A new semi-synthetic taxoid, docetaxel (taxotere) was recently developed in Japan. The phase I study was initiated in 1991, and the MTD was determined as 70-90 mg/m2, dose-limiting factor as leukopenia, and recommended dose for the phase II study as 60 mg/m2, every 3-4 weeks. The early and late phase II studies were conducted based on above dose schedule. After the late phase II studies, appreciable responses were obtained against advanced recurrent breast (50.4%) and inoperable lung (22.4%) cancers, and the results were accepted by MHW of the Japanese Government. Docetaxel possesses an unique tubulin-interacting activity (promotion of assembly of stable microtubules) and currently combination studies with other anticancer drugs or radiotherapy are ongoing.

The antiemetic effects on nausea and vomiting induced by anticancer drugs and safety of a 2-mg granisetron tablet were studied in cancer patients, particularly in the field of gynecology, who had been treated with anticancer drugs including cisplatin (CDDP) at 50 mg/m2 or more. The 1-mg granisetron tablet is already commercially available and used widely in clinical practice by oral administration of two tablets per dosage. In this investigation, the clinical efficacy, safety and usefulness of a 2-mg tablet, which can be taken more easily, were studied. The 2-mg granisetron tablet was judged to be "remarkably effective" or "effective" for nausea and vomiting in 22 (66.7%) of 33 patients. For safety, neither adverse experiences nor abnormal laboratory values were judged to be of clinical significance. The 2-mg granisetron tablet was considered "extremely useful" or "useful" in 22 (66.7%) of 33 patients. The above results confirmed the excellent antiemetic effect on nausea and vomiting induced by anticancer drugs including CDDP and the high degree of safety of a 2-mg granisetron tablet.

A phase I study with TUT-7, a new anthracycline antitumor antibiotic, was conducted in 35 malignant tumor patients at 11 institutions nationwide. The study was initiated with a single dose at 100 mg/body which was equivalent to 2n, then the dose as escalated up to 700 mg/body in accordance with the modified Fibonacci's scheme. The dose limiting factor (DLF) was considered to be leukopenia, and maximum tolerated dose (MTD) was 700 mg/ body. The consecutive days dosing study subsequently conducted started with 25 mg/body/day, and the dose level was escalated up to 150 mg /body/day. TUT-7 was orally administered for seven (7) to fourteen (14) consecutive days in principle. It was considered that DLF was leukopenia and MTD was 100 mg/body/day for consecutive days dosing. The study indicated that serum drug concentrations reached their plateaus on the 5th day after initiation of TUT-7 treatment and the accumulation of this compound was low. With these findings, a regimen with a dose of 100 mg/body/day orally administered for 14 consecutive days was recommended for early phase II studies.

In chronic myelogenous leukemia (CML), abnormalities develop in hematopoietic stem cells, affecting three hematopoietic cell series, including leukocytes, erythrocytes, and platelets. The occurrence of the Philadelphia (Ph1) chromosome and BCR/ABL fused genes are involved in its pathophysiology. Methods of treating CML consist of bone marrow transplantation, and administration of interferon (IFN) and other antineoplastic drugs. Bone marrow transplantation is strongly recommended when the patient is young (usually aged 45 years or younger) and a donor with identical human leukocyte antigens (HLA) is available. When bone marrow transplantation is impossible, administration of IFN is the treatment of choice. IFN administration may induce disappearance or a decrease in the Ph1 chromosome. IFN administration has been demonstrated to significantly increase the survival rate over conventional chemotherapy (hydroxyurea or busulfan).

The inhibitory effects of GG032X tablets, a new dosage form (fast dispersing tablet) of ondansetron, 5-HT2 receptor antagonist, on nausea and emesis induced by cisplatin (CDDP), were investigated along with safety and usefulness. Subjects were chemotherapy patients starting CDDP administration for the first time, who were receiving a high single dose of CDDP (50 mg/m2 or more and intravenous drip infusion of less than 4 hours), or lower multiple doses of CDDP (a single dose of 10 mg/m2 or more, administered intravenously for 3-5 consecutive days). GG032X tablets were administered orally 1-2 hours before CDDP administration. In lower multiple doses of CDDP, GG032X tablets and CDDP were administered, as much as possible, at the same respective time when they were administered on the first day. Efficacy of GG032X tablets was evaluated in terms of inhibitory effect on nausea and emesis 24 hours after administration of a high single dose of CDDP, and of the inhibitory effect on nausea and emesis during the study period (3-5 days) in lower multiple doses of CDDP. Efficacy, safety and usefulness were evaluated in accordance with the evaluation criteria used in the clinical study of already-approved ondanstron tablets. In a high single dose of CDDP, the cases judged "effective" or better in the investigation of the inhibitory effect of the drug on nausea and emesis, accounted for 52.9% (63/119 cases). As for the overall safety rating, the cases judged as "safe" accounted for 87.0% (107/123 cases), and as a "minor safety problem" accounted for 13.0% (16/123 cases). As for the usefulness rating, the cases judged "useful" or better accounted for 52.1% (62/119 cases). Major adverse effects included headache, fever, atrial fibrillation and increases in total bilirubin, GOT and GPT values. None of these was serious, and the patients recovered without any treatment or by nosotropic therapy. Meanwhile, in lower multiple doses of CDDP, the inhibitory effect judged "effective" or better accounted for 70.6% (12/17 cases). As for the overall safety rating, all cases were judged "safe". In terms of usefulness, those cases judged "useful" or better accounted for 70.6% (12/17 cases). No adverse effect was observed. Study results of these two groups were almost the same as those for already-approved ondansetron tablets. According to the results of questionnaires for the patients who participated in the study and took GG032X tablets, the drug was found to be easy to take and had favorable results. Based on the above results, GG032X tablets were evaluated as having the same inhibitory effect as the already-approved ondansetron tablets against CDDP-induced nausea and emesis, and were considered safe and clinically useful.

1. The clinical efficacy and safety of the 2 mg granisetron tablet were assessed in 32 mainly lung cancer patients who were to receive treatment with anticancer drugs including CDDP. 2. One 2 mg granisetron tablet was administered prophylactically one hour before the start of CDDP administration. 3. Based on the development of nausea and vomiting in 24 hours after the start of CDDP administration, the study medication was judged to be "remarkably effective" or "effective" in 71.0% (22/31) of cases. 4. The study medication was judged to be "safe" in 96.9% (31/32) of cases, without causing any adverse reactions. 5. The above results indicate that the 2 mg granisetron tablet is safe and useful.

The hepatic extraction ratios (EH) of adriamycin (ADR) and mitomycin C (MMC), which were administered clinically by an intra-hepatic arterial route, were measured in rats to clarify the disposition of ADR and MMC in liver. EH values of ADR and MMC were determined by comparing the femoral arterial and hepatic venous plasma concentrations at steady state during continuous intravenous administration. The EH value of ADR in rats at each infusion rate of 2, 10 and 50 micrograms/kg/min, was 0.290, 0.286 and 0.251, respectively. There was no significant difference between the EH values (p > 0.05). The systemic clearance (CLtot) at each infusion rate was 108, 77.6 and 72.9 ml/min/kg, respectively. The EH value of MMC in rats at each infusion rate of 2.5, 7.5 and 25 micrograms/kg/min, was 0.332, 0.358 and 0.360, respectively. There was no significant difference between the EH values, the same as for ADR. The systemic clearance (CLtot) at each infusion rate was 38.3, 36.1 and 35.3 ml/min/kg.

Nitrosoureas are antitumor alkylating agents widely used in the chemotherapy of malignant brain tumors. However, the effectiveness of adjuvant nitrosourea chemotherapy has proved inadequate, failing to provide any significant prolongation of survival time. One of the reasons for the poor results is a drug resistance system in the form of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). O6-alkylguanine derivatives are well known to be inhibitors of MGMT, and inactivation of MGMT by these derivatives leads to increased tumor cell sensitivity to nitrosoureas. In this study, the authors tested the ability of O6-benzylguanine, O6-(4-, 3- and 2-fluorobenzyl) guanines, O6-(4-, 3- and 2-trifluoromethylbenzyl) guanines, O6-(4-, 3- and 2-pyridylmethyl) guanines and O6-(2- and 1-naphthylmethyl) guanines to reduce MGMT activity in SF-188 cell-free extract by using [3H] methylated substrate DNA and analyzed their enhancing effect on the cytotoxicity of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl) -3-nitrosourea hydrochloride (ACNU) by using a calorimetric cytotoxicity assay. The MGMT activity in the SF-188 cell-free extract was 944 +/- 43 fmol/mg protein (Mean +/- SD, n = 5). O6-(4- and 3-fluorobenzyl) guanines were found to be more effective in inactivating MGMT than O6-benzylguanine. O6-(4-trifluoromethylbenzyl) guanine considerably reduced MGMT activity as did O6-benzylguanine. O6-(3-trifluoromethylbenzyl) guanine, O6-(4- and 3-pyridylmethyl) guanines, and O6-(2-naphthylmethyl) guanine were intermediately effective, but O6-(2-fluorobenzyl) guanine, O6-(2-trifluoromethylbenzyl) guanine and O6-(1-naphthylmethyl) guanine were less effective. ACNU cytotoxicity in SF-188 cells was strongly enhanced by pretreatment with O6-(4- and 3-fluorobenzyl) guanines and O6-(4-trifluoromethylbenzyl) guanine and moderately enhanced by O6-(3- trifluoromethylbenzyl) guanine and O6-(4- and 3-pyridylmethyl) guanines, but not enhanced by O6-(2-fluorobenzyl) guanine, O6-(2-trifluoromethylbenzyl) guanine and O6-(1-naphthylmethyl) guanine. The test compounds were not cytotoxic at concentrations between 0.5 and 5.0 microM. The enhancing effects on ACNU cytotoxicity were consistent with the inhibition of MGMT activity after two-hour pretreatment with O6-arylmethylguanine derivatives. These results indicate that the 2-position of the O6-benzyl group plays an important role in the inactivation of the MGMT activity and the potentiation of ACNU cytotoxicity.

Small cell lung cancer (stage IIIB) developed in a 61-year-old woman. She was treated with chemotherapy in which the cumulative dose of carboplatin was 662 mg/m2 and that of etoposide was 2,000 mg/ m2, and with concurrent irradiation in which the total dose of X-rays was 44.8 Gy. The response to chemotherapy and irradiation was very good. Radiation pneumonitis developed after discharge, but it resolved after steroid therapy. Nine months after the diagnosis of lung cancer the patient was readmitted because of bleeding and leukocytosis. Acute monocytic leukemia (M5a) was diagnosed after examination of a bone-marrow aspirate. The patient was treated with chemotherapy, but she died of severe bone-marrow suppression and multiple organ failure 3 months after the diagnosis of acute monocytic leukemia. Although chromosome analysis could not be done, we strongly suspect that this leukemia was induced by etoposide, because of the clinical course.

Azasetron, a selective 5-HT3 receptor antagonist, has been previously shown to be highly effective in the prophylaxis of nausea and vomiting induced by anticancer drugs, and is widely used in the clinical setting in Japan. In order to improve the antiemetic effect of azasetron, we designed two treatment methods using this drug and compared the antiemetic effect of this method with that of standard bolus intravenous injection on nausea and vomiting associated with anticancer drug including 75 mg/m cisplatin (CDDP). The two-treatment group received an intravenous bolus injection of 5 mg azasetron before and 8 hours after the start of chemotherapy, and a standard group was given an intravenous bolus injection of 10 mg azasetron only once a day. The inhibitory effect on vomiting in the two-treatment group was significantly greater than those of the standard group on day 1 and 2 (p = 0.0458, p = 0.0273), and the inhibitory effect on nausea of the two-treatment group tended to be superior those of the bolus group on day 2 (p = 0.0533). No adverse effects were observed in either group of this study. From these data, the two-treatment approach was considered to be highly effective in prophylaxis of nausea and vomiting induced by anticancer drug.

Glutathione levels in human colon cancer cell line M7609 and its sensitivity to anticancer drugs were investigated in a complete medium RPMI-1640 (medium A) and an incomplete medium (medium B), which was prepared by removing glutathione and sulfur amino acids from medium A. Four different medium conditions were prepared by combining a medium A and a medium B; a medium of 100% medium A (Control), a 50:50 mixture medium of medium A and medium B (Condition 2), a 20:80 mixture medium of medium A and medium B (Condition 3), and a 10:90 mixture medium of medium A and medium B (Condition 4). The cells were cultured in each medium for 14 days, and intracellular levels of glutathione were determined to estimate the cell sensitivity to anticancer drugs. There were no significant differences in glutathione levels among the cancer agents in condition 2, as compared to those in the control. In condition 3, the reduced glutathione levels were decreased to 23.1%, where CDDP, ADM, MMC and melphalane showed 2.5, 2.2, 1.8 and 1.5 times greater antitumor activity than in the control, respectively. In condition 4, cell proliferation was too low to collect adequate cells for glutathione determination. These results demonstrated that the decrease in cellular glutathione concentration with this method might enhance the cytotoxic effects of anticancer drugs.

Among new taxoids, taxuspines A-H and J-T, and known taxoids containing taxol and taxol-type compounds with an N-acylphenylisoserine group at C-13 and an oxetane ring at C-4 and C-5 isolated from stems and leaves of the Japanese yew Taxus cuspidata Sieb. et Zucc., two non-taxol-type compounds remarkably reduced CaCl2-induced depolymerization of microtubules. Furthermore, seven non-taxol-type compounds increased cellular accumulation of vincristine in multidrug-resistant(MDR) tumor cells as potent as verapamil, while taxol and taxol-type compounds did not show such an activity. In addition, the non-taxol-type compounds enhancing vincristine accumulation inhibited competitively binding of azidopine to P-glycoprotein. These results suggest that some non-taxol-type taxoids may be useful for overcoming MDR in tumor cells.

The emergence of multidrug resistance(MDR) is a major problem in cancer chemotherapy. Many compounds are developed to reverse MDR, and some of them are under clinical trials. Among them, MS-209, a novel quinoline derivative, is one of the most potent MDR reversing agents. MS-209 at 3 microM effectively reverses MDR in various cell lines in vitro. MS-209 directly interacts with P-glycoprotein and inhibits the P-glycoprotein-mediated drug transport. Oral administration of MS-209 combined with anticancer drugs markedly increases the life span of mice bearing MDR tumor cells without causing serious side effects. Thus, MS-209 is an orally active and potent MDR reversing drug without serious side effects.

P-glycoprotein plays a key role in the mechanisms of multidrug resistance in experimental tumors as well as in clinical tumors in acquired-type resistance and in intrinsic-type resistance. Thus the therapeutic approaches targeting the P-glycoprotein would provide benefits in eradication of drug-resistant tumor cells. Practical approaches to overcoming of multidrug resistance by targeting the P-glycoprotein would be; to use agents including calcium channel blocker-related agents and membrane-modifying agents that interact with P-glycoprotein, although some potential problems concerning side effects still remained to be studied.

Multidrug resistance(MDR), mediated by P-glycoprotein, is a well-understood mechanism of resistance to anticancer drugs. P-glycoprotein is thought to act as an efflux pump with broad specificity for variety of anticancer drugs. Cyclosporine and its analogue, SDZ PSC 833, have demonstrated ability to inhibit P-glycoprotein mediated transport function, restore accumulation defects for anticancer drugs, and reverse resistance in vitro and in vivo. The clinical trials of these drugs are on going. P-glycoprotein may also play a pivotal role in the evolution of pharmacological defence mechanisms, protecting organisms from cytotoxic agents. Approach to overcome resistance may result in serious challenges to the host's natural defenses. Clinical trials of MDR modulators, such as cyclosporine or SDZ PSC 833, should be designed with caution and with careful consideration for potential pharmacokinetic and pharmacodynamic interaction.

DNA topoisomerase(topo) I and II regulate the topological conformation and DNA molecules by catalyzing the concerted breakage of single or double strands. Topo I and II targeting anticancer agents such as camptothecins (CPT-II), epipodophyllotoxins (VP16 and VM26), and amsarcine are widely used in cancer chemotherapy. To enhance their therapeutic efficacies, one should understand how cellular sensitivities to these topo-targeting agents are regulated, and one should also understand what mechanisms or factors are involved in the appearance of tumor cells resistant to them. We will discuss if there is any marker useful for determining drug sensitivity to these topo-targeting agents in cancer cells.

Metallothionein is a low-molecular weight protein involved in resistance to toxicity of heavy metals. Recent experimental evidences indicate that metallothionein appears to be a factor in determining the responsiveness of tumor cells to anticancer drugs, such as cisplatin and adriamycin. The resistance of tumor cells having high concentration of metallothionein to cisplatin has been observed in cultured cells and transplanted tumors. On the other hand, increase in metallothionein concentration in normal tissues of tumor-bearing animals prevents side effects of anticancer drugs. Metallothionein may be an important endogenous factor in cancer chemotherapy.

P-glycoprotein, the MDR1 gene product which confers multidrug resistance to tumor cells and transports cationic or neutral compounds with high lipophilicity outward from the cells, excretes xenobiotics into the lumen in the kidney, small intestine and liver. The expression of P-glycoprotein is enhanced by stresses including exposure to various xenobiotics, while the activity is regulated to some extent by the phosphorylation. P-glycoprotein and P450 3A have similar substrate specificities and inducers, which may suggest they have complementary roles in the liver. The other subclass, MDR3, which does not show the multidrug resistance, translocates phosphatidyl choline selectively into the outer leaflet of the liver canalicular membrane, and may protect the liver from the detergent effect of bile acids.

There is considerable variation in the assays used to evaluate the expression of mdr1 in various human malignancies. Current methodology includes reverse transcriptase polymerase chain reaction (RT-PCR) for assay of mdr1 mRNA, and immunohistochemistry or flow cytometry for detection of the multidrug transporter, P-glycoprotein(P-gp). Normal tissues, such as gastrointestinal mucosa, biliary tract and kidney, express high levels of P-gp, which suggests physiologic functions for this transporter. The some evidence suggests that mdr1 expression is a prognostic factor for response to chemotherapy, as well as for subsequent survival in various kind of tumors. We have developed a novel method using flow cytometry for detection of P-gp in gastric carcinomas. A strong correlation was noted between the flow cytometric data and the degree of drug resistance assessed by thymidine incorporation assay (TIA). We believe that this technique may have a significant potential to be utilized in prediction of P-gp related drug resistance in clinical cancer chemotherapy.

In normal tissues, P-glycoprotein(P-gp), which is expressed in various tumor cells, is found on the luminal surface of epithelia of the kidney proximal tubule, small intestine and colon and bile canalicular face of hepatocytes, as well as, in the adrenal and capillary endothelial cells in the brain and testis. The physiological function of P-gp remains unclear but growing amounts of information suggest that it can play a important role in the absorption from intestine, elimination from liver and kidney and distribution into brain across the blood-brain barrier for many cancer chemotherapeutic agents as well as other drugs which reverse multidrug resistance. The competition for the P-gp-mediated transports in tissues and organs, which express multidrug-transporter, might lead to unsuspected drug interactions among these drugs.