Cut-off levels of docetaxel (DOC), paclitaxel (PAC), and gemcitabine (GEM) in histoculture drug response assay are determined by data acquisition of non-small cell lung cancer. Inhibition rates were 47.5 +/- 22.2% in DOC (n=181), 66.6 +/- 25.1% in PAC (n=57), and 25.4 +/- 18.4% in GEM (n=63), respectively. Cut-off levels were determined as 50% in DOC, 60% in PAC, and 30% in GEM. The positive rates such as 47.5% in DOC, 68.4% in PAC, and 33.3% in GEM were obtained.

A late phase II clinical study (II) of a novel vinca alkaloid derivative KW-2307 (vinorelbine ditartrate) in advanced/recurrent breast cancer patients was performed at 22 institutions throughout Japan. An intravenous dose of KW-2307, 20 mg/m2, was administered once a week. Of the 60 patients enrolled in the study, 58 were eligible and 56 were evaluable. The response rate was 33.9% (19/56; 95% confidence interval: 21.8 to 47.8%) with one CR and 18 PRs. The response rate was as high as 37.0% (17/46; 95% confidence interval: 23.2 to 52.5%) when KW-2307 was used as a first-line chemotherapy for advanced/recurrent disease. The most common adverse event was myelosuppression including leukopenia in 96.4% (54/56) and neutropenia in 94.3% (50/53). Other events observed were increased GOT in 51.8% (29/56), increased GPT in 55.4% (31/56), LDH increased in 50.0% (27/54), serum total protein decrease in 39.3% (22/56), anorexia in 41.1% (23/56), nausea and vomiting in 66.1% (37/56), constipation in 30.4% (17/56), alopecia in 33.9% (19/56) and general fatigue in 46.4% (26/56). None of them were serious. This study demonstrated that KW-2307 was an effective and safe treatment for advanced/recurrent breast cancer patients.

We studied on possible association between the tumor marker (CEA, CA 19-9, and SPan-1) change and the clinical outcome after treatment with gemcitabine (GEM) in 23 patients with unresectable or recurrent pancreatic cancer. GEM was administered intravenously at a standard dose of 1000 mg/m2 weekly. One course consisted of weekly administration for 3 weeks followed by 1 week's rest. When the adverse effect did not allow the weekly administration, GEM was given bi-weekly without dose modification. Objective responses were evaluated by computed tomography and tumor marker change. Two or more courses were given for only 6 (26.1%) patients. The number of patients, administered GEM 6 or more times including by the weekly and bi-weekly method, was 12 (52.2%). Antitumor effects were evaluable in 16 patients. The clinical efficacies were 1 partial response (PR), 6 stable disease (SD), and 9 progressive disease (PD). Decreases in tumor marker levels were recognized in 9 of the 16 patients. The median survival time (MST) of the PR+NC group was significantly longer than that of the PD group (9 vs 3.5 months; p=0.0151). MST of those in the decreasing tumor marker group was significantly longer than the group with no decreases in the tumor markers (7.0 vs 5.5 months; p = 0.0478). The adverse effects at grade 3 or more were 4 (17.3%) leukopenia, 2 (8.7%) thrombocytopenia, and 1 (4.3%) skin toxicity. In conclusion, the tumor marker change after GEM treatment may be a predictor of preferable prognosis in patients with pancreatic cancer.

Lung cancer is the leading cause of cancer-related death throughout the world including Japan. During the 1990s, new cytotoxic agents such as irinotecan, paclitaxel, docetaxel, vinorelbine, gemcitabine, and amrubicin showed impressive single-agent activity in patients with lung cancer. To date, clinical research has defined the current standard chemotherapy for advanced non-small cell lung cancer (NSCLC) as modern platinum-based doublets considered more efficacious than any single regimen and with no added benefit to triplet therapies. However, we have reached an efficacy plateau with these agents. Rearrangement of the drug combination or change of the drug doses and schedules will not result in significant further progress. New, less toxic agents that improve survival and quality of life are clearly needed. In the last three decades, we have gained a growing understanding of the molecular biologic changes and the complex series of cellular signals that allow cancer cells to manifest behavior. This provides an opportunity to develop novel therapies aimed at inhibiting some of these changes and signals. Targeted agents, primarily the epidermal growth factor receptor inhibitors, have led to a new era in the treatment of NSCLC. This paper will review the current status of cytotoxic agents and molecular targeted therapy in lung cancer potential useful in the treatment of the patients.

Methods for the effective production of plant secondary metabolites with antitumor activity using plant cell and tissue cultures were developed. The factors in tannin productivity were investigated using culture strains producing different types of hydrolyzable tannins, i.e., gallotannins (mixture of galloylglucoses), ellagi-, and dehydroellagitannins. Production of ellagi- and dehydroellagitannins was affected by the concentrations and ratio of nitrogen sources in the medium. The formation of oligomeric ellagitannins in shoots of Oenothera tetraptera was correlated with the differentiation of tissues. Cultured cells of Eriobotrya japonica producing ursane- and oleanane-type triterpenes with antitumor activities were also established.

The efficacy and safety of bi-weekly administration of medium-dose docetaxel (TXT) were evaluated in patients with advanced and recurrent breast cancers. The additional effect of 5'-DFUR for non-responders was also evaluated. Forty patients with advanced and recurrent breast cancers were treated and 38 cases of 40 were evaluated (34 with recurrent cases and 4 with advanced cases). All cases were female, and their mean age was 56.0 (38-74). TXT of 60 mg/body, which was equivalent to 30-50 mg/m2 for standard-sized Japanese women, was administered every two weeks. 5'-DFUR of 800 mg/body was added for non-responders after 5 weeks. The response rate was calculated from the data of 32 cases with measurable lesions, and side effects were evaluated in about 34 cases with exact records. Two hundred seventy-one courses were performed for 38 patients (4-24 courses per person, average 7.13 courses). The mean dosage per course of TXT was 58.4 mg/body (38.3 mg/ m2). Three complete and 7 partial responses were observed (overall response rate: 31.3%). Ten non-responders were evaluated for the additional effect of 5' DFUR, and one case reached PR. Grade 3/4 bone marrow suppression occurred in 9 patients, and Grade 3/4 general malaise was observed in two patient. According to the results, bi-weekly administration of medium dose TXT is an active and safe regimen in patients with advanced and recurrent breast cancers. The additional effect of 5'-DFUR was observed in one of 10 non-responders of bi-weekly chemotherapy with medium-dose TXT.

Anticancer drugs interact directly with their molecular targets in cancer cells for effective cancer chemotherapy. The direct interaction between drug and cancer cell depends on the pharmacokinetics, which consists of absorption, distribution, metabolism, and excretion phases. In the excretion phase, ATP-binding cassette (ABC) transporters are the most important proteins in cell membranes. The ABC transporters export drugs out of cells by ATP-dependent energy, leading to drug resistance with reduced concentrations of intracellular drugs. In addition, the transporters sequestrate intracellular drugs into membrane vesicles in cytoplasm, also resulting in drug resistance. On the other hand, they are also involved in drug absorption. To date, 48 ABC genes have been isolated and classified into the seven groups of ABCA to ABCG. Among them, P-glycoprotein/ABCB 1, MRP 1/ ABCC 1, MRP 2/ABCC 2, MRP 3/ABCC 3, and BCRP/ABCG 2 strongly confer anticancer drug resistance, and they have different substrate drugs. Interestingly, recent molecular-targeted drugs, such as imatinib and gefitinib, were very recently found to be substrates for P-glycoprotein and/or BCRP. Additionally, polymorphism of ABC genes affects pharmacokinetics, drug effectiveness, and adverse events. Thus, ABC transporters are clinically important molecules, and much information is needed in the clinic.

In 1993, a 55-year-old-man was diagnosed with chronic active hepatitis (HCV). In January 1999, a solitary hepatocellular carcinoma (HCC) was discovered in his liver S8, and a sub-segmental hepatectomy was performed. In July 1999, multiple recurrences in the liver were noticed, and on August 6, 1999, the first SMANCS-TAE was performed. After that, PEIT was added, and then on July 18, 2000 and November 9, 2000, a second and third SMANCS-TAE were carried out, respectively. This time multiple HCCs in the bilateral lobes were discovered, and the 4 th SMANCS-TAE was undergone on April 12, 2001. On a celiac angiogram, the right hepatic artery was shown to have been obliterated by the last TAE. In addition, accessory left gastric artery (accessory LGA) originating in the left hepatic artery (LHA) proximal to the umbilical point (UP) could be seen. So we advanced a microcatheter to the LHA distal to the accessory LGA and injected SMANCS (0.8 mg) into the left hepatic artery. On April 24, he was admitted to hospital by ambulance due to severe upper abdominal pain. The muscular defense was noticed, and an air pocket under the diaphragm was indicated on an X-ray. An emergency total gastrectomy and R-Y re-construction were performed under the diagnosis of gastric perforation. A hole of approximately 10 cm in diameter was found in the anterior wall between the cardia and the upper body, and the accessory left gastric artery (LGA) was obliterated. The principal known side effects of SMANCS are fever, nausea and vomiting. However, as far as this writer has investigated, gastric perforation has never been reported. SMANCS presumably can flow into the stomach wall through the accessory LGA, triggering necrosis of the gastric wall due to circulatory damage. Although arterial infusion of SMANCS is an effective treatment, it causes considerable vascular damage, so intensive follow-up treatment is necessary.

Dose response curves of paclitaxel were measured by histoculture drug response assay (HDRA) in 11 lung cancer patients. Inhibition rates of paclitaxel at several concentrations were measured and fitted to the sigmoid dose response curve, using non-linear least square analysis, with fitting equation y=A (1-1/(1+exp (b (x-log (ED50)). Parameters A, b, and ED50 were 88.3+/-6.0 (80.0-100.0) %, 9.57+/-4.32 (2.25-15.0), and 26.8+/-8.1 (15.0-41.0) microg/ml, respectively. The parameter b was lower in well-differentiated tumors compared with moderately and poorly-differentiated tumors. Dose response curves of paclitaxel could be measured by HDRA in lung cancer. This method provides us more information for drug sensitivity than the usual HDRA method. This may lead to the improved accuracy of HDRA.

Doses of nedaplatin (CDGP) were established for concurrent chemoradiation therapy (CCRT) for cervical cancer, and a collaborative dose escalation study involving 8 hospitals was conducted to investigate the safety and efficacy of this therapy. Radiotherapy was performed according to the standard treatment described in the Regulations of Cervical Carcinoma Treatment. CDGP at 80 mg/m2 as Level 1 or at 90 mg/m2 as Level 2 was administered on Days 1 and 29 of treatment. Dose-limiting toxicity (DLT) was observed in 1 of 6.patients receiving 80 mg/m2 of CDGP and in all 2 patients receiving 90 mg/m2 of CDGP; therefore, Level 2 was regarded as the maximum tolerated dose (MTD), and Level 1 as the recommended dose. DLT signs consisted of delayed improvement in the leukocyte count in 2 patients and anorexia in 1 patient, suggesting that delayed improvement in the leukocyte count is the main DLT of this combination therapy. The main side effects were digestive disorders such as nausea and anorexia and bone marrow suppression, such as leukopenia, neutropenia, and thrombopenia. Side effects in the Level 1 group were more mild than in the Level 2 group. The efficacy was PR or better in all patients. The CR rates were 60% (6/10) in the Level 1 group and 50% (1/2) in the Level 2 group; there was no marked difference between the two groups. These results suggest that CCRT involving administration of CDGP at 80 mg/m2 on Days 1 and 29 is safe and effective.

We report a case on hemodialysis with metastatic rectal cancer who was introduced to CPT-11. Although the expected pharmacokinetics was shown 24 hours post-dialysis with the infusion of dose-reduced CPT-11, grade 4 neutropenia was observed. Considering the chronic renal failure status with latent lower function of multiple organs, the dose escalation method was recommended while watching the pharmacokinetics. CPT-11 is not only the key compound for metastatic colorectal cancer, but is also effective with several other cancers. It is important for cancer patients with chronic renal failure that the feasibility and efficacy of CPT-11 should be determined by future study.

Rhamnose-binding lectins are widely found in fish eggs. However, their biologic effects on cultured cells are still unknown. Since catfish (Silurus asotus) egg lectin (SAL) bound to globotriaosylceramide (Gb3) expressed on the surface of cells, we analyzed the relationship between Gb3 expression and SAL binding in tumor cell lines using Raji, Daudi, ACHN, P388, and K562 cells. Gb3 was highly expressed on Raji cells but not on K562 cells. SAL bound abundantly to Raji cells but not to K562 cells, and SAL binding depended on the amount of Gb3 on the cell surface. SAL caused a reduction in cell size and increased annexin-V binding to and propidium iodide (PI) incorporation into Raji cells. Although this effect on Raji cells might represent damage at the late apoptosis or necrosis stage, SAL-treated Raji cells remained alive. Thus SAL enhanced PI incorporation into Raji cells without induction of cell death. We examined whether the effects of chemotherapeutic agent(s) are influenced by SAL. SAL increased the incorporation of doxorubicin (Dox) into Raji cells and consequently enhanced the cytotoxic effects of Dox. These results indicate that SAL may induce cell permeability without cytotoxity.

The constituents of Citrus plants were investigated to develop useful agents that are effective in cancer chemoprevention. We examined the roots and bark of the roots of various Citrus plants, resulting in the isolation of many novel compounds. Their structures were determined using spectroscopic methods, especially 2D-NMR spectra. The following new compounds of constituents were found: dimeric coumarins, dimeric acridone alkaloids, and acridone-coumarin dimers. Auraptene and nobiletin are known as useful constituents of the peel of Citrus plants for cancer chemoprevention. However, we found that 3,5,6,7,8,3',4'-heptamethoxyflavone (HPT) has both antitumor promotion and initiation activities and is more effective than auraptene and nobiletin. We synthesized pentaallyl quercetin (QPA), a useful antitumor compound that has the additional effects of a P-glycoprotein (P-gp) inhibitor. The inhibitory effects of QPA on P-gp were more effective than those of the typical P-gp inhibitors cyclosporin A and verapamil. Both HPT and QPA have antitumor promotion activity and are potential candidates for effective multidrug resistance agents in cancer chemotherapy.

Although prostate cancer patients with metastatic lesion initially respond to androgen ablation therapy, almost patients develop to hormone-refractory states. The optimal treatment for men with hormone refractory prostate cancer (HRPC) has not been established. Docetaxel is a semisynthetic taxane that inhibit tumor growth by induction of microtubule stabilization and promotion of bcl-2 inactivation, which induce apoptosis. Docetaxel as single agent has significant anti-tumor effect in HRPC patients. Docetaxel combined with estramustine or other antimicrotubular agents have shown further significant cytotoxicity in HRPC patients. In the United States, Food and Drug Administration (FDA) approved docetaxel, injection in combination with prednisone for the treatment of patients with advanced metastatic prostate cancer in 2004.

Immunosuppressants are often used in the treatment of cancer. Several recent studies have shown hepatitis B virus (HBV) reactivation after immunosuppressive chemotherapy in HB surface antigen (HBsAg)-negative patients who were positive for antibody to HB core antigen (anti-HBc) and/or antibody to HBsAg (anti-HBs). This study reports the medical course of 11 patients with blood cancer who underwent chemotherapy. All patients had at least one positive HBV marker (HBsAg, anti-HBs, anti-HBc). Before immunosuppressive chemotherapy, 5 patients were treated with lamivudine and 6 had no antiviral drug treatment. None of the lamivudine treated patients had HBV reactivation, but HBV was reactivated in all of the patients not treated with this antiviral drug, one of whom had severe exacerbation of liver function and died due to hepatic failure. Because lamivudine treatment was effective in preventing HBV reactivation in patients receiving immunosuppressive chemotherapy, HBsAg-negative patients with anti-HBs and/or anti-HBc need the antiviral medicines before immunosuppressive therapy.