HSP90 is one of the major molecular chaperones whose expression level increases by environmental stresses. Even under normal conditions, HSP90 is a highly abundant cytosolic protein and is essential for cell viability. HSP90 is involved in the maintenance of appropriate folding and conformation of many cellular functional proteins. These "HSP90 client proteins" are associated with HSP90 and they include a wide variety of signal-transducing proteins that regulate cell growth and differentiation, such as protein kinases and steroid hormone receptors. HSP90 functions in an ATP-dependent manner with other molecular chaperones such as Cdc37 and FKBP52. An HSP90 inhibitor, geldanamycin, binds the ATP-binding pocket of HSP90 and specifically inhibits the essential ATPase activity of HSP90. Thus, treatment of cells with geldanamycin results in inactivation, destabilization, and degradation of HSP90 client proteins. Because HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, and oncogenesis, geldanamycin obstructs the proliferation of cultured cancer cells and shows anti-cancer activity in experimental animals. Although the precise mechanism of the effect of HSP90 inhibitors on cancer cells remains to be clarified, HSP90 inhibitors will be potential and effective cancer chemotherapeutic drugs with a unique profile. In fact, a modified geldanamycin with lower toxicity, 17-allylaminogeldanamycin (17-AAG), has been examined in phase I clinic trials with encouraging results.

A randomized, multicenter, double-blind, parallel-group study was conducted in order to evaluate the hormonal kinetics, pharmacokinetics, efficacy and safety of TAP-144-SR (3M) a three-month sustained-release injectable preparation of leuprorelin acetate, a highly active luteinizing hormone-releasing hormone (LH-RH) derivative by comparing the treatment with two subcutaneous doses of the test medication TAP-144-SR (3M) and the treatment with six subcutaneous doses of the reference medication TAP-144-SR (1M), a 1-month sustained-release injectable preparation. Study participants were 103 patients with prostate cancer in whom a stable anti-tumor effect had been obtained with Leuplin Injection 3.75. The hormonal kinetics revealed that the proportion of the patients "maintaining the castration level of serum testosterone (maximum serum testosterone level during treatment below the castration level [100 ng/dl])" was 100% in both treatment groups. With regard to the efficacy, the proportions of the patients in whom the anti-tumor effects (> or = Stable) of the baseline treatment prior to the initiation of the treatment with the study medication were maintained during the study treatment period (6 months) were comparable; 84.0% with TAP-144-SR (1M) and 80.4% with TAP-144-SR (3M). On evaluation of the pharmacokinetics, the mean value of AUC1-12w of the serum TAP-144 concentration (including the metabolite M-I) for the treatment with TAP-144-SR (3M) was 77.0% that of the treatment with TAP-144-SR (1M). Adverse events were similar in the subjects on TAP-144-SR (3M) and in those on TAP-144-SR (1M). There existed no big differences in kind, incidence or time of occurrence of adverse events between two groups. TAP-144-SR (3M) showed no clinically relevant findings in particular. These results indicate that one dose of TAP-144-SR (3M) is comparable to three doses of the already approved Leuplin injection 3.75 in serum testosterone level-inhibitory effect, efficacy and safety. Hence, it is considered that TAP-144-SR (3M) is a drug suitable for treatment of prostate cancer over a prolonged period of time.

TAP-144-SR (3M) is a 3-month sustained releasing injection of a super-active agonist of luteinizing hormone releasing hormone (LH-RH), leuprorelin acetate. At the Department of Urology of Gunma University Hospital, TAP-144-SR (3M) was injected once subcutaneously into 10 prostatic cancer patients who had had no treatment in the past to investigate safety, serum testosterone levels, drug concentrations and efficacy. In safety, no problematic adverse reactions occurred, and the drug was well tolerated. Serum testosterone levels elevated temporarily up to 2 days after injection and then were reduced rapidly. The levels were reduced below the castration level (100 ng/dl) after 3 weeks and then remained reduced up to 12 weeks. Serum TAP-144 levels including metabolite M-I, elevated to maximal plasma concentration up to 3 hours after injection and then were maintained at about 0.2 ng/ml between 1 week and 12 weeks after injection. With respect to the anti-tumor effects, the response rate according to "criteria of prostate cancer" at 12 weeks after injection was 100% (stable response cases) and the ratio of PSA normalization at 12 weeks was 90%. These results showed that an injection of TAP-144-SR (3M) was well tolerated in prostate cancer patients having no prior treatment and inhibited serum testosterone persisting for at least 12 weeks so that TAP-144-SR (3M) was concluded to be safe and clinically effective for prostate cancer patients.

Cladribine (2-chlorodeoxyadenosine: 2-CdA) is a chlorinated purine analogue that is resistant to degradation by adenosine deaminase. Phosphorylated derivatives of 2-CdA accumulate in lymphocytes with high deoxycytidine kinase activity, resulting in DNA strand breaks and cell death. Since the cytotoxic properties of 2-CdA are independent of cell division, 2-CdA is expected to be an effective agent in the treatment of indolent lymphoid malignancy with low-growth fraction. The agent was synthesized and has been investigated extensively by researchers at the Scripps Clinic and Research Foundation in the United States. The FDA approved cladribine for use against hairy cell leukemia, in 1993, and it was approved against hairy cell leukemia and indolent B-cell lymphoma in Japan in 2002 as Leustatin (Janssen Pharma Co. Ltd., Tokyo, Japan). The efficacy, toxicity and clinical usefulness of this agent against indolent lymphoid malignancies will be described according to the data from several clinical trials conducted in the United States, European countries and Japan.

A combination therapy with CPT-11 and 5-FU/LV has been recently established as a first-line therapy for metastatic colorectal cancer. However, severe adverse effects have also been reported from this combination therapy, and a modality to reduce the adverse effects is desired. 5'-DFUR, a pro-drug of 5-FU, shows less myelotoxicity than 5-FU, and thus it may be a better partner to combine with CPT-11. However, since each drug has the possibility of inducing diarrhea, there is concern about their use in combination therapy. Therefore, in the present study, our aim was to establish an optimal schedule in murine models, which shows no increase in diarrhea but maintains potent antitumor activity. In non-tumor bearing mice, CPT-11 was given i.v. at 100 mg/kg/day q2d x 3, and 5'-DFUR was given p.o. at 172 mg/kg/day daily for 14 days. Each of these doses caused diarrhea in the single treatment. CPT-11 was administered simultaneously or sequentially with 5'-DFUR. With the simultaneously administered schedule, the diarrhea appeared stronger than that found in the CPT-11 single or in the 5'-DFUR single treatment groups. On the other hand, with the sequentially administered schedule the diarrhea was not much stronger than that found in the single agent treatment groups. When CPT-11 and 5'-DFUR administrations were separated by three-day intervals, the diarrhea was not augmented at all. In mice bearing human colorectal cancer COLO 205, the antitumor activity of CPT-11 in the combination with 5'-DFUR was additive in all of the examined schedules. The efficacy in the sequential schedule was the same as in the simultaneous schedule. These results suggest that a sequential administration schedule of CPT-11 and 5'-DFUR would be more tolerable than and equally efficacious to the simultaneous administration schedule. Clinical study of this sequential administration in combination therapy is warranted.

Individual differences exist in the pharmacodynamics of fluorouracil-derived anticancer agents, with circadian variability even in the same patient probably due to individual differences in the distribution of dihydrophrimidine dehydrogenase (DPD), a decomposing enzyme. Though DPD activity is usually determined in the liver or blood, a more simplified estimation of DPD activity has been recently attempted using urine uracil levels. However, because urine uracil level has the drawback of being easily affected by food ingestion or kidney function, in this study it was determined simultaneously with the determination of plasma 5-FU clearance after sustained instillation of 250 mg 5-FU, in order to estimate DPD activity more accurately. A correlation was observed between urine uracil levels and 5-FU clearance. In cases showing a baseline urine uracil level below 25.1 mumol/g. Creatinine, the blood concentration decreased due to large 5-FU clearance, with a tendency for diminished efficacy of FU-derived anticancer agents. In cases showing a baseline urine uracil level above 99.9 mumol/g. Creatinine, on the other hand, adverse reactions due to FU anticancer agents tended to become more serious. Since urine uracil level can be determined easily, it could be the first choice in screening to detect abnormal metabolism of fluorouracil-derived anticancer agents under present circumstances. By combining determination of urine uracil level with 5-FU clearance, it seems possible to predict adverse effects and the effective rate of these agents more accurately. Under existing circumstances, where genetic analysis remains unavailable as a general practice, the combined determination of urine uracil levels and plasma 5-FU clearance may be beneficial in developing order-made treatments in cancer chemotherapy.

The emergence of tumors resistant to anticancer agents has been recognized as one of the major obstacles to effective cancer chemotherapy. Recent studies have elucidated various mechanisms in this resistance, such as induction of drug efflux pumps, in particular certain of the ABC transporters. Experiments to predict the sensitivity of tumors to anticancer agents using DNA microarray and SNPs analyses are ongoing. The development of the new anticancer agent ST1571 and the emergence of tumors resistant to ST1571 indicate the urgent need for clinically available reversing agents.

The mammalian circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). Clock genes are the genes that control the circadian rhythms of physiology and behavior. The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24-h rhythms of biochemical, physiological, and behavioral processes under the control of the circadian clock. However, many drugs are still administered without regard to the time of day. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The monitoring of rhythmic markers may be useful in choosing the most appropriate time of day for administration of drugs and may increase their therapeutic effects and/or reduce their side effects. On the other hand, several drugs can cause alterations in 24-h rhythms, leading to illness and altered homeostatic regulation. Here, we show the disruptive effect of interferon on the rhythm of locomotor activity, body temperature, and clock gene mRNA expression in the periphery and SCN. The alteration of the clock function, a new concept of adverse effects, can be overcome by devising a dosing schedule that minimizes adverse drug effects on clock function. Furthermore, to produce new rhythmicity by manipulating the conditions of living organs using rhythmic administration of altered feeding schedules or several drugs appears to lead to the new concept of chronopharmacotherapy. One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best effective and/or tolerated.

We studied the pharmacokinetics of CPT-11 with intraperitoneal administration in a patient with a PTCD tube. The patient had advanced gastric cancer with peritoneal metastasis. CPT-11 was administrated in a dose of 40 mg and the intraperitoneal, plasma and bile levels of CPT-11, SN-38 and SN-38 glucuronide (SN-38 GLU) were measured periodically. The results showed that the periodical concentration pattern of CPT-11, SN-38 and SN-38 GLU in the bile was closely related to that of CPT-11 in the abdominal cavity.

A 51-year-old man underwent partial hepatectomy in July 2000 for metastatic liver tumor after gastrectomy for gastric cancer. He received seven cycles of hepatic arterial infusion with mitomycin C 20 mg during induced hypertension with angiotensin II from October 2000 to April 2001. His body temperature sometimes rose above 38 degrees C in June and jaundice appeared in August 2001. Blood biochemistry tests showed an elevated value of alkaline phosphatase, gamma-glutamyl transpepsidase and total bilirubin. Based on an enhanced CT scan of the liver showing a low-density area along intrahepatic biliary tracts and hepatic arteriography showing stenosis of the proper hepatic artery, we diagnosed bile duct necrosis and hepatic necrosis. Bile duct necrosis is a serious complication in arterial infusion chemotherapy, and the infusion chemotherapy should be suspended or the dose should be reduced for patients with abnormalities shown by hepato-biliary function tests.

To examine the adverse reactions to TS-1 for patients with recurrent head and neck cancer, five patients with locoregional recurrences and two with distant metastasis were enrolled in the present study and took TS-1 as outpatients. All patients underwent irradiation with or without surgery before administration of TS-1. One patient was given 100 mg of TS-1 daily, and six patients were given 120 mg of TS-1 daily. Thirteen courses consisted of the regimen of four weeks of TS-1 administration followed by two weeks of intermission, nine courses consisted of the regimen of two weeks of administration followed by one week of intermission, and seven courses consisted of the regimen of two weeks of administration followed by two weeks of intermission. Anemia, leukopenia, neutropenia, and liver dysfunction were often observed as adverse reactions to TS-1 administration. Grade 3 bilirubinemia was observed in only one course, but other adverse reactions consisted of grade 1 or grade 2. Almost all adverse reactions returned to normal after the cessation of drug administration. Based on these results, we conclude that TS-1 is a safe drug for the treatment of outpatients with recurrent head and neck cancer.

A 71-year-old man visited our hospital complaining of fever and a bleeding tendency. The peripheral blood WBC count was 10,400/microliter with 90% promyelocytes. The bone marrow was hypercellular with 88% promyelocytes. Disseminated intravascular coagulation was recognized. The patient was diagnosed as having acute promyelocytic leukemia and was treated with daily oral administration of all-trans retionic acid (ATRA) (45 mg/m2/day) and cytarabine (160 mg/day, intravenous drip infusion for the initial five days). The ATRA treatment induced leukemic cells to undergo mature myeloid differentiation. On day 24 after the start of treatment, the WBC count rapidly increased and acute myocardial infarction appeared, with consciousness disturbance and bilateral Babinski reflex appearing three hours later. Magnetic resonance imaging showed a fresh lacunar infarction of the right lenticular nucleus, and serum levels of IL-6 and PAI-1 were found to be elevated at the onset of infarction. Since there was a possibility that the retinoic acid syndrome (RAS) might have helped bring about the infarctions, we stopped the ATRA treatment and started administration of methyl-prednisolone (500 mg/body/day for 3 days) and gabexate mesilate. The WBC count decreased immediately and the consciousness disturbance improved. In this case, ATRA treatment might have initiated the RAS and resulted in some endothelial damage, thus causing the infarctions.

We have confirmed that theanine, a major amino acid in green tea, enhances the antitumor activity of doxorubicin (DOX) without an increase in DOX-induced side effects. We believe that the action of theanine is due to decreases in glutamate uptake via inhibition of the glutamate transporter, intracellular glutathione (GSH) synthesis, GS-DOX conjugate level, and subsequent extracellular transport of GS-DOX by the MRP5/GS-X pump. To increase the clinical usefulness of theanine, we examined its effects on the antitumor activity of cisplatin and irinotecan (CPT-11), which a known to be transported by the efflux system related to MRP. Cisplatin decreased tumor volume in M5076 tumor-bearing mice. Furthermore, the combination of theanine with cisplatin increased the decrease in tumor volume as compared with the cisplatin-alone group. Tumor volume in the CPT-11-alone group did not show a decrease, but the combination of theanine with CPT-11 significantly reduced tumor volume. The concentration of cisplatin in the tumor was significantly increased by combination with theanine, and thus we assume that it correlated with the enhancement on the antitumor activity of theanine. On the other hand, changes in drug concentrations with theanine were not observed in normal tissues, but rather it is indicated that theanine tends to reduce their concentrations. Therefore theanine enhances the antitumor activity not only of DOX but also of cisplatin or CPT-11.

This study was designed to evaluate the pharmacokinetics and toxicity of docetaxel administered via an intraperitoneal (i.p.) route for patients with gastric cancer. Eleven patients with peritoneal dissemination were entered into this trial. Patients were treated with 45 mg/m2 of i.p. docetaxel administration in 1 l of saline. Peak peritoneal concentration was 40.0 +/- 14.5 micrograms/ml and peritoneal concentration at 24 hours after drug administration was 4.3 +/- 3.9 micrograms/ml. The median pharmacokinetic advantage (AUC peritoneal/AUC plasma) was 515 (range 22-1, 770). Grade 2 and 3 toxicities included 5 episodes of diarrhea; 3 of abdominal pain; 3 of ascites; 2 of alopecia; and 1 of neutropenia. We conclude that intraperitoneal docetaxel administration is well tolerated and provides a peritoneal pharmacokinetic advantage for the treatment of peritoneal dissemination.

One of the most common and problematic side effects of interleukin-2 therapy (IL-2) is vascular leak syndrome (VLS). VLS is characterized by an increase in vascular permeability accompanied by extravasation of fluids and proteins from the capillary vessels into the tissues resulting in interstitial edema, weight gain, pleural effusion, ascites in severe form, multiple organ failure. We, herein, report two cases of VLS, which occurred following IL-2 therapy against metastatic renal cell carcinoma. One of them died of multiple organ failure one month after the cessation of IL-2 therapy.