinal epithelial cells. Due to these pharmacokinetic merits, capecitabine can be given at a higher dose, and therefore is expected to yield higher antitumor activity, than doxifluridine. To investigate the pharmacokinetic advantage of capecitabine compared to doxifluridine, pharmacological studies of both drugs have been conducted in phase II trials. These used the same study design,and compared the pharmacokinetics and pharmacodynamics between capecitabine and doxifluridine. The area under the curve of doxifluridine was 2.3 times higher after the administration of capecitabine than doxifluridine, suggesting that higher intratumor concentrations of fluorouracil were indeed achieved after capecitabine administration. This study clearly documents the pharmacokinetic superiority of capecitabine compared to doxifluridine.

TS-1 is an antitumor drug including 5-chloro-2,4 dihydroxypyridine (CDHP), which inhibits dihydriopyrimidine dehydrogenase (DPD) activity selectively in metabolism of 5-FU. However, TS-1 therapy tends to increase adverse events for patients with impaired renal function due to excessively high blood concentration of 5-FU, because CDHP is mainly excreted into the urine. In a 67-year-old male with advanced gastric cancer, renal dysfunction occurred during TS-1 administration as its adverse event. We studied the pharmacokinetics of 5-FU, which were analyzed on the T1/2 value and the AUC (0-infinity) of 5-FU with a single and consecutive TS-1 administration, and estimated an optimal TS-1 administration regimen for this patient. The regimen is 60 mg/body/day given in one divided dose for 28 days consecutively followed by 14 days rest. This regimen enabled a continuation of TS-1 treatment for the patient. In conclusion, individual dose adjustment using pharmacokinetic study of 5-FU might be beneficial to patients with impaired renal function.

This study was designed to evaluate the pharmacokinetics and toxicity of paclitaxel, administered via an intraperitoneal route for a gastric cancer patient with renal dysfunction. The patient was a woman in her 50's, who had been diagnosed with severe renal dysfunction but no treatment history was known. She complained of dyspnea for a large quantity of ascites and was urgently hospitalized. It was diagnosed as gastric cancer with peritoneal dissemination. At this hospital, PTX was administered weekly intraperitoneally through an infusion port without complication. This result suggested that intraperitoneal PTX chemotherapy for a patient with renal dysfunction was a safe treatment.

We performed intraperitoneal and intrapleural dosing gemcitabine (GEM) to eight patients with advanced pancreatic cancer having peritoneal or pleural carcinomatosis and evaluated its actions and safety. GEM (500 mg/m2) was infused into the abdominal cavity or thoracic cavity after drainage of peritoneal or pleural effusion. We checked the change of serum GEM concentration and the side effects after the GEM administration. Then, we repeated the GEM administration observing their systematic symptoms and evaluated the alteration of peritoneal or pleural effusion and cytology. Plasma concentration of GEM by infusing into the abdominal cavity or thoracic cavity was lower than by intravenous injection. In three of the five cases of peritoneal carcinomatosis, intraperitoneal administration revealed a decrease of peritoneal effusion. In two of the three cases of pleural carcinomatosis, intrapleural administration revealed a decrease of pleural effusion. Four cases had leukocytopenia of grade 1/2, three cases had thrombocytopenia, and two cases had alopecia as side effects, although all of them were minor side effects. Intraperitoneal and intrapleural dosing GEM had minor side effects and could improve QOL for the patients with advanced pancreatic cancer associated with peritoneal or pleural carcinomatosis.

The immunological functions of Ganoderma lucidum antlered form (AF) (Rokkaku-Reishi in Japanese), a variant type of Ganoderma lucidum, were investigated in C57BL/6 mice treated with cyclophosphamide (CY). Ganoderma lucidum AF alleviated CY-induced decrease in body weight and abnormal increase in blood neutrophil level, when the mice were fed a diet containing 2.5% Ganoderma lucidum AF starting one week before CY treatment (150 mg/kg, ip). The recovery of CD8+ and NK1.1+ cells in the spleen was accelerated in Ganoderma lucidum AF group compared to the control group. Ganoderma lucidum AF also both alleviated CY-induced splenic lymphopenia and suppressed the abnormal increase in splenocytes 7 days after CY treatment. These results suggest that ingestion of Ganoderma lucidum AF is beneficial for improvement of quality of life reduced by anti-cancer chemotherapeutic drugs such as CY.

Bcl-2 confers resistance to apoptosis resulting in reduction of the effectiveness of chemotherapy. We examined the effect of antisense (AS) Bcl-2 in combination with anticancer drug for targeting therapy against Bcl-2 in gastric and breast cancer cells.

Application of the human genome information would lead to the development of novel diagnostic methods and innovative therapies against cancer. In this article, two aspects of such application are reviewed; 1) genomic diagnosis for predicting efficacy and side effects associated with the administration of the anti-cancer drugs, 2) exploration of novel cancer associated gene products using genome-wide gene-expression profiling. Successful examination on genetic information of the patients/tumors would lead to the establishment of the "personalized" medicine which could be an ideal situation for the cancer patients treated with the chemotherapeutic drugs. Furthermore, the finding of tumor associated antigens lead to the development of not only new diagnostic methods but also novel therapeutic modalities including cancer vaccine. Some of the successful efforts are referred and discussed.

Gemcitabine mono-therapy was carried out in an unresectable pancreatic cancer. After six courses of treatment, pitting edema appeared and gradually became worse especially after gemcitabine infusion. Gemcitabine-induced edema was suspected after exclusion of other causes. Diuretics and steroids were useful to control the peripheral edema in this case, and gemcitabine therapy could be continued.

A pilot study was conducted to evaluate the safety and efficacy of weekly docetaxel(DOC) treatment for head and neck cancer as compared with those of 3-weekly DOC treatment at 60 mg/m(2). Weekly DOC was administered at doses ranging from 25-30 mg/m(2)/wk (mean dosage, 40 mg/body/wk) for 3 weeks followed by a 1-week rest or for 6 weeks followed by a 2-week rest. Weekly DOC was administered to 18 patients (1 of whom received prior chemotherapy), and 3-weekly DOC was administered to 29 patients (10 of whom received prior chemotherapy). The overall response rate was 22.2% in the weekly DOC group and 47.8% in the 3-weekly DOC group. In advanced or recurrent cancer, the overall response rate plus long NC (stable disease for at least 6 months) rate was 40.0% in the weekly DOC group, and 42.9% in the 3-weekly DOC group. Only 1 (5.6%) case of grade 3 mucositis developed in the group receiving weekly DOC, while 12 cases of grade 3 or 4 neutropenia (41.4%) and 2 of grade 3 or 4 thrombopenia (6.9%) developed in the 3-weekly DOC group. Based on these results, weekly DOC treatment appears to be useful and feasible for outpatients with head and neck cancer, even in high-risk and elderly patients.

In recent years, pharmacogenomics have received much attention from the increased expectations for so-called order-made medicine. It is experientially clear that inter-individual differences exist in the degree of efficacy and occurrence of adverse effects. These inter-individual differences are observed not only among anticancer chemotherapeutics but in almost all drugs. Several studies have revealed that genetic factors are involved in these inter-individual differences. To date, the relationships have been revealed between adverse effects of some anticancer drugs and polymorphisms of drug metabolizing genes. Such relationships include 5-FU and DPYD gene, methotorexate and MTHFR gene, irinotecan and UGT 1A1 gene and 6-MP and TPMT gene. By using information on these polymorphisms, it will be possible to predict the occurrence of adverse effects before using anticancer drugs. In particular, information on polymorphisms related to the possibly adverse effects of irinotecan is now given in its package leaflet. This means that order-made medicine is a step closer. In this review, we discuss the relationships between polymorphisms of genes and the adverse effects of anticancer drugs. Furthermore, we want to suggest the direction of further pharmacogenomic studies with an eye to the realization of order-made medicine.

Pharmacogenomics is a large-scale systematic approach using a variety of genomic technologies to discover drug response determinants and promote a better understanding of the genetic and molecular basis underlying variable drug response among patients. However, few critical prediction markers of drug response have been validated to date. Drug sensitivity is determined by multiple genes:drugs are often involved in complex metabolic pathways before they produce anti-cancer activity, and the related genes do not act in isolation. Although the worldwide research on the human genome exerts a major impact on medical science and advanced medicine, the detailed function and interaction of most genes remain unclear. There is clear evidence that a variety of genes are closely associated with cellular drug sensitivity, but most of the regulatory mechanisms of their expressions are poorly understood. To understand the drug sensitivity mechanism and identify the key biomarkers, recent attention has focused on the transcriptional mechanisms of drug sensitivity genes and their network. These approaches in genome research and the functional analysis may revolutionize the anticancer chemotherapy world. The possible contribution of new challenges and problems of the day were reviewed while showing recent findings on the analyses of 5-FU metabolic pathway and the key gene DPYD as an example.

Molecular targeting agents will likely play an increasing role in the management of cancer.However, resistance to anti-neoplastic drugs remains a serious obstacle to successful cancer treatment. Analysis of SNPs and microarray technologies should enable us to predict toxic responses and sensitivities to anticancer agents of each patient, and the prediction may permit patient-specific anticancer agents and dosages that reduce the risk of acute toxicity and emergence of drug-resistant tumors. The relationships are reviewed between the chemoresistance(chemosensitivity) and polymorphisms, tumor gene expression profiles or mutations of targeted molecules that confer resistance to molecular target therapy.

FDA issued guidance for industry regarding pharmarcogenomic data submission this year. Polymorphic cytochrome P450 2D6 and thiopurine S-methyltransferase in patients are now considered biomarkers for drugs which are predominantly metabolized by these enzymes. This article reviews current efforts to treat pharmacogenomic data for new drug development and personalized medicines.

In Europe and America, many health care workers have concerns about the risks to their health of handling anticancer drugs. The findings of the risks were reported in the late 1970's, and guidelines for the safe handling of anticancer drugs were established in the 1980's. The conditions of wearing personal protective equipment and of the working environment have improved dramatically as a result of introduction of the guidelines. Furthermore, researches and studies into the health effects of occupational exposure to anticancer drugs have been pursued actively. In Japan, the society of hospital pharmacists established guidelines for the safe handling of anticancer drugs in 1991. Since then, mainly nurses have been concerned about the safe handling of anticancer drugs, but in the medical setting, the present situation surrounding the safe handling of anticancer drugs has hardly changed. In the industrial hygiene field, the safe handling and the occupational exposure to anticancer drugs have been seldom reported and researched. The actual potential hazards to occupational exposure of anticancer drugs have not yet been determined. Nevertheless, the reduction of occupational exposure to anticancer drugs in health care workers has been an important challenge for the industrial hygiene field. In Japan, we need to promote action to spread the use of the appropriate personal protective equipment and the appropriate working environment. We also have to rethink the safe handling of anticancer drugs. We hope that the Japanese government will establish an effective authorized guideline as has been done in Europe and America.