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Biomedical subjects

N Saijo

Publications and source records attributed to N Saijo.

At least 307 records · Page 17Linked to original sources

The difference in surface phenotypes between cytotoxic lymphocytes induced in vivo by systemic administration of human recombinant interleukin-2 and lymphokine activated killer cells induced in vitro.

The cytotoxicity of spleen lymphocytes of C57BL/6 mice is augmented both by incubation of spleen lymphocytes with human recombinant interleukin-2 (rIL-2) in vitro (LAK cell) and by systemic administration of high doses of rIL-2 into C57BL/6 mice for more than 3 consecutive days. In this study, the precursors and effectors of LAK cells and the cytotoxic cells induced by systemic administration of rIL-2 were characterized by using anti-asialoGM1 and anti-Thy1.2 antibody. The in vitro induced LAK cells were demonstrated to be derived partly from asialoGM1 negative cells and the cytotoxicities of LAK cells induced in vitro with rIL-2 were partially resistant to lysis by anti-asialoGM1 antibody plus complement in comparison with NK cells. Contrary to this, the cytotoxicities of spleen lymphocytes of C57BL/6 mice pretreated with anti-asialoGM1 antibody were not augmented by in vivo injection of rIL-2. In addition, the cytotoxic activities of spleen lymphocytes, augmented by systemic administration of rIL-2, were completely suppressed by anti-asialoGM1 antibody and complement in vitro. These findings indicate that the cytotoxic lymphocytes induced in vivo by systemic administration of rIL-2 are different from in vitro induced LAK cells and have the same surface phenotype as NK cells.

Animals↗

Phase II study of carboplatin in small cell lung cancer.

Carboplatin (CBDCA; cis-diammine-1, 1-cyclobutane dicarboxylate platinum II), a new platinum analogue, was administered to 18 patients with small cell lung cancer (SCLC) at a dose of 300-450 mg/m2 intravenously every four weeks, in a phase II study. All patients could be evaluated to assess response and 17 for toxicity. The overall response rate was 28% (5/18), including one complete response. Of eight patients previously untreated, four (50%) showed a response, including one complete response. The response rate in patients with no previous cisplatin-treatment was 50% (5/10). Response durations in five responders were 2, 3, greater than 4, greater than 10 and 11 months. Toxicity was primarily hematologic, with thrombocytopenia being dose-limiting. Thrombocytopenia (less than 75,000/mm3) was observed in 12 patients (71%), six requiring platelet transfusion. Leukopenia (less than 3,000/mm3) was observed in 11 patients (65%). There were no episodes of serious infection or bleeding, however. Myelosuppression was more severe in heavily pretreated patients than in patients previously untreated. Dose reductions were required following multiple treatments for cumulative myelotoxicity. Mild to moderate nausea and vomiting occurred in seven patients (44%). Nephrotoxicity and ototoxicity were not observed. Carboplatin was demonstrated to be an active agent against SCLC. Further investigation into dose and schedule of CBDCA in combination chemotherapy is warranted.

Aged↗

Three schedules of recombinant human interleukin-2 in the treatment of malignancy: side effects and immunologic effects in relation to serum level.

Recombinant human interleukin-2 (rIL-2) was administered to 34 patients with advanced malignancy. Three schedules of rIL-2 administration employed were as follows: (A) 2-hr iv infusion of 6.7 X 10(5) U/m2/day (A1, 6 cases) or 2.2 X 10(6) U/m2/day (A2, 8 cases) for five consecutive days; (B) 24-hr continuous iv infusion of 3.3 X 10(5) U/m2/day (B1, 3 cases), 6.7 X 10(5) U/m2/day (B2, 7 cases) or 1.1 X 10(6) U/m2/day (B3, 5 cases) for 28 consecutive days; and (C) 24-hr continuous iv infusion of 6.7 X 10(5) U/m2/day (C, 5 cases) for 5 consecutive days per week for four weeks. The common side effects were fever (79%), eosinophilia (61%), malaise (56%), erythema or rash (50%), chills (38%) and nausea or vomiting (35%), with the dose-limiting toxicities being hypotension in group A, and renal dysfunction with fluid retention in groups B and C. In the case of 2-hr iv infusion, rIL-2 was rapidly cleared from the plasma, with a half life of about 30 min, while in the case of 24-hr continuous infusion, more than 1 U/ml serum IL-2 activity was maintained for 14 days in group B3. Natural killer (NK) and lymphokine-activated killer (LAK) activities were augmented by rIL-2 administration in patients of groups A, B3 and C. In eight patients of group B, NK and LAK activities transiently decreased after rIL-2 administration, and recovered by day 3. The percentage of IL-2 receptor and Leu HLA-DR positive cells reached the peak level on day 7 in group B. In patients of group C, the percentage of Leu HLA-DR positive cells as well as NK and LAK activities increased upon rIL-2 administration and decreased during an intermission of two days. However, the percentage of rIL-2 receptor positive cells increased during the intermission of rIL-2. The most effective schedule of rIL-2 administration was considered to be the schedule of group C on the basis of this study.

Adult↗

Treatment for small cell lung cancer--present status and future prospects.

Strategies for the treatment of small cell lung cancer (SCLC) were reviewed depending on the recent results of treatment. The development of new anti-cancer drugs are essential for the further improvement results of SCLC. However, the candidate of patient for phase II study of new anticancer drug is controversial. Intensified chemotherapy is essential in order to obtain long term survivors, however, the toxic death rate should be less than 5% of whole patients. The theory of non-cross resistant alternative chemotherapy has also been applied to the treatment of SCLC. The protocol study supported by grant-in-aid from the Ministry of Health and Welfare is now on-going by cooperative study. There are many discussions about the efficacy of combined modality in SCLC. However, present randomized trials gave clear answers about the priority of combined modality in SCLC. There are numerous biological studies about SCLC. These studies will contribute to improve the treatment results of SCLC.

Carcinoma, Small Cell↗

In vitro antitumor effect of recombinant human tumor necrotizing factor on cultured human cancer cell lines and freshly isolated lung cancer cells by the human tumor clonogenic assay.

In vitro antitumor effects of human recombinant tumor necrotizing factor (rH-TNF) were examined against nine lung cancer cell lines including six non small and three small cell lung cancer, four stomach cancer cell lines and 30 freshly isolated lung cancer cell samples by the human tumor clonogenic assay. rH-TNF did not show any inhibitory effect on the colony formations of lung and stomach cancer cell lines, except for PC10 established from squamous cell carcinoma even at the high concentration. The overall response rate of fresh material was 11.5%. The colony formations of only two materials from 20 patients without prior chemotherapy were significantly suppressed by rH-TNF in vitro. Three specimens of adenocarcinoma exhibited more than 70% decrease in colony number by treating with 100 and 1000 u/ml of rH-TNF resulting in the response rate of 15.8% (3/19). From these results, it can be concluded that rH-TNF has modest direct cytotoxic effect on lung cancer, and additional study against adenocarcinoma of the lung might be warranted.

Antineoplastic Agents↗

The colony inhibition of a new chemotherapeutic agent (KW2152) against human lung cancer cell lines.

The human tumor colony assay was used to evaluate the effect of a new chemotherapeutic agent (KW2152) on colony inhibition of four non-small cell lung cancer cell lines and a mouse cell line. With continuous exposure experiments, KW2152 induced greater than or equal to 70% colony inhibition of PC-7 (human adenocarcinoma), PC-10 (human squamous cell) and PC-13 (human large cell) at a drug concentration of 10 mcg/ml. In one hour exposure experiments, KW2152 caused a significant reduction in colony formation (less than or equal to 30% of control) only at the highest concentration tested (100 mcg/ml). KW2152 showed significant in vitro activity against human non-small cell lung cancer cell lines. Due to these promising results, it was suggested that KW2152 should be evaluated in clinical trials.

Antineoplastic Agents↗

The different effects of recombinant human tumor necrosis factor on rat fibrosarcoma sublines.

The antitumor effect of recombinant human tumor necrosis factor (rH-TNF) on two clones of rat fibrosarcoma with different metastatic potential to lymph nodes was examined. The colony formation of clone A, which has high metastatic potential, was completely inhibited by continuous exposure to rH-TNF at 50 U/ml. In contrast, colony formation of clone G, which has low metastatic potential, was not inhibited by high concentrations of rH-TNF (10,000 U/ml). The inhibitory effect of rH-TNF on colony formation by clone A was also observed with a 1-h exposure to rH-TNF. This effect was time and concentration dependent, as determined by the colony assay, 3H-thymidine uptake assay, and 51Cr-release assay. 3H-thymidine and 3H-uridine uptake per cell of clone A exposed to rH-TNF was not decreased. This suggests that the mechanisms of the antitumor effect of rH-TNF were not due to inhibition of DNA and RNA synthesis of tumor cells. In vivo growth and lymph node metastases of clone A inoculated i.p. to Donryu strain rats were completely suppressed by 14 consecutive i.p. injections of 10(5) or 10(6) U/kg per day of rH-TNF. On the other hand the growth of clone G was not influenced by rH-TNF administration.

Animals↗

In vitro colony inhibition of carboplatin against stomach and lung cancer cell lines in comparison with cisplatin.

The effects of carboplatin and cisplatin on colony formation in stomach and lung cancer cell lines were examined and compared. The colony-inhibitory activity of carboplatin against stomach and lung cancer cell lines was similar to that of cisplatin when one-tenth of the peak plasma concentration of each drug was used (r = 0.80). One of the four stomach cancer cell lines was sensitive to carboplatin although all the stomach cancer cell lines were resistant to cisplatin. Of the three small cell lung cancer cell lines tested, two were sensitive to both carboplatin and cisplatin, and only one cell line (N857) was resistant to cisplatin; all the non-small cell cancer cell lines tested were resistant to both drugs. On the basis of these preliminary results, we suggest that carboplatin has potential therapeutic activity against stomach cancer and should be evaluated carefully from this aspect.

Carboplatin↗

Human tumor clonogenic assay for carcinoma of the lung. II. Factors that influence colony formation in soft agar.

The human tumor clonogenic assay (HTCA) has potential value for studies of both the chemosensitivity and biology of human tumors. However, many technical problems including low plating efficiencies and the preparation of sufficient numbers of viable cells remain. In this study, an improved method for disaggregation of solid tumors increased the yield of single cells. Consequently, more than 10 anticancer drugs could be tested in 94 of 168 specimens (56%). Removal of peripheral blood lymphocytes from cell suspensions derived from effusions also improved colony formation. Adequate growth for sensitivity testing (greater than 30 colonies/plate) was obtained in 122 cases (73%), inadequate growth for drug evaluation (5-29 colonies/plate) in 29 cases (17%), and no colony formation (less than 5 colonies/plate) in 17 cases (10%) of the 168 viable samples. The cloning efficiencies of cells derived from primary tumors (median 0.015%) were higher than those of cells derived from metastatic tumors (0.012%), and they varied with the location of the metastatic site. Cloning efficiencies varied markedly from specimen to specimen, and were unaffected by tumor histology, grade of differentiation, patient age, stage of disease, or prior chemotherapy. The HTCA is promising as a potential tool for studying the biology of tumors.

Agar↗

Comparative studies of pulse and continuous exposure in human tumor clonogenic assay.

To assess the influence of different schedules of drug exposure in human tumor clonogenic assay on in vitro cytotoxicity of antitumor drugs, the in vitro sensitivities of a human carcinoma cell line, PC-9, to various antitumor drugs were measured by using two different procedures: exposure was either by pulse for 1 h prior to plating or continuous throughout the period of growth in agar. Marked differences between the two procedures in testing actinomycin D, etoposide, 5-fluorouracil, vinblastine and vindesine but not in adriamycin, daunomycin, melphalan, nimustine and ranomustine were observed. The former and the latter were classified as schedule dependent drugs and a schedule independent drugs, respectively. In this study, the schedule dependency of in vitro drug response appears to be related mainly to time-dependency and partially to other factors, such as stability during culture in medium.

Adenocarcinoma↗

Colony inhibitory effect of recombinant human tumor necrosis factor (rH-TNF) and/or recombinant human interferon (rH-IFN)-alpha, -beta and -gamma on human lung cancer cell lines.

This study was conducted to assess, by continuous exposure, the inhibitory effects of rH-TNF and rH-IFN-alpha, -beta and -gamma, either alone or in combination, on the colony formations of human lung cancer cell lines. The cell lines tested were PC-7 and PC-9 (adenocarcinoma), PC-10 (squamous cell carcinoma) and PC-13 (large cell carcinoma). Additional experiments were performed with L929 (transformed murine fibroblast), because of its known high sensitivity to TNF. rH-TNF inhibited the colony formations of PC-10 and L929 even at a low concentration (10 U/ml). However, PC-7, PC-9 and PC-13 were resistant to rH-TNF. rH-IFN-alpha, -beta and -gamma inhibited the colony formation of PC-10 (less than 50% of control) at the highest concentration tested (10(4) U/ml), but only rH-IFN-beta inhibited that of PC-7. PC-9, PC-13 and L929 were insensitive to all three rH-IFNs, even at the highest concentrations tested. Combination effects of rH-TNF and rH-IFN-alpha or -gamma were synergistic only at the highest concentration combinations tested in PC-9. However, the maximum inhibition of colony formation of PC-7, PC-9 or PC-13 in any concentration combination treatment was less than 50%.

Antineoplastic Combined Chemotherapy Protocols↗

[The changes in serum neuron-specific enolase in patients with small cell lung cancer].

Serum neuron-specific enolase (NSE) was measured in 48 newly diagnosed untreated patients with small cell lung cancer (SCLC) by radioimmunoassay. Serum NSE level elevated (greater than or equal to 15 ng/ml) in 50% of all patients. The positive ratio of NSE in patients with extensive disease (64%) was significantly higher than those in the patients with limited disease (30%) (p less than 0.05). The positive ratio of NSE in the patients with one metastatic site was 50%, that with two or more metastatic sites was 100% (p less than 0.05). No significant correlation was found between serum NSE levels and metastatic site as well as between serum NSE levels and response to the chemotherapy. In the patients with extensive disease, survival time was shorter in the patients with positive NSE levels than the patients with normal NSE levels. These findings indicate that serum NSE may be a useful marker for staging, monitoring and prognosis in patients with SCLC.

Carcinoma, Small Cell↗

[Recent status of the diagnosis and treatment of bone metastasis in patients with advanced lung cancer].

The incidence and prognosis of patients with bone metastasis in primary advanced lung cancer were studied retrospectively. Between Jan. 1980 and Dec. 1985, 289 cases entered various kinds of chemotherapy protocol studies. Patients with bone metastasis of non-small cell lung cancer (NSC) comprised 44% (86/192), and those with small cell lung cancer (SC) comprised 43% (42/97). Histologically, 48% of adenocarcinoma, 50% of large cell carcinoma and 31% of squamous cell carcinoma showed bone metastasis. 8 percent of NSC bone meta (+) cases had an initial symptom of bone metastasis. Bone scan and bone X-ray were complementary and useful for diagnosis of bone metastasis, and sequential examinations tended to reduce the incidence of false-positive cases. Vertebral column, rib, pelvis and femur were the most common sites. Over 70% of the bone metastasis were in multiple skeletal systems, and 90% showed multiple-site involvement for both NSC and SC. Radiation therapy effectively reduced severe pain but paralysis was hard to control. In very few cases surgical treatment was indicated because of multiple bone metastasis, and systemic dissemination. Bone scan in 12% of SC patients showed apparent improvement with systemic chemotherapy. Among the M1 group of adenocarcinoma, median survival was 9 months in bone (+) cases, 11 months in bone (-) cases, 2 year survival was 8%, and 24%, and 3-year survival 2% and 22%, respectively. Among the bone(+) group and bone(-) group in ED cases of SC, median survival was 10 months vs. 11 months, and 2-year survival rates were both 13%. 22 percent (8/36) of squamous cell carcinomas without bone metastasis showed hypercalcemia (5.5 mEq/l). In patients with advanced lung cancer the major goal of treatment is recovery of the performance status of the patient and the relief of pain. In the case of SC, intensive systemic chemotherapy should be conducted as an adjuvant to local therapy.

Adenocarcinoma↗

[Direct and indirect antitumor effect of murine recombinant interferons].

The antitumor effects of murine recombinant interferons (beta) and (gamma) against B-16 melanoma and B16-F10 melanoma were examined. In a pharmacokinetic study, intraperitoneal injection of Mu-rIFN (gamma) produced higher and longer detectable IFN activity than administration of Mu-rIFN (beta) in both plasma and organs. In clonogenic assay, Mu-rIFN (gamma) at 1,000 units/ml showed 80% inhibition of colonies of B16-F10 melanoma. However, Mu-rIFN (beta) hardly inhibited the colony formation of B16-F10 melanoma. Furthermore, both IFNs had different characteristics from each other in the augmentation of NK cell and macrophage activities. In the experimental metastasis of B-16 melanoma, the inhibitory effect of Mu-rIFN (beta) on the pulmonary metastasis was mediated by the host defense mechanism, and NK cells and macrophages were important for the inhibition. Mu-rIFN (gamma) showed a stronger effect against B16-F10 melanoma in the inhibition of the growth of sc implanted tumor and artificial metastasis.

Animals↗

Prediction of hematologic toxicity of carboplatin by creatinine clearance rate.

Twenty-six patients with histologically proven lung cancer, treated with carboplatin at the National Cancer Center Hospital between October 1985 and October 1986, were retrospectively analyzed to determine the hematologic toxicity of carboplatin (CBDCA) and to develop guidelines for dose modification. A total of 34 courses of CBDCA were administered, of which 21 were adequate for assessment of the myelosuppression in relation to the renal function. One of three doses of CBDCA was administered by iv drip infusion over one hour (450 mg/m2, 19 courses; 400 12; 300, 3). Myelosuppression was dose-limiting, with thrombocytopenia being more sensitive than leukopenia, neutropenia or anemia. No significant correlation of the absolute count of platelets, white blood cells, polymorphoneutrophils, or hemoglobin with patient's creatinine clearance (Ccr) and dose of CBDCA administered was found. However, the percent reduction in platelets, white blood cells, polymorphoneutrophils, or hemoglobin correlated well with the relative dose of CBDCA [RD = total dose of carboplatin administered (mg/m2)/pretreatment Ccr/m2]. As thrombocytopenia was dose-limiting, we have developed an equation for modification of the dose of CBDCA from the relationship between the relative dose and percent reduction at platelet count nadir: Dosage (mg/m2) = (Ccr/m2/5.34) x [(1-desired platelet count nadir/pretreatment platelet count) x 100-12.9]. After consideration of the range of thrombocytopenia, we have further developed a simple equation to use CBDCA easily and safely: Dosage (mg/m2) = (1/10) x Ccr/m2 x desired % reduction in platelet count nadir = 10 x Ccr/m2 x (1-desired platelet count nadir/pretreatment platelet count. The clinical validity of these two equations is now being evaluated in prospective studies.

Adult↗