Biomedical subjects
Publications and source records attributed to M Oguro.
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4-Piperidinopiperidine is a side residue of CPT-11, a derivative of camptothecin. We have previously established a 4-piperidinopiperidine-resistant lymphoma cell line, 4-pp-R, which was co-resistant to CPT-11. We report here that this cell line is cross-resistant to dexamethasone and A23187 which induce apoptosis in parent RVC cells. Examination of apoptosis-related gene expression by RT-PCR showed that bcl-2 expression was greater in 4-pp-R than in RVC. p53, bax and bcl-xL were expressed at the same level in 4-pp-R and RVC cells. These results suggest that upregulation of bcl-2 in 4-pp-R cells is related to the resistance to CPT-11 as well as to A23187 or dexamethasone.
CPT-11 is a promising new anticancer drug in which 4-piperidinopiperidine is a side-chain structure. In the present studies, we examined the role played by 4-piperidinopiperidine in the pharmacological activity of CPT-11. When T-cell lymphoma RVC cells were incubated with 4-piperidinopiperidine at concentrations higher than 50 micrograms/ml, the cells underwent apoptosis with a nucleosomal ladder of chromosomal DNA on agarose gels in a dose-dependent manner. We then established a cell line resistant to 4-piperidinopiperidine (4-pp-R), which was about 20-fold more resistant to 4-piperidinopiperidine than the parent RVC cells. Moreover, 4-pp-R cells showed coresistance to CPT-11. However, the growth rate and cell cycle population of 4-pp-R cells were not different from those of the parent RVC cells, and there were no differences between the two cells lines with regard to their drug transport system. CPT-11-metabolizing activity, their activity and amount of topoisomerase I, or their sensitivity to either SN-38 or etoposide, suggesting that the cytotoxicity of CPT-11 is not a consequence of the activity of its metabolite SN-38. The present studies suggested that resistance to CPT-11 is in part due to insensitivity to 4-piperidinopiperidine and its metabolites, since 4-piperidinopiperidine was cytotoxic and 4-pp-R cells were less sensitive to CPT-11.
Human thermal physiological and comfort models will soon be able to simulate both transient and spatial inhomogeneities in the thermal environment. With this increasing detail comes the need for anatomically specific convective and radiative heat transfer coefficients for the human body. The present study used an articulated thermal manikin with 16 body segments (head, chest, back, upper arms, forearms, hands, pelvis, upper legs, lower legs, feet) to generate radiative heat transfer coefficients as well as natural- and forced-mode convective coefficients. The tests were conducted across a range of wind speeds from still air to 5.0 m/s, representing atmospheric conditions typical of both indoors and outdoors. Both standing and seated postures were investigated, as were eight different wind azimuth angles. The radiative heat transfer coefficient measured for the whole-body was 4.5 W/m2 per K for both the seated and standing cases, closely matching the generally accepted whole-body value of 4.7 W/m2 per K. Similarly, the whole-body natural convection coefficient for the manikin fell within the mid-range of previously published values at 3.4 and 3.3 W/m2 per K when standing and seated respectively. In the forced convective regime, heat transfer coefficients were higher for hands, feet and peripheral limbs compared to the central torso region. Wind direction had little effect on convective heat transfers from individual body segments. A general-purpose forced convection equation suitable for application to both seated and standing postures indoors was hc = 10.3v0.6 for the whole-body. Similar equations were generated for individual body segments in both seated and standing postures.
BACKGROUND: Measurements of serum alpha-fetoprotein (AFP) concentration and plasma concentration of des-gamma-carboxy prothrombin (DCP) have been widely used for the early diagnosis of hepatocellular carcinoma (HCC). The two markers generally run parallel to each other. However, in our study, they sometimes fluctuated independently in response to tumor regression or recurrence. METHODS: A longitudinal series of concentrations of serum AFP and plasma DCP were determined simultaneously for 245 patients with HCC from the time of diagnosis to tumor recurrence after treatment. RESULTS: Positive reactions for AFP were noted in 168 patients (69%) and for DCP in 126 patients (51%). One hundred and ten of 245 patients with HCC (45%) were positive for both AFP and DCP. In 35 patients (14%), these 2 tumor markers fluctuated independently in response to tumor regression and recurrence. These patients were categorized into four groups as follows: Group 1 had elevated AFP only at diagnosis; it then decreased after treatment, but DCP was elevated at the time of tumor recurrence without AFP elevation (3 patients); Group 2 had elevated DCP at diagnosis and elevated AFP at tumor recurrence (4 patients); Group 3 had elevated AFP and DCP at diagnosis, but only AFP (8 patients) or DCP (7 patients) was elevated at tumor recurrence; Group 4 had only elevated AFP (2 patients) or DCP (11 patients) at diagnosis, but both AFP and DCP were elevated at tumor recurrence. CONCLUSIONS: The results of this study indicate that simultaneous determinations of AFP and DCP are useful for monitoring recurrence in patients with HCC after treatment, and that the decrease to normal levels of a single marker does not always indicate the absence of tumor recurrence.
A feasibility study was carried out on the treatment for refractory and relapsed non-Hodgkin's lymphomas with a combination of two oral topoisomerase II inhibitors, MST-16 and VP-16. On the basis of the synergistic activity in preclinical studies and the schedule dependency in these drugs, low-dose and long-term administration was planned. For the anticipated myelosuppression, two different regimens were designed as an open label trial in this study. In Regimen I, 400 mg of MST-16 combined with 25 mg of VP-16 was administered daily. With this regimen, the response rate (RR)/median time to tumor progression (TTP) in all evaluable patients was 50% (2/4)8.5 months in low grade (indolent) lymphoma and 60% (6/10)/5.2 months in intermediate/high grade (aggressive) lymphomas. In Regimen II, 400 mg of MST-16 combined with 25 mg of VP-16 was administered intermittently (3 days a week or every other day). With this regimen, there was an RR/median TTP of 60% (3/5)/7.0 months in indolent lymphoma and 33.3% (4/12)/1.1 months in aggressive lymphoma. A major side effect in both of these regimens was myelosuppression, with the incidence of grades 3 and 4 toxicity being higher in Regimen I than in Regimen II. The other side effects were uncommon and not severe. These findings indicated that two regimens were tolerated well and were promising for refractory and relapsed aggressive non-Hodgkin's lymphomas. To define the anti-tumor activity and safety of these regimens precisely, large-scale prospective randomized trials are necessary.
A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.
The antigenicity tests of Tazobactam/piperacillin (TAZ/PIPC), tazobactam (TAZ:beta-lactamase inhibitor) and piperacillin (PIPC:penicillin antibiotic) were performed in mice and guinea pigs. The following results were obtained. 1. TAZ/PIPC, TAZ or PIPC had no immunogenicity and allergenicity in either passive cutaneous anaphylaxis (PCA) test using BALB/c and C3H/He mice or in PCA test using guinea pigs. 2. Guinea pigs sensitized with TAZ/PIPC, TAZ or PIPC showed no anaphylactic symptoms in active systemic anaphylaxis (ASA) test. 3. Guinea pig PCA tests using protein conjugates as sensitizing and challenging antigens showed positive reactions. Immunological cross-reactivity tests were performed by using these conjugates in guinea pig PCA reaction. Results showed that TAZ/PIPC and PIPC cross-reacted with penicillin G (PCG) and ampicillin (ABPC), but not with cephalothin (CET) and cephmetazol (CMZ). TAZ did not cross-react with PCG, ABPC, CET or CMZ. 4. From the results of the passive hemagglutination (PHA) test, no antibody against TAZ/PIPC, TAZ or PIPC was detected. 5. In direct Coombs' test using human blood, TAZ/PIPC, TAZ, PCG and CET showed positive reactions at 20-80, 5-20, 80 and 10-20 mg/ml, respectively. 6. The results of a test on in vitro covalent binding activity with human serum albumin indicated that the order of binding potency was CET > CMZ > ABPC > PCG = PIPC > TAZ under the physiological condition (pH 7.2-7.4), and was CMZ > CET > ABPC > PIPC > TAZ > PCG under the alkaline condition (pH 10.0-10.5), respectively.
A 63-year-old woman was in hospital for persistent backache. Four months prior to admission she had been pointed out as having hypertension for the first time. On admission, she had anemia (hemoglobin 7.0 g/dl) with reticulocytosis, and a blood smear showed fragmented erythrocytes. A bone marrow aspirate disclosed erythroid hyperplasia and invasion of cancer cells. The chest roentgenogram showed a coin-lesion of the right lung and left pleural effusion. A diagnosis of microangiopathic hemolytic anemia (MAHA) associated with carcinomatosis was made, but the primary site of the cancer was unknown. Respiratory failure developed and the patient died a month later. Surprisingly, the autopsy revealed a malignant pheochromocytoma arising from the right adrenal gland with massive metastases to the lungs, liver, lymph nodes and systemic bones, and also disseminated intravascular coagulation (DIC). The DIC would probably account for the MAHA in this case. To our knowledge, this is the first reported case of malignant pheochromocytoma accompanied by MAHA.
An early phase II study of CPT-11 (irinotecan hydrochloride) was conducted in patients with hematological malignancies by 4 administration regimens in a cooperative study involving 13 institutes in Japan. The overall response rate was 23% (7/30) for non-Hodgkin's lymphoma, 33% (1/3) for Hodgkin's disease, 18% (2/11) for acute lymphoblastic leukemia and 7% (1/15) for acute myelogenous leukemia. One PR was also obtained in a patient with chronic myelogenous leukemia. Among responders, 6 relapsed and refractory malignant lymphomas (ML) and 2 relapsed and refractory acute leukemias (AL) were involved. The response rates in ML with the regimens B (40 mg/m2 for 5 days every 3-4 weeks) and C (40 mg/m2 for 3 days every weeks) were 31% (5/16) and 33% (3/9), respectively. The other regimens (regimen A, 200 mg/m2 once a day every 3-4 weeks and regimen D) resulted in no response. Responses in AL were only observed in regimen D (20 mg/m2 twice a day for 7 days every 3-4 weeks). Major toxicities were leukopenia (91%), nausea/vomiting (74%), diarrhea (73%) and anorexia (64%). The incidence of severe gastrointestinal symptoms was higher in regimen B than regimen C. Further studies are warranted to confirm the effectiveness and safety of CPT-11 against ML and AL. The recommended administration schedule was regimen C for ML and regimen D for AL.
An early phase II study of irinotecan (CPT-11) in patients with advanced or recurrent breast cancer was undertaken by a cooperative study group of 15 institutes in Japan. CPT-11 was administered by intravenous drip-infusion. The administration schedules were 100 mg/m2 weekly (regimen A), 150 mg/m2 biweekly (regimen B), and 200 mg/m2 every 3-4 weeks (regimen C). There were 4 partial responses (PRs), 12 cases with no changes (1 minor response) and 9 cases of progressive diseases with a response rate of 16% (4/25). One out of 7 patients on regimen A and 3 patients out of 15 patients on regimen C achieved PR with a response rate of 14% and 20%, respectively. In three out of 4 PRs, prior chemotherapy, endocrinotherapy or radiotherapy had failed. Major adverse reactions were leukopenia 28/33 (85%), neutropenia 19/25 (76%), anemia 15/33 (46%), nausea/vomiting 28/33 (85%), anorexia 25/33 (76%), diarrhea 22/33 (67%) and alopecia 20/33 (61%). The incidence of leukopenia and thrombocytopenia seemed to be higher in regimen C than regimen A, and diarrhea was also more severe in regimen C than regimen A. The recovery of leukopenia was delayed in some patients on regimen C. The results suggested that CPT-11 was effective against advanced or recurrent breast cancer. The recommended administration schedule for a late phase II study was thought to be 100 mg/m2 weekly, considering efficacy and safety.
Liblomycin (NK313) is a bleomycin analog that has proved to be associated with less pulmonary toxicity and with more potent antitumor activity than bleomycin in animal tumors. In a phase I study, pulmonary toxicity was not observed, whereas myelosuppression was the dose-limiting factor. The maximum tolerated dose was 140 mg/m2 given once a week for 4 weeks. In the present phase II study, patients with malignant lymphomas received liblomycin at 80 or 100 mg/m2 by intravenous infusion over 15 min once a week for 4 weeks. A total of 39 patients were entered, and 31 [4 with Hodgkin's disease (HD) and 27 with non-Hodgkin's lymphoma (NHL)] were evaluable. The median age of the patients was 52 years (range, 22-74 years), and their performance status ranged from 0 to 3. In all, 28 of the patients had a history of intensive anticancer chemotherapy. Responses were evaluated according to WHO criteria. We obtained 1 complete remission and 9 partial remissions (PRs), for an overall response rate of 37%, in the 27 patients with NHL, whereas 1 PR was achieved in the 4 patients with HD. In all, 9 PRs (32.1%) were obtained in patients who had been exposed to prior chemotherapy, including 4 PRs (33.3%) in 12 patients who had previously been treated with bleomycin. Myelosuppression and nausea and vomiting were the major toxicities, which occurred in about 50% of the patients, and myelosuppression was severe in two patients treated at a dose of 100 mg/m2. We concluded that liblomycin demonstrated significant antitumor activity against malignant lymphomas.
Chemical structures of the sugar chains of various human alpha-fetoprotein (AFP) species with different affinity for Concanavalin A (Con A) and Lens culinaris agglutinin (LCA) were examined by pyridylamination of their oligosaccharides and stepwise exoglycosidase digestion. Using reversed-phase and size-fractionation high performance liquid chromatography systems we identified six pyridylamino-sugar chains. The Con A-reactive and LCA-nonreactive species of AFP from patients with hepatocellular carcinoma contained a biantennary sugar chain, and the Con A-reactive and LCA-reactive species had a biantennary one with a fucose residue at the innermost N-acetylglucosamine residue. The Con A-nonreactive and LCA-reactive species contained a biantennary sugar chain both with a bisecting-N-acetylglucosamine residue at the trimannosyl core and with a focus residue at the innermost N-acetylglucosamine residue. The Con A-nonreactive and LCA-nonreactive species contained a fucosylated triantennary sugar chain as a major component, and two minor components: a triantennary sugar chain and a biantennary sugar chain with a bisecting-N-acetylglucosamine residue at the trimannosyl core. Thus, the fucosylated and non-fucosylated triantennary sugar chains were newly identified in human AFP. Essentially identical results were obtained for AFP from the patient with gallbladder carcinoma which metastasizes to the liver. These results indicate that the increment in fucosylation and branching to form new antennae is a characteristic feature of the carbohydrate chains of AFP from patients with neoplastic diseases of the liver.
A 56-year-old man had been treated with phenobarbital seven weeks prior to admission. One month after initiation of administration of phenobarbital, fever, skin rash and lymphadenopathy occurred. Nine days later, marked atypical lymphocytosis, eosinophilia and hepatic injury was noticed. The histology of the biopsied skin was indistinguishable from lymphoma. CHOP-therapy was started but the patient was followed without further treatment because of polyclonal T-lymphocytosis. Afterward, clinical and hematologic improvement ensued and he has been well until now, 52 months later. The marked T-lymphocytosis observed in this case is probably a lymphoid leukemoid reaction secondary to hypersensitivity to phenobarbital.
We report here on three patients with cirrhosis for whom an early recognition of hepatocellular carcinoma was made possible by the measurement of the degree of fucosylation (fucosylation index) of alpha-fetoprotein. Increased levels of this index associated with a moderate increment of serum concentration of alpha-fetoprotein were observed in three patients with cirrhosis who showed no indication of hepatocellular carcinoma by several imaging modalities. Four years after the onset of an increase in the fucosylation index, small hepatocellular carcinoma with a tumor diameter less than 2 cm was revealed in case 1. In cases 2 and 3, small hepatocellular carcinomas were detected 24 mo and 9 mo, respectively, after the first sign of the increase in the index. However, the development to hepatocellular carcinoma was not detected in five patients with cirrhosis in whom continuous increments of serum concentration of alpha-fetoprotein with low levels of fucosylation index were observed during the prospective follow-up from 3 to 9 yr. These findings indicated that the fucosylation index of alpha-fetoprotein can be used as an aid in an early recognition of hepatocellular carcinoma, especially in patients with cirrhosis during the follow-up process in which the moderate increment of serum concentration of alpha-fetoprotein is noted.
Twenty-one patients with advanced-stage, intermediate- and high-grade non-Hodgkin's lymphomas were treated with alternating CHOP-MEVP chemotherapy. CHOP therapy consisted of CPA 650 mg/m2, ADM 45 mg/m2, VCR 1.4 mg/m2 and Pred 40 mg/m2 (po). MEVP therapy consisted of MIT 10 mg/m2 (iv) VDS 2 mg/m2 (iv) on day 1, etoposide 200 mg/m2 (po) on days 1-3, and Pred 40 mg/m2 (po) on days 1-5. Three courses of CHOP therapy and MEVP therapy were alternatively administered every three weeks. CR was achieved in 15 (71.4%) of 21 patients. Survival rate and relapse-free rate at 2 years for all 21 patients were 61.9% and 30.9%, respectively. Toxicity was generally tolerable except for CMV interstitial pneumonitis in a patient with IBL-like T-cell lymphoma and secondary leukemia in a patient with T-cell lymphoma. Chemotherapy of higher dose intensity is required to improve the relapse-free survival rate in these subsets of lymphoma.
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A 48-year-old woman with malignant lymphoma, who was diagnosed as a hepatitis B virus (HBV) carrier because of positive HBs antigen, was admitted to Chiba Cancer Center Hospital. Complete remission was achieved by two courses of combination chemotherapy, but fulminant hepatitis developed after withdrawal of chemotherapy and she died of hepatic failure. Retrospective analysis of viral DNA disclosed a mutation in the precore region of HBV-DNA in her serum. We consider that the precoremutant virus was associated with the pathogenesis of severe hepatic failure after withdrawal of cytotoxic chemotherapy.