Differently from target-based anticancer drugs, molecular mechanisms of actions are not well-known in many of the classical antineoplastic agents. With the exception of vinca alkaloids and taxanes, all of the classical antineoplastic agents work on DNA metabolism in cells and can therefore be categorised as 'DNA metabolism inhibitor'. Cellular sensitivity against these drugs largely depends on various activities in DNA metabolism, particularly in DNA repair. However, DNA repair as a determinant of drug sensitivity had long received little attention. DNA mismatch repair (MMR) is now regarded as an important determinant to alter cellular sensitivities against various drugs including fluoropyrimidines, platinum compounds and topoisomerase inhibitors. However, molecular mechanisms of this connection are still unknown. In particular, the relationship between MMR and 5-fluorouraci (l 5-FU) sensitivity is now being approached by examining the tumour MMR status and clinical outcomes in colorectal cancer patients treated with 5-FU-based adjuvant chemotherapies. However, reported results lack consistency, possibly due to the methodological problems in assays used to determine the MMR status. On the other hand, nucleotide excision repair (NER) is also regarded as an important determinant of cisplatin (CDDP) sensitivity. Expression of ERCC 1, a component of this complex multi-protein system, has been reported to be a determinant of prognosis in CDDP-treated non-small-cell lung cancer patients. In order to establish the significance of DNA repair as a determinant of tumour chemosensitivity, further basic studies, particularly ones approached from biochemical viewpoints, are required. Clinical studies supported by accurate assay techniques are also needed.

In the United States, Expanded Access Program is allowed by FDA to facilitate the availability of promising new drugs to desperately ill patients as early in the drug development process as possible, before marketing begins, and to obtain additional data on the drug's safety and effectiveness. Eli Lilly conducted Alimta Expanded Access Programs for 1200 malignant mesothelioma patients with free of charge and obtained clinical efficacy and severe adverse events. The system development for Expanded Access Program should be discussed for future Japanese participation to this program.

We report a case of a 56-year-old woman with hypersensitivity reactions (HSRs) symptoms against paclitaxel (PTX) which were suppressed by pre-injection of a low-dose of PTX before the full-dose injection. She received PTX chemotherapy (120 mg/body/week for three weeks on the 1st, 8th, and 15th day, followed by no drug for one week) in October 2004 for right breast cancer. However, continuation of the therapy was in jeopardy due to respiratory difficulties and facial flushing, considered to be HSRs symptoms, on day 15. However,we were able to continue the PTX chemotherapy by administering a low-dose pre-injection (2 mg/100 mL/30 min) before the full-dose injection. After that, HSRs symptoms were observed, but we were able to administer another low-dose pre-injection (1 mg/100 mL/30 min). Three courses of chemotherapy were successfully performed, followed by radical surgery in February 2005. A pathological complete response (pCR) of the maintumor was achieved. We suggest that pre-injection of a low-dose of PTX before the full-dose injection may be effective for prevention of the onset of HSRs symptoms.

Antineoplastic drugs have been shown to exert direct effects on the gut and induce the release of serotonin from the enterochromaffin cells of small intestinal mucosa. It is thought that released serotonin stimulates vagal afferent fibers through 5-HT3 receptors located in the vagal afferent terminals in the gastrointestinal tract and initiates sensory signals to the area postrema and the emetic center, thereby initiating nausea and vomiting. A 5-HT3 antagonist competitively inhibits serotonin at its specific binding sites, 5-HT3 receptors, and thereby elicits an antiemetic effect. Therefore 5-HT3 receptor occupancy of serotonin may be an appropriate indicator of the antiemetic activity of 5-HT3 antagonists. We analyzed 5-HT3 receptor occupancy of serotonin by integrating pharmacokinetic and receptor-binding kinetic parameters based on the receptor occupancy theory to compare the strength of the antiemetic effects of three dosage regimens of azasetron hydrochloride. The inhibitory effects on the binding of serotonin to 5-HT3 receptor of regimen 2 (an intravenous bolus injection of 5 mg of azasetron hydrochloride before and 8 h after chemotherapy) and regimen 3 (an intravenous bolus injection of 2.5 mg followed by 7.5 mg continuous intravenous infusion for 24 h) were longer-lasting than those of regimen 1 (an intravenous bolus injection of 10 mg before the start of chemotherapy). Furthermore, a positive relationship was found between the time of inhibitory effects on the binding of serotonin to 5-HT3 receptor and antiemetic effects of azasetron hydrochloride. From these results, dosage regimens 2 and 3 were considered to be more effective in the long term than regimen 1 in prophylaxis of nausea and vomiting induced by cisplatin.

Although Lentinan (LNT) is sold as a medicine, and Micellapist (MME) sold as a food supplement, both LNT and MME are beta-glucans isolated from the Shiitake mushroom (Lentinula edodes). These two substances have been thought to be the same component of Shiitake. In the present study, we evaluated anti tumor activities of LNT and MME in tumor-bearing mice (B10.D2 mice implanted with S908D2 tumor cells) and examined the mechanism of immunopotentiation of these substances. The tumor growth was significantly suppressed in the LNT-treated group. In ex vivo evaluation, the tumor cytotoxicity was significantly reduced by a treatment of splenocytes with anti-CD8 antibody in the LNT-treated group. Furthermore, the tumor cytotoxicity of the LNT-treated group was also significantly reduced by a treatment of splenocytes with anti-CD8 antibody and its complement and with an anti-CD4 and its complement in the effector phase and the induction phase, respectively. A significant prolongation of the survival of tumor-bearing mice as compared to the untreated control group was noted in the LNT-treated group. In the mice treated intraperitoneally with LNT, CD8-positive cells appeared to have suppressed tumor cell proliferation. CD4-positive cells appeared to be involved in this activity of CD8-positive cells. On the other hand, orally administered MME has exerted no clear cytotoxic effects.

Oxaliplatin (L-OHP) is a new third-generation platinum which is efficacious in treating advanced unresectable recurrent colorectal cancer as a first-line regimen. The marketing authorization was given in Japan in March, 2005. Its increased use has resulted in rare serious adverse effects, including anaphylactic shock. We experienced a case that developed anaphylactic shock by L-OHP. We report a 69-year-old man who was treated for recurrent colorectal cancer who underwent systemic chemotherapy with FOLFOX 4. After eight cycles he developed severe L-OHP associated neuropathy and lung metastases was a progressive tendency. The FOLFOX 4 regimen was discontinued and another modality, FOLFIRI regimen, was used. After eight cycles of FOLFIRI regimen, lung and liver metastases showed progressive disease for response assessment by RECIST criteria. Although a patient was stopped L-OHP for neurotoxicity, neuropathy was disappeared after 4 months interval. Therefore, we reintroduced L-OHP, FOLFOX 4 regimen. Anaphylactic shock occurred in the second cycle of reintroduction of the FOLFOX 4 regimen (total 10 cycles), 30 minutes after infusion of L-OHP. L-OHP infusion was immediately withdrawn and he was treated with intravenous hydroxyzine hydrochloride and methylprednisolone. The anaphylaxis symptoms resolved in 30 minutes. Chemotherapy based on L-OHP for unresectable recurrence colorectal cancer causes anaphylactic shock as a rare severe complication. The prediction factor is not proved. We should take steps for early detection of anaphylactic reaction and perform the appropriate treatment.

A 55-year-old woman had received total gastrectomy for advanced gastric cancer in March 2002, and was subsequently treated with adjuvant chemotherapy using oral anti-metabolite TS-1 for 21 months. She was well with no evidence of recurrence of gastric cancer, but leukocytosis was found in June 2005. The analysis of bone marrow revealed that Philadelphia (Ph) chromosome and bcr-abl fusion gene were positive. On the basis of these findings, the chronic phase of secondary chronic myeloid leukemia (CML) was diagnosed. Three months after being started on imatinib therapy, Ph chromosome positive cells disappeared in the bone marrow, and a complete cytogenetic response was achieved. Although CML is rare in secondary leukemia, this is, to our knowledge, the first reported case of therapy-related CML following TS-1 treatment. The present case suggested that imatinib therapy was also effective for secondary CML as well as de novo CML.

The safety of the intraperitoneal (ip) plus intravenous (iv) paclitaxel against gastric cancer with peritoneal dissemination was evaluated on a phase I dose escalation trial. Patients were treated with ip paclitaxel administered in 500 ml of normal saline before closing the abdomen, using the following dose levels: level 1, 50 mg/m(2); level 2, 60 mg/m(2); level 3, 70 mg/m(2); and level 4, 80 mg/m(2), followed by iv infusion of the same doses of paclitaxel on days 14 and 21. Twelve patients were enrolled in this study: 7 underwent reduction surgery,while 5 had only a laparotomy. ip therapy was well tolerated, and did not bring about any postoperative complications even in patients who underwent gastrectomy. Although multiple NCI/CTC grade 1 toxicities and grade 2 anemia (4 of six patients at dose levels 2 and 3) were observed, there was no dose-limiting toxicity. The overall median survival time was 316 days, and that for patients who underwent gastrectomy was 413 days. Paclitaxel at a dose of 80 mg/m(2) can be delivered by the operative ip route with acceptable toxicity profile.

We prospectively assessed the effectiveness of cryotherapy after high-dose L-PAM to prevent oral mucositis. Cryotherapy with ice tips was commenced 15 minutes before L-PAM administration, and continued until the end of administration. Twenty-six patients were enrolled in this study. Thirteen patients with myeloma were treated with 200 mg/m2 L-PAM followed by autologous peripheral blood stem cell transplantation, and 13 patients (4 AML, 4 MDS, 2 ALL, 2 lymphoma and 1 CML) were treated with 140 mg/m2 L-PAM followed by allogeneic stem cell transplantation. Grade 1 mucositis occurred in four of 13 patients (31%) with 200 mg/m2 L-PAM, and 2 of 13 patients (16%) with 140 mg/m2 L-PAM. Only one patient had grade 2 mucositis, and no grade 3 mucositis were observed. The procedure was well tolerated in all patients. These data suggest that cryotherapy is effective to minimize L-PAM-induced oral mucositis.

Temozolomide (TMZ) has demonstrated activity and acceptable toxicity for the treatment of recurrent malignant gliomas in carious prospective phase II studies. No information is, however, available on TMZ treatment for recurrent malignant glioma in Japanese patients. We report Hokkaido University Hospital experience on 35 adult patients with a recurrent malignant glioma, including 13 glioblastomas, 9 anaplastic astrocytomas, and 13 anaplastic oligondendroglial tumors. The median age was 52 years. The starting dose of TMZ was 150 mg/m2/day for 5 days. When no remarkable toxicity was observed, the dose was increased to 200 mg/m2 for subsequent cycles, every 4 week. In the 35 patients, the overall objective response rate (partial response) was 12% and 74% of the patients achieved disease stabilization. The median progression-free survival was 28 weeks and the median overall survival was 43 weeks. Although hematological toxicity was the most frequent adverse event (CTC grade 3 or 4 in 6 patients), overall toxicity was generally mild. Four patients required hospitalization due to the toxicity, but 28 patients had been treated with TMZ at our outpatient clinic. These results suggested that the reported efficacy and toxicity profile of TMZ for the treatment of Japanese patients with recurrent malignant glioma is reproducible from the setting of clinical trials in the western countries.

S-1 is a new oral anticancer drug containing tegafur, which is a prodrug of 5-fluorouracil. In this report, we describe the clinical features of three patients who suffered corneal disorders that seemed to be caused by S-1 administration.

CPT-11 (irinotecan hydrochloride, trade name: Campto or Topotecin) was launched in 1994. L-OHP (oxaliplatin, trade name: Elplat) was approved based on the fast track evaluation system and launched in 2005. Originally, both of these drugs were synthesized in Japan. Just after the launch of CPT-11, the severity of its toxicity was reported more frequently than its efficacy, therefore it spent much time to spread the use of this drug. As for L-OHP, the approved regimen is FOLFOX in spite the regimen was not actually studied in its registration studies in Japan. However, L-OHP is widely used after its launch. Thus, we find a progress in terms of regulatory system to introduce the widely accepted standard chemotherapy to the Japanese practice sites rapidly. We also find a further understanding for cancer chemotherapy in Japanese society. Recently, mass media reported cancer patients who were eager to receive the standard chemotherapy and requesting the regulatory authorities its quick approval. We have never seen such a scene 10 years ago. These patients' activities could be a key factor to change the infrastructure of cancer therapy.

5-Fluorouracil (5-FU) and its derivatives are widely known as some of the most commonly prescribed anticancer drugs, especially for gastrointestinal cancer. Orotate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are initial key enzymes in the 5-FU metabolic pathway. The activities of these enzymes may have the potential to affect the chemosensitivity of 5-FU.

A 54-year-old woman with scirrhous gastric cancer in the upper third area was admitted to our hospital. She was diagnosed with advanced gastric cancer that was inoperable due to peritoneal metastasis, so weekly paclitaxel (PTX) therapy was carried out. After 2 courses, malignant ascites completely disappeared and bilateral hydronephrosis improved. After 4 courses, no ascites or hydronephrosis were seen. Only neutropenia (grade 2) and alopecia (grade 1) were observed as adverse events during the therapy, but no major adverse events were noted. We also investigated the concentration of paclitaxel in ascites. Two hours after intravenous injection of PTX, the concentration of PTX in ascites rose over the reported cytotoxic dose of PTX, and this available concentration was maintained after 48 hours. Weekly paclitaxel therapy is suggested to be one of the safe and useful treatments for advanced gastric cancer with malignant ascites.

The goal of this study was to elucidate the functional roles of PI3K/AKT and MEK/ERK signaling on the proliferation and apoptosis of STI571-sensitive and -resistant CML cell lines in a co-culture system with human marrow stromal cells (MSCs), mimicking the bone marrow microenvironment. The phosphorylation of AKT and ERK was enhanced by co-culture with MSCs in both STI571-sensitive KBM-5 and STI571-resistant KBM-5/STI cells. In KBM-5 cells, the STI571 and PI3K inhibitor LY294002 combination was effective on apoptosis induction in the MSC co-culture system. In KBM-5/STI cells, treatment with LY294002 or PD98059 alone resulted in massive apoptosis, which was enhanced by co-culture with MSCs. These results provide a rationale for multi-molecular target therapy approaches based on a combination of signal transduction inhibitors with STI571 in CML.

We report a patient with chemotherapy-naïve advanced pancreatic cancer having multiple liver metastases which dramatically responded to S-1, an oral fluoropyrimidine. The patient was enrolled in the "Late Phase II Clinical Study of S-1 in Patients with Advanced Pancreatic Cancer." Anti-tumor efficacy after the first four courses of S-1 monotherapy was confirmed to be partial response (PR) in overall response by Response Evaluation Criteria in Solid Tumors (RECIST). Grade 3 neutropenia was observed, but no other severe toxicities were noted. On the basis of the results of the late phase II clinical study, S-1 is a promising agent for systemic chemotherapy against advanced pancreatic cancers because of its excellent efficacy, high tolerability, and convenient route of oral administration.

We report two metastatic pancreatic cancer patients who showed marked tumor shrinkage following administration of the oral fluorinated pyrimidine anticancer drug, S-1. In the early phase II trial of S-1 for metastatic pancreatic cancer, both patients showed a partial response (Japan Society for Cancer Therapy Criteria): the reduction ratio of the tumor volume was 81.4% in the patient with liver metastasis (Case 1) and 86.9% in the patient with lung metastasis (Case 2). Case 1 showed grade 3 anorexia and decrease of the serum hemoglobin as severe adverse effects, but the other adverse reactions were mild. Both patients could be treated as outpatients. S-1 showed a promising antitumor effect and tolerability in patients with metastatic pancreatic cancer, and it was also considered to be beneficial for patients in terms of convenience of administration, that is, by the oral route.