Biomedical subjects

M Kawase

Publications and source records attributed to M Kawase.

230 records · Page 13Linked to original sources

PubMedDate not supplied

Biological activity of feijoa peel extracts.

Fractionated extracts of Feijoa peels were studied for cytotoxic activity, anti-human immunodeficiency virus (HIV) activity and antibacterial activity. Two most cytotoxic fractions A3 of acetone extract and M2 of methanol extract had potent inhibitory activity against Gram-positive and Gram-negative bacteria as well as fungi tested. Fraction A4 of acetone extract showed multidrug resistance (MDR)-reversal activity comparable with that of verapamil (positive control). These results indicate the therapeutic value of Feijoa peel extracts as potential antimicrobial and MDR-modulating agents.

Anti-Bacterial Agents↗

PubMedDate not supplied

Enhanced antibacterial effect of erythromycin in the presence of 3,5-dibenzoyl-1,4-dihydropyridines.

Fifteen 3,5-dibenzoyl-1,4-dihydropyridines (BzDHP, GB1-GB15) (nifedipine (NP) analogs) were tested on three different E. coli strains. The compounds had relatively high MIC values on these strains. In combination with erythromycin (Er), compounds (G1,3,4,6,7,10,12) reduced MIC values of Er. When the BzDHPs were tested on E. coli Gy-1/Apsen.Erres strain isolated from a clinical specimen, the reduction of MIC values were similar to the previous strains, but not identical. In the polyresistant clinically isolated E. coli Gy-2/Apres.Erres strain, the MIC values of Er were slightly reduced in the presence of GB1-GB7. Compound GB12 was the most effective in enhancing the activity of Er, and was selected for plasmid elimination studies. However, GB12 itself had no antiplasmid effect and did not alter the promethazine induced plasmid elimination.

Anti-Bacterial Agents↗

PubMedDate not supplied

Biological activity of a fruit vegetable, "Anastasia green", a species of sweet pepper.

Russian green sweet pepper (Anastasia Green) was successively extracted with hexane, acetone, methanol and 70% methanol and the extracts were further separated into a total of twenty fractions by silica gel or ODS column chromatographies. The biological activities of these extracts and fractions were compared. The extracts and fractions showed higher cytotoxic activity against two human oral tumor cell lines than against normal human gingival fibroblasts, suggesting their tumor-specific action. Several fractions [H3, H4, A4] reversed the multidrug resistant gene (MDR1) against L5178 mouse T-cell lymphoma more effectively than (+/-) verapamil (positive control). All extracts and fractions showed no anti-human immunodeficiency virus (HIV) nor anti-Helicobacter pylori activity. These data suggest the medicinal importance of an Anastasia Green extract.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Post-transfusion graft-versus-host disease following open heart surgery. Report of six cases.

Six cases of post-operative erythroderma after open heart surgery are described. About 10 days after seemingly uneventful recovery, all patients developed fever, erythroderma, liver enzyme elevation, pancytopenia, and an aplastic bone marrow. Their condition rapidly deteriorated, and they died within 20 days of the onset of symptoms. Skin biopsy specimens from two patients showed mild leukocytic infiltration in the epidermal basal layer and upper dermis. Immunostaining by the ABC method showed that most of these infiltrating cells were suppressor/cytotoxic T cells. HLA study of peripheral lymphocytes from two patients and their families revealed that the patients' HLA phenotypes were incompatible from their children's HLA findings. Y chromatin was present in the lymphocytes of the skin biopsy specimen of a female patient. Based on the clinical picture, skin biopsy, HLA study, and Y chromatin study, the authors strongly suspect post-transfusion GVHD as the etiology of postoperative erythroderma, although these patients lacked any known immunodeficiency.

Adult↗

PubMedDate not supplied

Immunomodulating activities on cellular cytotoxicity and the blast transformation of human lymphocytes by 10-[n-(phthalimido)alkyl-2-substituted-10H-phenothiazines and 1-(2-chloroethyl)-3-(2-substituted-10 H-phenothiazin-10-yl)alkyl-1-ureas.

Phenothiazines, 10-[n-(phthalimido)alkyl-2-substituted-10H- phenothiazines, and 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1- ureas were investigated for their effects on antibody-dependent cellular cytotoxicity (ADCC), natural killer (NK) cells and the blast transformation of human peripheral blood mononuclear cells. All of the compounds dose-dependently suppressed mitogen-stimulated T cell proliferation. In contrast, a strong enhancing effect on NK cell activity was detected mostly in the case of 1-(2-choroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alk yl-1-ureas and their related compounds. The stimulating effect directly influenced the NK cells and was demonstrated at all tested concentrations.

Adjuvants, Immunologic↗

PubMedDate not supplied

Antitumor activity of phenothiazine-related compounds.

One of the biggest challenges in health care is the fight against tumors. Some phenothiazines have antitumor activity on HEp-2 tumor cells. In this study, we tested the antitumor effects of three series such as 10-nonsubstituted phenothiazines, 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines and 1-(chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1-ureas with H, Cl and CF3 substitution at position C2. The TCID50 of phenothiazines was affected by the H, Cl and CF3 at C2. Trifluoromethyl derivative of phenothiazine showed potent (R = CF3, TCID50 = 4.7 micrograms) activity, whereas the chlorine derivative of phenothiazine (R = Cl, TCID50 = 62.5 micrograms) had a relatively weak effect. In the group of 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines, 10-[3-(phthalimido)propyl]-10H-phenothiazine (R = H, n = 3, TCID50 = 11.5 micrograms), 10-[4-(phthalimido)butyl]-10H-phenothiazine (R = H, n = 4, TCID50 = 7.8 micrograms) and 10-[3-(phthalimido)propyl]-2-trifluoromethyl-10H- phenothiazine (R = CF3, n = 3, TCID50 = 11.5 micrograms) was very effective. On the other hand, TCID50 of 10-[3-(phthalimido)propyl]-2-chloro-10H-phenothiazine (R = Cl, n = 3, TCID50 = 75.0 micrograms), 10-[4-(phthalimido)butyl]-2-chloro-10H-phenothiazine (R = Cl, n = 4, TCID50 = 31.3 micrograms) and 10-[4-(phthalimido)butyl]-2-trifluoromethyl-10H-phenothiazine (R = CF3, n = 4, TCID50 = 50.0 micrograms) were about 4-8 times less effective than 10-[4-(phthalimido)butyl]-10H-phenothiazine (R = H, n = 4, TCID50 = 7.8 micrograms). Among six 1-(chloroethyl)-3- (2-substituted-10H-phenothiazin-10-yl)alkyl-1-ureas, two chlorine compounds such as 1-(2-chloroethyl)-3-(2-chloro-10H-phenothiazin-10-yl)propyl-1-urea (R = Cl, n = 3, TCID50 = 6.3 micrograms), 1-(2-chloroethyl)-3-(2-chloro-10H-phenothiazin-10-yl) butyl-1-urea (R = Cl, n = 4, TCID50 = 7.8 micrograms), and 1-(2-chloroethyl)-3-(2-trifluoromethyl-10H-phenothiazin-10-yl)buty l-1-ur ea (R = CF3, n = 4, TCID50 = 7.8 micrograms) were significantly active. Tests showed that the substitution at 2C position apparently affected the anti-HEp-2 tumor cell activity; that the length of the aliphatic side chain at 10N contributes to the anti-tumor activity; and that the TCID50 values of the derivatives with butylene group (-C4H8-) were lower than those with propylene group (-C3H6-) except 10-[4-(phthalimido) butyl]-2-trifuoromethyl-10H-phenothiazine and 1-(2-chloroethyl)-3-(2-chloro-10H-pheno-thiazin-10-yl) butyl-1-urea.

Antineoplastic Agents↗

PubMedDate not supplied

Synthesis and antitumor activity of 1-[2-(chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl- 1-urea s as potent anticancer agents.

10-[N-(Phthalimido)alkyl]-2-substituted-10H-phenothiazines and 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1- ureas were synthesized and found to have antiproliferative effects on human HEp-2 and L5178Y cell cultures. The multi-drug resistant subline of mouse lymphoma was sensitive to the reversal effects of some 10-[N-(phthalimido)alkyl]-2-substituted-10H-phenothiazines, while 1-(2-chloro-ethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1 -ureas were less effective but had a similar degree of antiproliferative effect on both cell lines.

Animals↗

PubMedDate not supplied

The primary in vitro antitumor screening of "half-mustard type" phenothiazines.

The antitumor effects of "half-mustard type" phenothiazines were studied on 57 different tumor cell lines, including leukemias, non-small lung cancer, colon, central nervous system, ovarian, renal, breast, and prostate cancer, as well as melanoma cell cultures. Alkyl-urea derivatives of phenothiazines displayed in vitro antitumor activity. The phenothiazine phthalimido derivatives (1-6) were not active on the majority of cancer cell cultures. In contrast, propylureas (9, 11) were active against some leukemia cell types. Only two compounds with the butylene [(CH2)4] linker (10, 12) were active against non-small lung cancer cells. Compounds containing the propylene linker were less effective. On colon cancer lines, tumor cells from the central nervous system and on melanoma cells the same compounds were effective, however, having substituents at the 2-position of phenothiazine seems to be important. Surprisingly, the majority of ovarian cancer cell lines (except one type, IGROVI) and five of eight renal cancer lines were not sensitive to these phenothiazine derivatives. The two butylene linked phenothiazine ureas (10, 12) had moderate antiproliferative action on two renal cancer cell lines. The prostate cancer and some breast cancer cell lines were not sensitive. Nevertheless some breast cancer cell lines were apparently sensitive to CF3-substituted phenothiazine alkylureas. On the basis of these experiments one may postulate that in the case of insensitive cells an mdr-gene encoded multidrug resistance efflux pump is responsible for the resistance. The selectivity or organ cell specificity of the effective phenothiazines will be targeted for improvement in further studies, in order to avoid the general cytotoxic effects of "half mustard type" phenothiazines.

Antineoplastic Agents↗

PubMedDate not supplied

The in vitro antitumor assay of "half-mustard type" phenothiazines in screens of AIDS-related leukemia and lymphomas.

Twelve different "half-mustard type" phenothiazines were newly synthesized and tested on seven AIDS-related lymphoma (ARL) tumor cell lines, one leukemia CCRF-CEM cell culture and five different lymphoma lines; RL, KD-488, AS283, PA682 and SU-DHL-7 cell lines. The alkylene-urea substituted phenothiazines affected the growth and inhibited the growth rate of AIDS-related lymphoma cells. The Cl-substituent at the 2-position was more effective than the CF3 substitution. In AIDS-related leukemia also the compounds with Cl at the 2-position with propylene or butylene linkers, -(CH2)3- and -(CH2)4-, respectively, were more effective than the CF3 substituted compounds. Two of the six phenothiazine-substituted alkyl-urea derivatives, i.e., 1-(2-chloroethyl)-3-(2-chloro-10H-phenothiazin-10-yl)propyl-l-urea (9, GI50 = -5.66, TGI = -5.04) and 1-(2-chloroethyl)- 3-(2-chloro-10H-phenothiazin-10-yl)butyl-1-urea (10, GI50 = -5.61, TGI = -5.12) exhibited antitumor activity for AIDS-related leukemia and five AIDS-related lymphomas. The trifluoromethyl-substituted derivatives were not as effective on AIDS-related tumor cell lines. Apparently, the substituent at the 2-position on the phenothiazine and the alkylene number of the linker attached to the nitrogen of the phenothiazine ring have an important role in the compound's antitumor effects on AIDS-related leukemia and lymphomas.

Antineoplastic Agents↗

PubMedDate not supplied

Drug resistance reversal, anti-mutagenicity and antiretroviral effect of phthalimido- and chloroethyl-phenothiazines.

The effect of substituted phenothiazines was studied in three different systems; bacteria and cancer cells and reverse transcriptase enzyme of Moloney leukemia virus. F'lac and hemolysin plasmids were eliminated by some substituted phenothiazines from E. coli at a very low frequency. The same phenothiazine derivatives also were synergistic with tetracycline in bacteria and shown antimutagenic effect in Ames test. No mutagenic effects were observed in TA 98 strain of Salmonella typhimunium. Chloroethyl-substituted phenothiazines showed antimutagenicity equivalent to the parent compounds; however, phthalimido-substituted phenothiazines had higher antimutagenicity of 50%. P-glycoprotein responsible for multidrug resistance was also inhibited in tumor cells. The accumulation of the fluorescent rhodamine 123 in the phenothiazine treated multi-drug resistant tumor cells was measured by flow cytometry. Some of the substituted phenothiazines were effective P-glycoprotein blockers, while some compounds had moderate activity, but others were without effect as compared to 5 microM verapamil. On the basis of computer analysis there are some correlations between the biological activities and the dipole moments, and entropy of the studied molecules. Our results suggest that the inhibition of Hly+ plasmid replication and P-glycoprotein function may depend partly on similar electronic properties of the studied phenothiazine derivatives. The activity of Moloney leukemia virus reverse transcriptase was inhibited by the substituted phenothiazines, however, no basic differences were found in the activities of phthalimido- and chloroethyl substituted phenothiazines.

Antimutagenic Agents↗

PubMedDate not supplied

Biological activity of 6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones.

Ten 6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones (Coumarins)[1-7] and related coumarins [8-10] were compared for their cytotoxic activity and radical intensity. Among these compounds, compound 7 showed highest cytotoxic activity against human promyelocytic leukemic HL-60 cells. Compound 7 produced radicals under alkaline conditions, and showed the lowest pi-spin density at S-atom of the molecule, suggesting the delocalization of pi-spin density. These data suggest the possible relation between radical intensity and biological activity.

Antineoplastic Agents↗

PubMedDate not supplied

The primary in vitro anticancer activity of "half-mustard type" phenothiazines in NCI's revised anticancer screening paradigm.

Some new phenothiazines have been synthesized on the basis of previous studies. The anticancer activity of "half-mustard type" phenothiazines was investigated on sixty different cancer cell lines in vitro. The percentage of growth (PG), 50% inhibition of growth (GI50), the tumor growth inhibition (TGI) and the concentration required for 50% lethality of cells (IC50) were examined and calculated in the presence of various (from 10(-4) to 10(-8) M) concentrations of phenothiazine alkylurea derivatives. The following cell lines were involved in the study: 6 leukemia, 9 non-small-cell lung cancer, 7 colon cancer, 6 central nervous system cancer, 8 melanoma, 6 ovarian cancer, 8 renal cancer, 2 prostate and 8 breast cancer cell lines. The antileukemic activity of four chloroethyl-substituted phenothiazine-alkylureas was shown by considerable growth inhibition, in the 10(-5) M range, of the six different leukemia cell lines. The 50% inhibition of growth was nearly the same for the four compounds on all cell lines. Tumor growth inhibition (TGI) and IC50 value to cells varied from -4.0 to -4.66. The two derivatives with the butylene bridge were more effective than propylene linked compounds against the CCRP-CEM, HL60 (TB), K-562 and MOLT-4 cell lines. However, the anti-leukemic activity of the derivatives was nearly the same for RPMT 8226 and SR cell lines. The substituent at the 2- position of phenothiazine ring and the length of the linker between the side chain nitrogen and the phenothiazine ring system are apparently important for antileukemic activity. Four of the 9 non-small-cell lung cancer cell lines were sensitive, while the other 5 cell lines were not. The compounds had a slight growth inhibitory effect on colon cell carcinoma and melanoma cells in which case the butylene linker seemed to be more effective than the propylene linker. At the same time, all of the compounds were weak or mostly inactive on cancer cells from the central nervous system. One ovarian cancer line of the 6, the IGROVI was sensitive to butylurea phenothiazines, however, the other five were not sensitive at all. The difference in the sensitivity of various renal cell carcinomas was significant: 5 lines were not sensitive, three of them (786-0, RXF-393 and TK-10) were sensitive to only butylene-substituted phenothiazine-ureas, propylene substitution resulted in ineffective compounds. The compounds were not able to inhibit the 2 prostate and 4 breast cancer cell lines, even at 10(-4) M. It was interesting that propylene-linked ureas were more effective than butylene-linked derivatives on MCF-7, but butylene-linked derivatives were more effective than propylene-linked compounds on MDA MB-231 and MDA-N. In addition, MDA MB 435 was more sensitive to the trifluoromethyl derivatives than the compounds without this substituent. Since the phthalimido-alkyl phenothiazines were not active at the first level of prescreen, these compounds were omitted from this study. The drug sensitivity of some cancer cell lines was not uniform for the different groups, therefore we postulate that the resistance can be related to some kind of (existing) drug-efflux mechanism. Apparently, the tumor specificity of phenothiazine alkylureas is more related to the leukemia specificity of alkylureas than to any CNS or lung specificity of phenothiazines.

Antineoplastic Agents↗

PubMedDate not supplied

Relationship between radical intensity and cytotoxic activity of dopamine-related compounds.

Millimolar concentrations of dopamine (DA), norepinephrine (NE), and 3,4-dihydroxyphenylacetic acid (DOPAC) were cytotoxic to human promyelocytic leukemiC HL-60 cells. However, their metabolites (3,4-dihydroxymandelic acid (DOMA), 3-methoxytyramine (MT), normetanephrine (NMN)) and six synthetic derivatives (which have two OCH3 groups replacing two OH groups on catechol backbone) displayed much lower cytotoxic activity. Three active compounds, but not other less potent compounds, produced radicals under alkaline conditions. All active compounds significantly enhanced the decay of ascorbic acid endogenously present in rat brain homogenate, whereas all synthetic derivatives were inactive. Ascorbic acid induced apoptotic cell death in HL-60 cells and the apoptosis induction was significantly reduced by simultaneous addition of (DA). The cytotoxic activity of (DA) was also neutralized by ascorbic acid. These data suggest the possible interaction between (DA) and ascorbic acid.

Animals↗

PubMedDate not supplied

6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones: synthesis and mdr reversal in tumor cells.

Six 6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones and three coumarins were systematically investigated for reversal of multidrug resistance of bacteria and cancer cells in model experiments. 7-Methylcoumarin was able to eliminate the E. coli plasmid significantly; however, the other derivatives were ineffective. Four of 6,12-dihydro-1-benzopyrano[3,4-b] [1,4]benzothiazin-6-ones had a moderate effect on the multidrug resistance efflux pump of mouse lymphoma cells in vitro. Despite of the similarity of resistance mechanisms of bacteria and tumor cells, the reversal of drug resistance in bacteria and in cancer cells is not uniform because the structure-activity requirements are apparently different.

Animals↗