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Biomedical subjects

N Saijo

Publications and source records attributed to N Saijo.

At least 217 records · Page 12Linked to original sources
PubMed1994

[The present status and prospects for clinical oncology in Japan].

The present status and prospects for clinical oncology in Japan were reported. Clinical oncology in Japan is still developing, although some research has attained the international level. This is because there are some problems in ethics of clinical trials, education of medical oncologists in medical schools, systems of cancer-related associations and the research system of clinical trials for cancer treatment. The education of medical oncologists and improvement of the research system in clinical oncology are required in order to develop clinical oncology in Japan.

Clinical Protocols↗
PubMed1994

[Clinical efficacy of arbekacin in patients with methicillin-resistant Staphylococcus aureus infections. Research Group of MRSA Forum].

We investigated the clinical efficacy of arbekacin (ABK) in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections, and also studied coagulase types, beta-lactamase producing activity and drug sensitivity of MRSA isolated from various clinical specimens. A total of 23 patients with MRSA infections (13 cases of pneumonia, 1 case of sepsis, 1 case of pneumonia and sepsis and 8 cases of the others) who were hospitalized from April 1992 to September 1993 were enrolled in this study. They were 14 males and 9 females, and the mean age was 66.9 years (range, 18-91 years). All patients had underlying diseases (mainly malignant tumors and cerebrovascular diseases). ABK was given intravenously at doses ranging from 75 to 100 mg twice daily. The clinical efficacy rate was 90%; 8 cases showed excellent responses, 10 cases good, 1 case fair, 1 case poor and 3 cases were unevaluable. The eradication rate of MRSA was 81.8%; 16 cases were judged as eradicated, 3 cases decreased, 2 cases replaced, 1 case unchanged and in 1 case the bacteriological response was unknown. Side effects were not observed, but S-GPT was elevated in 1 case. Coagulase types of MRSA (123 strains) isolated at the institutes involved in the study were type II (56 strains), type IV (12 strains), type VII (13 strains) and other types (2 strains), but coagulase types of 40 strains could not be determined. Eighty-four strains (68.3%) produced beta-lactamases. MICs of ABK were 0.5 microgram/ml against 43 strains and 1 microgram/ml against 37 strains, and all of the MICs were under 4 micrograms/ml. In summary, ABK showed high antimicrobial activity against MRSA and clinical usefulness in the infections investigated.

Adolescent↗
PubMed1994

[Effect of cisplatin on cell cycle regulators].

An anticancer agent, cisplatin (CDDP), induced G2-phase arrest in PC-9 human cancer cells. To elucidate how CDDP acts on cell-cycle regulation, we analyzed the effect of CDDP on cell-cycle regulators such as P34cdc2 protein kinase. P34cdc2 kinase activity was maximum in G2 phase and decreased after G2/M transition in synchronized PC-9 cells. Evidence for a phosphorylated p34cdc2 complexed with cyclin B was obtained from cells in G2 phase and the p34cdc2 appeared to be dephosphorylated at M phase. After exposure to CDDP in G1 phase, PC-9 cells were arrested at G2 phase. The activation of p34cdc2 was inhibited by CDDP. Cyclin A, B and wee-1 kinase were not affected by the exposure to CDDP. Our data suggested that the effect of CDDP on cell-cycle phase might be regulated by the dephosphorylation of p34cdc2. We hypothesize that inhibition of p34cdc2 dephosphorylation by CDDP is important for its growth-inhibiting properties.

CDC2 Protein Kinase↗
PubMed1994

[Anticancer agents and apoptosis].

We reviewed recent reports on apoptosis and summarized the presentations at the Shirafu Cancer Symposium, 1993. The study of programmed cell death, apoptosis, has become one of the mainstream in cell biology, particularly in immunology, developmental biology and oncology. To determine whether the apoptotic cell death induced by anti-cancer agents could be inhibited by bcl-2, we established a bcl-2-transfected human small cell lung cancer cell line, SBC-3/Bcl-2. SBC-3/Bcl-2 showed higher resistance to ADM, CPT-11 and MMC compared with the parental line SBC-3. Agarose gel electrophoresis showed typical DNA fragmentation of SBC-3 following treatment with CPT-11 or MMC. In contrast, the same concentration of the drugs did not induce DNA fragmentation in SBC-3/Bcl-2. However, there was no difference in sensitivity to CDDP, VP-16, ACNU, MTX and Taxol between SBC-3 and SBC-3/Bcl-2 (Ohmori, T. et al. Biochem. Biophys. Res. Commun. 1993). These studies indicate that bcl-2 can modulate the cytotoxicity of some anti-cancer agents by inhibiting the process of apoptosis. We speculate that some apoptotic pathways are bcl-2-sensitive and others bcl-2-independent.

Animals↗
PubMed1994

[Vibratory perception threshold in normal volunteers].

A feasibility study on the vibratory perception threshold (VPT) in normal volunteers was conducted to detect anti-cancer drug induced peripheral neuropathy. The VPT was found to increase with age. The mean VPT in the main hand in 25 normal volunteers was significantly higher than in the other hand. No variation of VPT was observed in one day or one week. Variation of VPT in the lower extremities was detected between two examiners. In conclusion, the measurement of VPT was expected to be useful for the detection of anti-cancer drug induced peripheral neuropathy, if there is one examiner and the examined hand is specified.

Adult↗
PubMed1993

Intradural parenchymal involvement in the spinal subarachnoid space associated with primary lung cancer.

BACKGROUND: Intradural parenchymal involvement (IPI) in the spinal subarachnoid space associated with primary lung cancer is rare. A retrospective study was undertaken to investigate the clinical and pathologic features of IPI. METHOD: A total of 1215 cases of primary lung cancer were studied at autopsy; the results were reviewed retrospectively. RESULTS: Twenty (1.65%) of the cases revealed IPI in the spinal subarachnoid space. The histologic diagnoses were small cell carcinoma in ten cases, adenocarcinoma in eight cases, and squamous cell carcinoma in two cases. In 14 (70%) cases, the IPI was located between the lumbar and cauda equina of the spinal cord. However, no metastases were observed in the cervical spinal cord. Brain metastasis, vertebral metastasis, and meningeal carcinomatosis were seen in 70%, 60%, and 40% of the 20 cases, respectively, suggesting that these metastases may be related to the metastatic pathway to the spinal cord. Most patients had neurologic symptoms or signs referable to IPI; IPI could be diagnosed before death in only one patient by magnetic resonance imaging. The median interval between diagnosis of lung cancer and development of IPI and median survival after the onset of neurologic symptoms referable to IPI were 415 days and 110 days, respectively. CONCLUSION: The authors retrospectively received 1215 autopsies of patients with primary lung cancer and found 20 (1.65%) with IPI.

Adult↗
PubMed1993

Modulation of cisplatin sensitivity and accumulation by amphotericin B in cisplatin-resistant human lung cancer cell lines.

To ascertain whether resistance to cis-diamminedichloroplatinum(II) (cisplatin) could be overcome, we determined the effects of amphotericin B (AmB), an antifungal agent, on cisplatin cytotoxicity, cisplatin-induced DNA interstrand cross-links formation, and cellular accumulation of cisplatin in human lung cancer cell lines, PC-9, PC-14, PC-7, and H69 and their corresponding respective cisplatin-resistant sublines PC-9/CDDP, PC-14/CDDP, PC-7/CDDP, and H69/CDDP in vitro. In PC-9/CDDP but not PC-9 cells, augmentation of cytotoxicity was observed when a nontoxic concentration (10 micrograms/ml) of AmB was combined with cisplatin, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), and cis-diammine(glycolato)platinum(II). Sensitizing effects of AmB of varying magnitudes on cisplatin cytotoxicity also were observed in all the other cell lines except PC-14. AmB-induced increases in cisplatin-induced interstrand cross-links formation were observed, the magnitudes of which corresponded to the magnitudes of AmB-augmented cisplatin cytotoxicity. Increased intracellular cisplatin accumulation was observed in the presence of AmB in all the cells that were sensitized to cisplatin by AmB. Therefore, the increases in cisplatin accumulation were considered to be responsible, at least in part, for the mechanism of the sensitizing effect. Further experiments using other human lung cancer cell lines showed that cells that were more resistant to cisplatin were more sensitized to cisplatin by AmB than cells that were cisplatin-sensitive.

Amphotericin B↗
PubMed1993

Combination effect of vaccination with IL2 and IL4 cDNA transfected cells on the induction of a therapeutic immune response against Lewis lung carcinoma cells.

In order to develop a more effective method of immunotherapy we have transfected mouse interleukin-2 (IL2) or mouse interleukin-4 (IL4) cDNA into a spontaneous non-immunogenic murine lung cancer. Lewis lung carcinoma (LLC). IL2 cDNA transfection more strongly decreases tumorigenicity of LLC than IL4 cDNA transfection. Recombinant-human-IL2 treatment of mice that were transplanted with untransfected LLC could not prolong their survival. In contrast, vaccination with IL2-cDNA-transfected LLC (LLC-IL2) and LLC-IL2 mixed with IL4-cDNA-transfected LLC (LLC-IL4) could significantly suppress tumor growth of LLC in a tumor-specific manner. The vaccination with LLC-IL2 mixed with the same number of LLC-IL4 cells was more suppressive to the growth of LLC than that with LLC-IL2 cells alone, while LLC-IL4 vaccination alone was ineffective. Nude, severe-combined-immune-deficient (SCID) and beige mice were unable to reject LLC-IL2 cells. However, immunodeficient mice responded to LLC-IL2, but not to LLC, since their survival times after transplantation with LLC-IL2 cells were significantly longer than the survival time of normal or immunodeficient mice transplanted with untransfected LLC cells. We conclude that vaccination with IL2-producing tumors and, with more pronounced effect, in combination with IL4-producing tumors, is able to induce an immune response to this normally non-immunogenic tumor. Tumor rejection appears to be achieved by the combined activity of CTL and NK cells. This strategy has potential for new immunotherapeutic interventions in cancer patients.

Animals↗
PubMed1993

Cardiac tamponade caused by primary lung cancer and the management of pericardial effusion.

BACKGROUND AND METHODS: Between 1978 and 1990, 51 cases of pericardial effusion secondary to lung cancer were treated at the National Cancer Center Hospital by creating a pericardial window, using the subxiphoid approach, that was connected to a water-sealed drainage system. RESULTS: Most patients had advanced disease, such as distant metastasis (76%), pleural effusion (88%), and clinical Stage N2 or N3 disease (98%). Forty-five patients had cardiac tamponade, and six had no symptoms attributable to pericardial effusion. Cardiac tamponade was the initial manifestation of lung cancer in only 3 patients; it was a late manifestation in 48. Of those specimens that were examined cytologically, 92% had positive findings. The interval from creation of the pericardial window until removal of the drainage tube ranged from 4-135 days (median, 11 days). The interval was significantly longer in patients who previously had received thoracic radiation therapy (P < 0.05). The overall median survival was 80 days, and the 1-year survival rate was 10.5%. Postmortem examination showed that constrictive heart failure caused by pericardial lesions was the major contributory cause of death in 32% of patients. Using multivariate analysis, factors indicating a poor prognosis were: (1) the interval from the diagnosis of lung cancer to pericardial effusion development (P = 0.005) and (2) the absence of prior surgery (P = 0.007). CONCLUSIONS: The creation of a pericardial window effectively treated pericardial effusion in 85% of cases. However, the role of intrapericardial instillation of anticancer or sclerosing agents was unclear in this retrospective analysis.

Adult↗
PubMed1993

Characterisation of a vindesine-resistant human small-cell lung cancer cell line.

We established a vindesine-resistant (x 11.6) human small-cell lung cancer cell line (H69/VDS) by stepwise exposure of parent line H69 to vindesine. H69/VDS showed cross-resistance to taxol (x 10.1), vincristine (x 6.9) and colchicine (x 3.4) but not to doxorubicin, cisplatin or etoposide. There was no significant difference in intracellular [3H]-vincristine and doxorubicin accumulation between H69 and H69/VDS cells. The human mdr1 mRNA was not detected in either of the cell lines. These results indicated that H69/VDS did not express a typical multidrug resistant phenotype. Addition of 20 microM verapamil enhanced the growth inhibitory effect of vindesine on both H69/VDS (x 12.0) and H69 cells (x 3.8). The amount of total tubulin in H69/VDS cells was lower than that in the H69 parental cells. No significant increase was observed in the amount of total and polymerised tubulins of H69 cells. In H69/VDS cells, however, verapamil increased the amount of total tubulin to the level of parental cells, but decreased the amount of polymerised tubulin. Modulation of tubulin may play a role in the resistance to vindesine.

Antineoplastic Agents↗
PubMed1993

Guidelines for analysis and reporting of clinical trials in oncology.

When analyzing and reporting the results of clinical trials, investigators should follow a simple approach. The purpose of a trial is to estimate an effect or treatment difference, which if present would have clinical utility when treating new patients. Procedures or methods that do not facilitate precisely and impartially estimating and reporting the treatment effect are likely to mislead investigators. Most often in clinical trials, investigators are interested in estimates of risk ratios (specifically odds or hazard ratios) between the treatment groups or levels of a prognostic factor. These simple ideas suggest that the most useful results from clinical trials will be estimated risk ratios and their confidence limits. Especially in cancer, where disease progression, recurrence, and death are common events following treatment, estimates of risk difference are very relevant. Hypothesis tests and associated P-values, although often (or exclusively) reported, are of lesser utility because they do not fully summarize the data. These recommendations may be seen by some investigators to be contrary to accepted practice. It is true that they are somewhat contrary to common practice but their general acceptance is evident in many journals and presentations by clinical trial methodologists. Despite some disagreement among statisticians regarding the need for adjustment of analyses for imbalanced prognostic factors, it is helpful to see if treatment effects change after accounting for imbalances. When this occurs, it may be of clinical interest. Although we discourage analyses that exclude any patients who meet the eligibility criteria, some circumstances will require that this be done (e.g., when a patient refuses to participate after randomization). Investigators should report, and emphasize as primary, those analyses that include all eligible patients. It is our hope and belief that analysis and reporting of trial results along the guidelines suggested here will result in impartial and useful information for journal readers.

Clinical Trials as Topic↗
PubMed1993

The mechanism of the difference in cellular uptake of platinum derivatives in non-small cell lung cancer cell line (PC-14) and its cisplatin-resistant subline (PC-14/CDDP).

A cisplatin-resistant non-small cell lung cancer cell line, PC-14/CDDP, was established from PC-14 by stepwise escalation of CDDP concentrations in vitro. PC-14/CDDP cells were 11.4-fold more resistant to CDDP compared with PC-14 cells. This resistant cell line was cross-resistant to platinum analogues, such as carboplatin (CBDCA) (x 3.5), cis-diammine(glycolate-O,O')platinum(II) (254-S) (x 5.6) and cis-dichloro(ethylenediammine)platinum(II) (cis-DEP) (x 4.2). On the other hand, relative resistance value to ormaplatin was only 1.4-fold. To elucidate the mechanism(s) of CDDP resistance and of its circumvention by ormaplatin, we investigated the characteristics of this cell line. Total sulfhydryl content was slightly elevated in PC-14/CDDP cells compared with PC-14 cells. There was no significant difference in the DNA repair ability between the two cell lines. Cellular accumulations of CDDP, CBDCA, 254-S, and cis-DEP in PC-14/CDDP cells were markedly decreased to 23%, 27%, 29%, and 32% of those in PC-14 cells, respectively. However, the accumulation of ormaplatin in PC-14/CDDP was almost the same as that in PC-14. To elucidate the mechanisms of uptake of these platinum analogs in the cells, we studied the effects of ouabain, an Na+,K(+)-ATPase inhibitor, on cellular drug uptake in both cell lines. Preincubation with 300 nM ouabain for 1 h inhibited approximately 60% of CDDP accumulation in PC-14. However ouabain preincubation at any concentration up to 300 nM did not affect CDDP accumulation in PC-14/CDDP. The accumulation of ormaplatin was not inhibited by ouabain in either of the cell lines. These data suggest that the mechanism of the uptake of ormaplatin is different from that of CDDP, and that ormaplatin exerts a cytotoxic effect in CDDP-resistant cells which have defective cisplatin accumulation.

Antineoplastic Agents↗
PubMed1993

Novel water-soluble derivatives of docosahexaenoic acid increase diacylglycerol production mediated by phosphatidylcholine-specific phospholipase C.

The effect of ascorbic acid 6-docosahexaenoate (DHA-VC) on the phospholipase-C-mediated hydrolysis of phosphatidylcholine was investigated. In human non-small cell lung cancer cells (PC-14) exposed to DHA-VC for 24 hr, a dose-dependent increase in phosphatidylcholine-specific phospholipase C (PC-PLC) activity was seen. PC-PLC activity in whole-cell homogenate of PC-14 cells was increased about 2.5-fold by 2 hr of treatment with DHA-VC (20 micrograms/ml). Treatment with DHA-VC also augmented PC-PLC activity in the crude membrane extract. On the other hand, DHA-VC inhibited the activity of phospholipase A2 (ID50 = 800 micrograms/ml). Another water-soluble analog, choline docosahexaenoate, also stimulated PC-PLC activity. To explore the effect of DHA-VC on phosphatidylcholine turnover, we analyzed phospholipids labeled with [14C] choline or [3H]myristate by thin-layer chromatography, and found that the amount of [14C]- and [3H]-labeled phosphatidylcholine was constant in the presence of DHA-VC. These results suggest that phosphatidylcholine turnover was not influenced by DHA-VC. DHA-VC treatment increased protein kinase C activity of the cells in the late phase (120 min), suggesting that DHA-VC-induced diacylglycerol production mediated by PC-PLC causes protein kinase C activation. Considering that significant inhibition of DNA synthesis occurred 12 hr after 2 hr of treatment with DHA-VC (20 micrograms/ml), DHA-VC-induced PC-PLC activation seems to be an early event in DHA-VC-induced cytotoxicity, which suggests that the effects of DHA-VC on signal transduction pathways may play an important role in the cytotoxicity of DHA-VC.

Ascorbic Acid↗
PubMed1993

[Chemotherapy for small cell lung cancer].

This paper describes the results of a randomized trial comparing alternating chemotherapy with standard chemotherapy and of a trial of dose intensive chemotherapy with or without recombinant human granulocyte-colony stimulating factor (G-CSF) in small cell lung cancer (SCLC). 1) Between April 1985 and May 1988, the Japan Clinical Oncology Group conducted a randomized phase III trial of cyclophosphamide, doxorubicin and vincristine (CAV) versus cisplatin and etoposide (PE) versus CAV alternating with PE (CAV/PE). Three hundred patients were entered in the study, and 288 of them were eligible for analysis. The response rates for PE (78%) and CAV/PE (76%) were significantly higher than the rate for CAV (55%) (p < 0.01). The median survival time (MST) with CAV/PE (11.8 months) was superior to that with CAV (9.9 months) (p = 0.027) or that with PE (9.9 months) (p = 0.056); however, the survival advantage of CAV/PE disappeared when the data were adjusted for prognostic factors. These results have shown that CAB/PE is a reasonable approach for the management of SCLC. 2) Between May 1989 and September 1991, we carried out a randomized study to determine whether the dose intensity of the weekly CODE (cyclophosphamide, Oncovin, doxorubicin and etoposide) chemotherapy could be increased by the addition of G-CSF support. Sixty-three patients were entered in this study. The use of G-CSF was associated with a reduced incidence of neutropenic fever and an increase in the dose intensity. The MST for the patients treated with CODE plus G-CSF (58 weeks) was significantly longer than that for the patients treated with CODE alone (36 weeks). The results of this study showed that dose intensive weekly chemotherapy may improve the outcome of patients with ED-SCLC.

Aged↗
PubMed1993

[Phase II clinical trials in patients with lung cancer].

The goal of phase II clinical trials is to determine whether a new drug has activity against particular cancers. This trial, therefore, is the most important study in the process of development of investigational new agents and frequently may give misleading results. The design of phase II clinical trials of new anticancer agents in lung cancer has been reviewed based on the Guidelines for the Clinical Evaluation of Antineoplastic Agents notified by the Ministry of Health and Welfare in Japan. These guidelines present general approaches to clinical trials and should be adhered to in the development of investigational drugs in humans, although they are not directly mandated by law or regulations. We considered the policies of these guidelines and instituted them based on the actual circumstances in Japan, in order to develop a scientific and rational approach for clinical phase II trials. In addition, we introduced new active agents having a novel mechanism of action that show clinical activity in the treatment of lung cancer, such as irinotecan (CPT-11), a topoisomerase I inhibitor, and paclitaxel (taxol) and taxotere, targeting the microtubules.

Antineoplastic Combined Chemotherapy Protocols↗