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Biomedical subjects

K Minato

Publications and source records attributed to K Minato.

At least 73 records · Page 4Linked to original sources
PubMed1989

In vitro evaluation of the new anticancer agents KT6149, MX-2, SM5887, menogaril, and liblomycin using cisplatin- or adriamycin-resistant human cancer cell lines.

A new model to predict antitumor activity of new analogues was developed, and the cross-resistance against cisplatin (CDDP) and Adriamycin (ADM) was examined. A preclinical evaluation of various new analogues using this new model was performed. The antitumor activities of KT6149, MX-2 (KRN8602), SM5887, menogaril (TUT-7), and liblomycin (NK313) were evaluated against four non-small cell lung cancer cell lines, PC-7, -9, -13, and -14; two small cell lung cancer cell lines, H69 and N231; four CDDP-resistant cell lines, PC-7/1.0, PC-9/0.5, PC-14/1.5, and H69/0.4; a human myelogenous leukemia cell line, K562; and its ADM-resistant subline, K562/ADM by clonogenic assay. The relative antitumor activities of these new analogues were compared with those of parental agents, mitomycin C, ADM, bleomycin, and several anticancer drugs, CDDP, daunomycin, vindesine, and etoposide. KT6149 was more active than mitomycin C against all lung cancer cell lines and the human myelogenous leukemia cell line. Menogaril showed greater activity than ADM, and MX-2 showed activity similar to ADM. However, the antitumor activity of SM5887 was lower than that of ADM. SM5887 and menogaril showed cross-resistance to K562/ADM. Nevertheless, the antitumor activity against K562/ADM of MX-2 was similar to that of the parental cell lines. The activity of liblomycin was similar to that of bleomycin. Thus, KT6149 appears to be the best analogue for use in a clinical trial against lung cancer. MX-2 was active even against ADM-resistant cancer cells. The values of relative resistance to CDDP or ADM were 4.7, 8.1, 7.5, 20.0, and 13.6 for PC-7/1.0, PC-9/0.5, PC-14/1.5, H69/0.4, and K562/ADM, respectively. CDDP-resistant cell lines showed no cross-resistance with other drugs in this study. K562/ADM showed cross-resistance against daunomycin, etoposide, and vindesine. In contrast, mitomycin C and bleomycin had nearly equal activity against K562 and K562/ADM. However, K562/ADM was 2.4-fold more sensitive to CDDP than its parental cell line, K562 (P less than 0.001). These results suggested that the mechanism of CDDP resistance is different from that of multidrug resistance.

Anthracyclines↗
PubMed1989

Phase I study of combination therapy with interleukin 2 and beta-interferon in patients with advanced malignancy.

Based on a preclinical study demonstrating the synergistic antitumor effect of recombinant interleukin 2 (rIL-2) and beta-interferon (IFN-beta) on mouse tumors and previous results of a phase I study of rIL-2, a phase I study of combination therapy with human rIL-2 and IFN-beta was conducted in 26 patients with advanced malignancy. Patients were given rIL-2 by 24-h continuous i.v. infusion and IFN-beta by 2-h i.v. infusion for 5 days each week for 4 weeks. The common side-effects were fever, malaise, chills, appetite loss, and diarrhea. Leukocytosis and eosinophilia were observed in 56% and 69% of the patients, respectively. Transient leukopenia and thrombocytopenia were also observed in some patients. Dose-limiting manifestations were intolerable fatigue and liver dysfunction, and it was concluded that the maximum tolerated doses of rIL-2 combined with IFN-beta were 1.1 x 10(6) U/m2/day for rIL-2 and 6.0 x 10(6) IU/m2/day for IFN-beta. No patients achieved complete and partial response to therapy in this study. One patient with pulmonary metastasis from pharyngeal cancer showed a minor response. Natural killer (NK) and lymphokine-activated killer (LAK) activities increased during the 5 days of treatment and decreased during the 2-day intermission. The percentage of IL-2 receptor-positive cells increased markedly until Day 12, and gradually decreased thereafter. The percentage of OKT 4-positive cells and the OKT 4/OKT 8 ratio increased. In contrast, the percentage of Leu 7- or Leu 11-positive cells decreased over the 4-week treatment. A phase II study of this combination therapy is ongoing against head and neck cancer, and renal cell carcinoma.

Adult↗
PubMed1989

Phenotypic heterogeneity of lymphoma of the skin.

We studied surface markers present in 56 cases of lymphoma of the skin by immunohistochemical staining, using the ABC (avidin-biotin-peroxidase complex) and PAP (peroxidase-antiperoxidase complex) methods. Of these cases, 49 were T-cell lymphoma and 7 were B-cell lymphoma. Ten of the 49 cases of T-cell lymphoma were adult T-cell leukemia/lymphoma (ATL). Twenty-five of 31 cases of T-cell lymphoma except ATL analyzed by the ABC method showed a helper/inducer phenotype (Leu2a-,Leu3a+), two cases showed a suppressor/cytotoxic phenotype (Leu2a+, Leu3a-), one case showed Leu2a+Leu3a+, one case showed an inducer phenotype (Leu2a-, Leu3a+, Leu9+), and one case showed OKT11+, Leu2a-, Leu3a-, Leu1-, Leu9+, CD25+, Leu10+, CD30+. One CD8+ lymphoma was Pagetoid reticulosis, and a CD4+, CD8+ lymphoma was lymphomatoid papulosis with erythematous plaque. Cutaneous T-cell lymphoma (CTCL), previously described by Edelson et al., is defined as a helper T-cell lymphoma with marked affinity for the skin. In our study, 5 cases of T-cell lymphoma of the skin were not CTCL as described by Edelson et al. These results show that T-cell lymphoma of the skin is heterogeneous in nature. In other words, CTCL is one type but represents a major proportion of T-cell lymphomas of the skin.

Humans↗
PubMed1989

Multidrug resistance in cultured human leukemia and lymphoma cell lines detected by a monoclonal antibody, MRK16.

Forty cultured human leukemia and lymphoma cell lines never exposed to anticancer agents in culture, apart from doxorubicin (ADM)-resistant K562/ADM, were examined for reactivity with a monoclonal antibody, MRK16 in F(ab')2 form [MRK16-F(ab')2], which recognizes P-glycoprotein (P-gp). The relative resistance index to various drugs was calculated by dividing the 50% growth inhibitory concentration (IC50) of the test cell line by IC50 of K562, which was the negative control in the antibody experiment. MRK16-F(ab')2 reacted with four cell lines, K562/ADM, KYO-1, HEL and CMK, which had relative resistance index values of 2 or more to vincristine (VCR), vindesine, vinblastine, ADM, daunorubicin, mitoxantrone (MIT), etoposide (VP-16) and actinomycin-D (ACT-D). The level of resistance to VCR and ADM in these cell lines decreased significantly in the presence of 10 microM verapamil in vitro. Significant expression of mRNA of P-gp gene was also detected in K562/ADM, KYO-1 and HEL. MRK16-F(ab')2 did not react with 36 other cell lines. Among them, three cell lines, PL-21, P31/FUJ and KOPM-28, had relative resistance index values of 2 or more to anthracyclines, MIT and VP-16, but not to vinca alkaloids or ACT-D. The level of ADM-resistance in these cell lines did not decrease significantly in the presence of 10 microM verapamil. Five cell lines, ATL-1K, HL-60, KMOE-2, ML-1 and U266, had relative resistance index values of 2 or more to some of the drugs, but not to the others, and 19 other cell lines did not. These results indicate that the reactivity of MRK16-F(ab')2 correlates with a relative resistance index of 2 or more to all these drugs in cultured human leukemia and lymphoma cell lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Serial measurement of sister chromatid exchanges in the peripheral lymphocytes of patients with lung cancer receiving chemotherapy in relation to bone marrow toxicity.

The frequencies of sister chromatid exchanges (SCE) in the peripheral lymphocytes of patients with lung cancer before and after initial chemotherapy were serially measured and the correlation between SCE frequencies and bone marrow toxicity was evaluated. The addition of mitomycin C to vindesine plus cisplatin increased SCE frequencies significantly in patients with non-small cell lung cancer. A significant increase in frequencies of SCE was observed in patients treated with cyclophosphamide plus adriamycin plus vincristine as compared with those treated with cisplatin plus etoposide in small cell lung cancer. A significant inverse correlation was observed between SCE frequencies in the peripheral lymphocytes 7 days after treatment (x) and the nadir value/pretreatment value of platelets (y)(r = -0.685, P = 0.0007, y = 0.842-0.022x). The relation between SCE frequency and leukopenia showed the same trend as thrombocytopenia, but the correlation was not statistically significant (r = -0.444, P = 0.057). SCE assay may have potential clinical use for the prediction of chemotherapy-induced thrombocytopenia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

A novel multidrug resistance in cultured leukemia and lymphoma cells detected by a monoclonal antibody to 85-kDa protein, MRK20.

A monoclonal antibody, MRK20, in F(ab')2 form [MRK20-F(ab')2], which reacts with 85-kDa membrane protein in a doxorubicin (ADM)-resistant subline (K562/ADM) of human myelogenous leukemia cell line, K562, was examined for reactivity with 41 cultured human leukemia and lymphoma cell lines. None of these cell lines had ever been exposed to any anticancer agent in vitro except K562/ADM. The relative resistance index to various drugs was calculated by dividing the 50% growth-inhibitory concentration (IC50) of the test cell line by IC50 of K562 (the negative control in the antibody experiment). MRK20-F(ab')2 reacted with seven cell lines, KYO-1 derived from chronic myelogenous leukemia in blastic crisis (CMLbc), CMK from acute megakaryoblastic leukemia, HEL from erythroleukemia, P31/FUJ from acute monocytic leukemia, KOPM-28 from CMLbc, PL-21 from acute promyelocytic leukemia and K562/ADM. MRK20-F(ab')2 did not react with 34 other cell lines. All seven MRK20-F(ab')2-positive cell lines had relative resistance index values of 2 or more to anthracyclines (ADM, pyrarubicin, daunorubicin), mitoxantrone, etoposide, bleomycin, and pepleomycin. There was no distinct correlation between the reactivity to MRK20-F(ab')2 and a higher relative resistance index than 2 to vinca alkaloids, actinomycin-D, cisplatin, 4-hydroperoxycyclophosphamide, nimustine hydrochloride, methotrexate or cytarabine. These results indicate that MRK20-F(ab')2 detects a novel multidrug resistance to anthracyclines, mitoxantrone, etoposide, bleomycin and pepleomycin in cultured human leukemia and lymphoma cells.

Antibiotics, Antineoplastic↗
PubMed1989

Inhibition of colony formation of drug-resistant human tumor cell lines by combinations of interleukin-2-activated killer cells and antitumor drugs.

The cytotoxicity of interleukin-2-activated killer (LAK) cells with or without anticancer drugs against cell lines with acquired drug resistance was evaluated in vitro by colony assay. Human non-small cell lung cancer cell lines, PC-9 and PC-14, human leukemia cell line, K-562, and their sublines resistant to cisplatin (CDDP), PC-9/CDDP and PC-14/CDDP, and to adriamycin (ADM), K-562/ADM, were used as target cells. PC-9/CDDP demonstrated a marked increase in susceptibility to killing by both peripheral blood lymphocytes (PBL) and LAK cells, as compared to the parental cell line, PC-9. The cytotoxicity of PBL and LAK cells against PC-14/CDDP and K-562/ADM was similar to that against their parental cell lines. Moreover, the combination of LAK and CDDP had a synergistic effect on PC-14 and PC-14/CDDP.

Adenocarcinoma↗
PubMed1989

Phase II study of carboplatin in non-small cell lung cancer.

Forty four patients with advanced non-small cell lung cancer (NSCLC) were treated with carboplatin (CBDCA; cis-diammine-1, 1-cyclobutane dicarboxylate platinum II) at a dose of 400-450 mg/m2 intravenously every four weeks in a phase II study. Forty three patients were evaluated for response and toxicity. Two patients achieved responses resulting in an overall response rate of 4.7% (95% confidence limits: 0.6-15.8%); one of these had not been treated previously and the other had been treated previously with vinblastine. The durations of their responses were 5 and 7 months, respectively. The response rate in 28 previously untreated patients was 3.6% (1/28; 95% confidence limits: 0.1-18.3%). Myelosuppression was the most commonly found toxicity, and thrombocytopenia especially was dose-limiting. Thrombocytopenia (less than 75,000/mm3) was observed in 12 patients (28%). Leukopenia (less than 3,000/mm3) was observed in 14 patients (33%). No serious infection or bleeding occurred, however. Treatment with 400-450 mg CBDCA/m2 was well tolerated in the good risk patients in this study. Mild to moderate emesis was observed in 28 patients (65%). No renal toxicity, neurotoxicity or ototoxicity was seen. It was demonstrated that CBDCA had little efficacy in NSCLC at the dose and schedule given in the present study.

Adult↗
PubMed1989

[Detection of multidrug resistant cells in human malignant diseases by monoclonal antibodies and strategy to eradicate resistant malignant cells].

Two monoclonal antibodies of F (ab')2 form, MRK 16 and MRK 20 that recognize P-glycoprotein and P85 kD protein respectively, were useful to detect multidrug resistant cells in human lymphoma, leukemia and gastrointestinal cancer cell lines. They were classified into 4 groups: Group I (4 cell lines) was insensitive to vinca alkaloids, anthracyclines, etoposide (VP-16) and actinomycin-D (ACT-D), and reactive to MRK 16 and MRL 20. Group II (2 cell lines) was insensitive to vincristine (VCR), but not reactive to both antibodies. Group III (3 cell lines) was insensitive to anthracyclines and VP-16, but sensitive to vinca alkaloids and ACT-D, and reactive to MRK 20 but not to MRK 16. Group IV (all other cell lines) was sensitive to these drugs, and not reactive to both antibodies. MRK 16 detects P-glycoprotein-associated multidrug resistance (MDR), while MRK 20 detects P 85kd-associated novel MDR. These monoclonal antibodies were useful for detection of MDR cells in clinical samples.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Non-Hodgkin's lymphoma of the pleural cavity developing from long-standing pyothorax. Summary of clinical and pathological findings in thirty-seven cases.

Our previous study suggested a close relation between a preceding chronic tuberculous pyothorax and the development of non-Hodgkin's lymphoma (NHL) in the pleural cavity. To confirm this further, 37 cases were collected from Japanese hospitals, and their clinical and pathological findings summarized. The age at first admission for lymphoma of patients ranged from 46 to 81 (mean 63) years, the male to female ratio being 5.2:1. All patients were admitted after a 22-55 (mean 33) year history of pyothorax resulting from artificial pneumothorax for the treatment of pulmonary tuberculosis (29 cases) or tuberculous pleuritis (seven cases). The most common presenting symptom was chest pain. The main tumor mass, detected by chest roentgenogram and computed tomographic scans, was situated in the pleura (28 patients), the lung near the pleura (five patients) and the pleura and lung (four patients). The diagnosis of pleural NHL was made by biopsy for 31 of the patients and at autopsy for the other six. Histologically 30 (81%) of the 37 cases were of the diffuse large cell type, and of these the immunoblastic type was the most common (22 cases). Immunological and immunohistologic studies revealed a B-cell nature of the proliferating cells in all but one tumor. Thirty-two patients received chemotherapy and/or radiotherapy. Twenty-seven patients died between one and 144 (median eight) months of diagnosis. Autopsies carried out in 23 cases revealed the disease to have been localized to the thorax in 11 patients. These findings indicated that malignant B-cell lymphoma arose as a monoclonal growth from a pool of proliferating polyclonal B lymphocytes in tissues affected by the chronic tuberculous pyothorax.

Aged↗
PubMed1989

[Cross and non-cross resistant anticancer agents to multidrug-resistant cultured cells from hematologic malignancies].

We report here that typical and atypical multidrug resistant (MDR) cells can be identified by monoclonal antibodies, MRK16 and MRK20, respectively. Typical MDR cells were cross-resistant to vinca alkaloids, anthracyclines, mitoxantrone (MXT), etoposide (VP-16) and actinomycin-D (ACT-D), and reactive to MRK16. Atypical MDR cells were cross-resistant to anthracyclines, MXT, VP-16, and bleomycin but sensitive to vinca alkaloids and ACT-D. They were reactive to MRK20, but not to MRK16. Among anthracyclines, aclacinomycin A was not cross-resistant to either typical or atypical MDR cells. Methotrexate was not cross-resistant to doxorubicin, vincristine, Ara-C and cisplatin. Cisplatin was not cross resistant to 5-FU, either. Identification of cross and non-cross resistant anticancer agents may be useful to plan a cure-oriented combination chemotherapy for hematologic malignancies.

Antibodies, Monoclonal↗
PubMed1988

Establishment and characterization of cisplatin-resistant sublines of human lung cancer cell lines.

Human lung cancer sublines resistant to cisplatin (CDDP) have been developed by continuously exposing cells to gradually increasing doses of CDDP and use of the limiting dilution technique. The cell lines used were PC-7, PC-9 and PC-14 (pulmonary adenocarcinoma) and H69 and N231 (small-cell lung cancer). The resistant phenotype of the resistant sublines was stable for more than 2 months in the absence of drug. PC-7/1.2 (i.e., PC-7 cells growing stably in medium containing 1.2 micrograms/ml of CDDP), PC-9/0.5, PC-14/1.5, H69/0.4, and N231/0.2 have been developed, which are 22.9, 7.1, 3.1, 25.6, and 8.4 times more resistant to CDDP than the respective parent cell line in terms of IC50 in the soft agar colony assay with continuous drug exposure. Cloning efficiency decreased significantly in N231/0.2. The doubling times increased significantly in most of the resistant sublines. Cellular DNA contents increased in all resistant sublines, but statistical significance was observed only in H69/0.4 (p less than 0.05). Cells of the resistant sublines of PC-7, PC-9, PC-14 and H69 were larger than cells of the parent lines, but the differences were not significant. The growth morphologies of all resistant sublines in the drug-free medium were similar to those of parent cell lines. All resistant sublines tested were significantly cross-resistant to carboplatin. The patterns of cross-resistance, cross-sensitivity and collateral sensitivity to adriamycin, mitomycin-C, 5-fluorouracil, vindesine, etoposide, aclacinomycin and vincristine were different in each resistant subline. Verapamil (3.3 micrograms/ml) showed little modifying effect on CDDP resistance in 5 CDDP-resistant sublines tested except N231/0.2 (Modification Index: 0.49). Cyclosporin A (5.0 micrograms/ml) modified CDDP resistance in CDDP-resistant small-cell lung cancer sublines (H69/0.4 and N231/0.2) (Modification Index: 0.45 and 0.07, respectively), while in CDDP-resistant NSCLC sublines (PC-7/1.0 and PC-9/0.5), cyclosporin A reduced the sensitivity to CDDP.

Cell Line↗
PubMed1988

Comparative study of the antitumor effect of two types of murine recombinant interferons, (beta) and (gamma), against B16-F10 melanoma.

A comparative study of the antitumor effect of murine recombinant interferon(beta) less than Mu-rIFN(beta) greater than and murine recombinant interferon(gamma) less than Mu-rIFN(gamma) greater on B16-F10 melanoma was conducted. Administration of Mu-rIFN(gamma) i.p. into C57BL/6 mice on days 1 to 7 produced a higher suppressive effect than Mu-rIFN(beta) both on the growth of s.c. implanted tumor and on the formation of artificial pulmonary metastasis. Pharmacokinetic study of Mu-rIFN(gamma) demonstrated that high plasma levels were retained for a long time. In clonogenic assay, Mu-rIFN(gamma) at 1000 units/ml showed about 80% inhibition of colonies of B16-F10 melanoma. However, Mu-rIFN(beta) hardly inhibited the colonies, even at 1000 units/ml. Augmentation of natural killer (NK) cytotoxicity was much greater with Mu-rIFN(beta) than Mu-rIFN(gamma), whereas Mu-rIFN(gamma) enhanced the cytotoxicity of peritoneal macrophages more strongly than Mu-rIFN(beta). Injection of Mu-rIFN(gamma) i.p. 1 day before tumor challenge also inhibited the formation of pulmonary metastasis of B16-F10 melanoma. However, pretreatment of mice with carrageenan significantly suppressed the inhibitory effect of Mu-rIFN(gamma). From these results, it is suggested that the inhibitory effect of Mu-rIFN(gamma) on the tumor growth and metastases of B16-F10 melanoma is mediated partly by direct antitumor effect and partly by the activation of macrophages, and that the augmentation of NK activity contributes mainly to the antitumor effect of Mu-rIFN(beta).

Animals↗
PubMed1988

In vitro antitumor activity of mitomycin C derivative (RM-49) and new anticancer antibiotics (FK973) against lung cancer cell lines determined by tetrazolium dye (MTT) assay.

Seven small- (SCLC) and four non-small-cell (NSCLC) lung cancer cell lines were used to examine the in vitro cytotoxicity of cytotoxic drugs such as (1aS-(1a alpha,8 beta,8a alpha,8b alpha]-8-[aminocarbonyl)oxy)methyl)-4,8a- dimethoxy-1,1a,2,8,8a,8b-hexahydro-7-hydroxy-5-methyl-6- nitrosoazirino(2',3':3,4)-pyrrolo-(1,2-a)indole (RM-49) and 11-acetyl-8-carboxymethyl-4-formyl-14oxa-1,11-diaze- tetracyclo(7.4.1.0(2,7),0(10,12]tetradeca-2-4-6-trien-6,9-++ +diyl-diacetate (FK973). In vitro cytotoxicities of RM-49 and FK973 were compared with those of mitomycin C (MMC), cisplatin (CDDP), carboplatin (CBDCA), etoposide (VP16), adriamycin (ADM) and vindesin (VDS). Drug sensitivity was determined using a tetrazolium (MTT)-based assay. Average IC50 values of these two drugs were not statistically different compared with that of MMC, although FK973 showed strong antitumor activity against SCLC cell lines such as LT3, N857, and H69 at the same concentration. The predicted peak plasma concentration (predicted PPC) calculated by the formula proposed by Scheithauer, log (predicted PPC) = -0.788 + (0.755 x log(LD50], and relative antitumor activity, RAA (PPC/IC50), of RM-49 were higher than those of other drugs such as MMC, CDDP, CBDCA, and ADM against SCLC cell lines (P less than or equal to 0.05), and those of FK973 were also higher than those of other drugs such as MMC, CDDP, CBDCA, and ADM against SCLC cell lines (P less than or equal to 0.05). Based on these promising in vitro studies, the clinical trials of RM-49 and FK973 were warranted.

Antibiotics, Antineoplastic↗
PubMed1988

Cell cycle-related expression of surface antigens on myelomonocytic leukemia cells.

We investigated the relationship between the expression of surface antigens and the cell cycle phase in leukemic cells from cell lines and one patient using two-color flow cytometry, in order to determine the reason for the uneven expression of some markers which frequently leads to equivocal results as to leukemic phenotyping. As a result, it was demonstrated that monocyte-related differentiation markers, including I2, My4, Mo1 and Mo2, on monocytoid leukemic cells are preferentially expressed at the G0/G1 phase. Consequently, it is expected that the positivities for such markers vary with the proliferation status of the leukemic cells.

Antigens, Differentiation, Myelomonocytic↗