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Biomedical subjects

T Tsuruo

Publications and source records attributed to T Tsuruo.

At least 433 records · Page 24Linked to original sources
PubMed1988

Cytotoxicity and antitumor activities of fungal bis(naphtho-gamma-pyrone) derivatives.

Cytotoxicities of twenty-seven fungal naphtho-gamma-pyrone derivatives to KB cells were examined. Chaetochromins A-D (1-4) and ustilaginoidins D (10) and E (11) exhibited strong effects and the structure-activity relationships are discussed. The antitumor effects in vivo of some of these compounds were examined but, due to their toxicity and to their marginal activity, development as antitumor agents was abandoned. Deoxyribonucleic acid, ribonucleic acid and protein synthesis in KB cells were equally inhibited by chaetochromin A (1), cephalochromin (5), and ustilaginoidin A (7) in parallel with the cytotoxicity of the drugs. Thus it was suggested that other still unknown mechanism(s) might induce cytotoxic lesion, resulting in the inhibition of the macromolecule syntheses.

Acremonium↗
PubMed1988

Antitumor activity of new morpholino anthracyclines.

Antitumor activity of 3'-deamino-3'-morpholino anthracyclines was examined. Morpholino derivatives of 13-deoxocarminomycins, MX2 (1), MX (2) and MY5 (3) shown in Fig. 1, administered iv showed increase in life span (ILS) values over 110% against ip-inoculated P388 leukemia. The ranges of effective doses of these compounds were broader than those of their parent drugs. The morpholino derivatives of doxorubicin and carminomycin, however, were not so effective as their parent drugs. Among these compounds, MX2 administered orally showed nearly the same effects as those obtained by iv administration against P388 leukemia. MX2 administered iv showed 89% ILS against intracerebrally-inoculated L1210 leukemia. The highly lipophilic nature of MX2 could contribute partly to achieving chemotherapeutic responses against intracerebrally-inoculated tumors or by oral administration.

Animals↗
PubMed1988

[Therapeutic approach targeting the proteins involved in mechanisms of multidrug resistance].

Recently, the mechanisms of multidrug resistance have been partly elucidated. Based on these resistant mechanisms, therapeutic approaches targeting the proteins involved in the mechanisms of multidrug resistance are under investigation. These include therapies with monoclonal antibodies, drug resistant genes and agents interacting with the proteins of resistant tumor cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

[Therapeutic approaches for multidrug resistance].

One of the major problems in cancer chemotherapy is the development of drug resistance during treatment. In the treatment of tumors with antitumor agents, tumor cells can acquire resistance to the drugs. This type of resistance is called as acquired drug resistance and the acquired drug resistances is a major factor for limiting the clinical use of antitumor agents. The elucidation of the resistance mechanisms has progressed well recently owing to the application of cellular and molecular techniques in addition to the usual biological and biochemical techniques. In this article, the mechanisms of cellular resistance, especially those of multidrug resistance at a molecular level, and possible approaches to overcoming drug resistance are described and discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

[Detection of multidrug resistant phenotype in leukemia and lymphoma by monoclonal antibodies].

Two monoclonal antibodies, MRK16 and MRK20 that recognize P-glycoprotein and P-85 kd protein on the surface of adriamycin (ADM) resistant cells, respectively, were tested for the reactivity with 40 cultured leukemia/lymphoma cell lines. F(ab')2 form is essential to avoid false reaction through Fc gamma-R. Drug sensitivity of 19 representative cell lines were also examined in vitro. From this study, it was found that these cell lines were classified into 4 groups. Group 1 (4 cell lines) was insensitive to ADM, mitoxantron (MXT), etoposide (VP-16) and vincristine (VCR), and reactive to MRK16 and MRL20. Group II (1 cell line) was insensitive to the 4 drugs, but not reactive to both antibodies. Group III (3 cell lines) was insensitive to ADM, MXT and VP-16, but sensitive to VCR, and reactive to MRK20, but not to MRK16. Group IV (all other cell lines) was sensitive to these drugs, and not reactive to both antibodies. From these results, MRK16 detects P-glycoprotein-associated multidrug resistance (MDR), while MRK20 does P 85-kd-associated another type MDR (cross resistance to ADM, MXT and VP-16, but not to VCR). MRK20 reacted with monocytes, but MRK16 did not with any WBC type. One hundred and ninety eight clinical samples obtained from blood cancer were tested for the reactivity with MRK16. MRK16 did not react with any of 98 samples obtained before treatment, but did with 9 of 100 obtained at relapse or refractory stage after chemotherapy. The results indicate that MRK16 is useful to detect drug resistance phenotype of leukemia and lymphoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

Acquisition of metastatic ability in hybridomas between two low metastatic clones of murine colon adenocarcinoma 26 defective in either platelet-aggregating activity or in vivo growth potential.

Two low metastatic clones, NL-14 and NL-44, had been isolated from the murine colon 26 adenocarcinoma after in vivo selection and subsequent in vitro cloning. NL-14 is defective in the ability to induce platelet aggregation, but it has good in vivo growth potential. NL-44 possesses low growth potential after s.c. inoculation, but it has strong platelet-aggregating ability. A ouabain-resistant variant of NL-14 and a G418-resistant variant of NL-44 were established. Each resistant cell line conserved the phenotypes of platelet-aggregating ability or in vivo growth potential as compared to the respective parental cell line. These two clones were fused to examine the metastatic potential of hybridomas. Of eight hybridomas tested, six possessed both platelet-aggregating ability and good in vivo growth potential. These six hybridomas formed a higher number of pulmonary metastases after i.v. inoculation than the parental cells. Of the two low metastatic hybridomas, one was lacking in the ability to induce platelet aggregation, and the other showed the least potential for in vivo growth. Hybridoma clones with high platelet-aggregating activity in vitro were generally arrested well in the lung following i.v. inoculation. These results suggest that platelet-aggregating ability and in vivo growth potential are two major determinants for successful experimental lung metastasis of the colon 26 adenocarcinoma.

Adenocarcinoma↗
PubMed1987

Enhancement of voltage-gated Na+ channel current associated with multidrug resistance in human leukemia cells.

Membrane currents were examined in a drug-sensitive human leukemia cell line (K562) and its multidrug-resistant cell line (K562/ADM) under the whole-cell variation of the patch electrode voltage clamp technique. Most K562 cells showed only the outward current, which was completely suppressed by internal Cs+ ions and 20 mM ethyleneglycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. In contrast to K562 cells, most K562/ADM cells showed tetrodotoxin-sensitive, voltage-gated Na+ channel current in addition to the outward current. Na+ current was observed in four of 29 K562 cells examined, while it was observed in 29 of 33 K562/ADM cells. Two revertant cell lines (R1-3, R1-5) did not show Na+ current. It was concluded that the amplitude of voltage-gated Na+ current increases in association with multidrug resistance in human leukemia cells.

Antineoplastic Agents↗
PubMed1987

Phosphorylation of the Mr 170,000 to 180,000 glycoprotein specific to multidrug-resistant tumor cells: effects of verapamil, trifluoperazine, and phorbol esters.

An overexpression of plasma membrane glycoprotein with a relative molecular mass (Mr) of 170,000-180,000 is consistently found in different multidrug-resistant human and animal cell lines, although the functional role of the protein in multidrug resistance is not fully understood. It has been reported previously that the Mr 170,000-180,000 glycoprotein is involved, directly or indirectly, in the drug transport mechanism and the proliferation of multidrug-resistant tumor cells. In an attempt to clarify further the function of the Mr 170,000-180,000 glycoprotein, we have studied the phosphorylation state of the protein in intact K562/ADM cells and found that: the protein is phosphorylated in the basal state; verapamil and trifluoperazine, which inhibit the active drug efflux and restore drug sensitivity in resistant cells, caused an increase in the phosphorylation of the Mr 170,000-180,000 glycoprotein; 4 beta-phorbol 12 beta-myristate 13 alpha-acetate and 1-oleoyl 2-acetylglycerol enhanced phosphorylation of the protein; the protein was phosphorylated at serine residues; tryptic phosphopeptide mapping of the Mr 170,000-180,000 glycoprotein showed that 4 beta-phorbol 12 beta-myristate 13 alpha-acetate treatment induced an increase in phosphorylation at different sites of the protein from those induced by verapamil or trifluoperazine treatment, suggesting that the protein is phosphorylated by an array of complex regulation mechanisms. Phosphorylation of the Mr 170,000-180,000 glycoprotein might play a role in the regulation of processes affecting cellular function in multidrug resistance.

Antibodies, Monoclonal↗
PubMed1987

DNA-mediated transfer and cloning of a human multidrug-resistant gene of adriamycin-resistant myelogenous leukemia K562.

We have successfully transferred and cloned a fragment of a human multidrug-resistant gene by using DNA-mediated gene transfer. Macromolecular DNA of human multidrug-resistant K562 cells was transfected to drug-sensitive mouse Ltk- cells to obtain a drug-resistant transfectant with a human resistant gene. Both primary and secondary transfectants showed similar patterns of cross-resistance to Adriamycin and vincristine. The mechanism of drug resistance of the transfectants was attributed to decreased retention of the drug. Three secondary transfectants obtained independently contained common Alu-containing EcoRI fragments 15, 6.5, 3.7, 2.6, and 1.9 kilobases long. The 2.6-kilobase EcoRI fragment was cloned from a lambda phage genomic library made from DNA of a secondary transfectant. The 2.6-kilobase fragment was detected in the primary and secondary transfectants but not in the parental Ltk-, Adriamycin-resistant Ltk-, and Adriamycin-resistant P388 cells. This sequence was found to be amplified in several multidrug-resistant cell lines such as Adriamycin-resistant ovarian carcinoma A2780 and colchicine-resistant KB carcinoma cells. The 2.6-kilobase fragment hybridized with a 4.5-kilobase mRNA which is overexpressed in the Adriamycin-resistant K562 cells and the Adriamycin-resistant A2780 cells but not detected in the parental K562 cells. The gene transferred and cloned in this study seems to be related to the P-glycoprotein gene as judged from the size of mRNA and its overexpression in some of the multidrug-resistant cell lines where P-glycoprotein was found to be highly expressed.

Animals↗
PubMed1987

Determination of membrane antigens by a covalent crosslinking method with monoclonal antibodies.

Monoclonal antibodies that recognize cell surface proteins may serve as very useful tools for the study of the biological functions of membrane proteins. However, solubilization of the antigens with detergents may lead to major conformational changes of the protein, making their determination with monoclonal antibodies by immune blot or ordinary immunoprecipitation methods difficult. This is especially evident when the monoclonal antibodies recognize tertiary structures of the proteins in the membrane. We have generated two monoclonal antibodies which are specific for the cell surface antigens of multidrug-resistant human cell lines. However, the antigens of both monoclonal antibodies were difficult to detect by either immune blot or ordinary immunoprecipitation methods. We used a cleavable crosslinking reagent dithiobis(succinimidyl propionate) to covalently link the monoclonal antibody with its antigenic determinant in the membrane of intact cells. By this method, we were able to detect the antigens for these two monoclonal antibodies following solubilization, immunoprecipitation, and analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This method should have wide applicability in determination of membrane antigens recognized by monoclonal antibodies when immune blot or ordinary immunoprecipitation methods are not successful.

Antibodies, Monoclonal↗
PubMed1987

Synthesis and antitumor activity of tropolone derivatives. 5.

As part of a study on the structure-activity relationship of antitumor-active tropolone derivatives, a series of bistropone analogues, related to potently active bistropolone 1a, were synthesized and tested for their antitumor activity in in vitro (KB cell) and in vivo (leukemia P388 in mice) systems. The methoxytropones 3 and 5, hydroxytropothione 10, and (N-methylamino)tropones 12 and 13 were inactive in both systems. Methoxytropone 6 exhibited weak activity, whose potency was equal to that of monotropolone 2a.

Animals↗
PubMed1987

Synthesis and antitumor activity of tropolone derivatives. 6. Structure-activity relationships of antitumor-active tropolone and 8-hydroxyquinoline derivatives.

The bis derivative 6 of 8-hydroxyquinoline, which, like tropolones, readily forms a chelate, was synthesized and found to have high potency (dose = 12.5 mg/kg, T/C % = 164) against leukemia P388 in mice approximately equivalent to that of the bistropolone 1b. 8-Hydroxyquinoline analogues with broad structural variation were synthesized and their structure-activity relationships followed the same pattern as in the tropolone series. In addition, the bistropolones 1a-e were tested for their ability to bind to tubulin and found to have no such property. The results of this study suggested that bistropolone and bis(8-hydroxyquinoline) derivatives must form a chelate with the metal necessary for the enzyme, such as ribonucleotide reductase, which catalyzes the DNA biosynthetic pathways.

Animals↗
PubMed1987

A monoclonal antibody-Pseudomonas toxin conjugate that specifically kills multidrug-resistant cells.

One form of multidrug resistance is due to the expression of a 170-kDa energy-dependent drug efflux pump called P-glycoprotein in the plasma membranes of human cancer cells. We have prepared conjugates of Pseudomonas toxin with the anti-P-glycoprotein monoclonal antibody MRK-16. These anti-P-glycoprotein-toxin conjugates specifically kill multidrug-resistant human KB cells. Similar conjugates could be useful in cancer therapy to reduce or eliminate multidrug-resistant tumor populations in tumors intrinsically resistant to chemotherapy or in populations that become resistant during combination chemotherapy.

ADP Ribose Transferases↗
PubMed1987

Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues.

Monoclonal antibody MRK16 was used to determine the location of P-glycoprotein, the product of the multidrug-resistance gene (MDR1), in normal human tissues. The protein was found to be concentrated in a small number of specific sites. Most tissues examined revealed very little P-glycoprotein. However, certain cell types in liver, pancreas, kidney, colon, and jejunum showed specific localization of P-glycoprotein. In liver, P-glycoprotein was found exclusively on the biliary canalicular front of hepatocytes and on the apical surface of epithelial cells in small biliary ductules. In pancreas, P-glycoprotein was found on the apical surface of the epithelial cells of small ductules but not larger pancreatic ducts. In kidney, P-glycoprotein was found concentrated on the apical surface of epithelial cells of the proximal tubules. Colon and jejunum both showed high levels of P-glycoprotein on the apical surfaces of superficial columnar epithelial cells. Adrenal gland showed high levels of P-glycoprotein diffusely distributed on the surface of cells in both the cortex and medulla. These results suggest that the protein has a role in the normal secretion of metabolites and certain anti-cancer drugs into bile, urine, and directly into the lumen of the gastrointestinal tract.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

ATP-binding properties of P glycoprotein from multidrug-resistant KB cells.

The photoaffinity reagent 8-azido-alpha-[32P]ATP was used to label a protein of 170 kDa in membrane vesicle preparations from a highly multidrug-resistant cell line, KB-V1, but not from the drug-sensitive parental cell line KB-3-1. The 170-kDa labeled protein was immunoprecipitated with a monoclonal antibody (MRK-16) to P glycoprotein. Both ATP and GTP inhibited labeling by 8-azido-alpha-[32P]ATP. Labeling of P170 was not inhibited by 5 mM ADP, 5 mM ribose-5-phosphate, or 100 microM vinblastine. These data directly demonstrate that P glycoprotein has a nucleotide-binding site that could supply energy for drug transport.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

Decreased expression of the amplified mdr1 gene in revertants of multidrug-resistant human myelogenous leukemia K562 occurs without loss of amplified DNA.

Amplification and increased expression of the mdr1 gene associated with multidrug resistance in human tumors were found in multidrug-resistant sublines of human myelogenous leukemia K562 selected with vincristine (K562/VCR) or adriamycin (K562/ADM). In two revertant cell lines of K562/ADM, amplification of the mdr1 gene was maintained at the same level as in K562/ADM, but expression of the 4.5-kilobase mdr1 mRNA was greatly decreased, indicating that amplified genes may be inactivated at the level of transcription without a corresponding loss of amplified DNA.

DNA, Neoplasm↗