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Biomedical subjects

Y Sakurai

Publications and source records attributed to Y Sakurai.

At least 577 records · Page 32Linked to original sources
PubMed1982

New antitumor imidazole derivative, 5-carbamoyl-1H-imidazol-4-yl piperonylate, as an inhibitor of purine synthesis and its activation by adenine phosphoribosyltransferase.

The mechanism of action of 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250), which has a broad antitumor spectrum, was examined by in vitro cell culture and enzymatic studies. In the serum-containing culture medium, SL-1250 was rapidly deacylated to 4-carbamoylimidazolium 5-olate (SM-108). Thus, SL-1250 might be acting on the cells in the form of SM-108. The growth of L5178Y cells was completely inhibited by 10(-5) M SL-1250. It should be noted that this growth inhibition was significantly reversed in the presence of equimolar concentrations of guanine, guanosine, or guanosine 5'-monophosphate to those of SL-1250. However, hypoxanthine and xanthine were not effective. These effects of purine addition were observed to be quite similar in growth inhibition by SM-108. It was found that inosine 5'-monophosphate dehydrogenase (EC 1.2.1.14; IMP dehydrogenase), a key enzyme of de novo purine synthesis, from Ehrlich carcinoma cells was inhibited by SM-108 only when 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) and MgCl2 coexisted with SM-108. In contrast, a chemically synthetic ribonucleotide of SM-108 inhibited IMP dehydrogenase without PRPP and MgCl2, and the mode of inhibition was competitive with the Ki value of 2 x 10(-8) M. On the other hand, the inhibition of either growth of L5178Y cells or IMP dehydrogenase in the presence of PRPP and MgCl2 by these compounds was reversed by adenine. A nucleotide of SM-108 was chromatographically identified when [14C]SM-108 was incubated in the enzyme solution with PRPP and MgCl2. This conversion by enzyme was also inhibited by adenine. Viewed together, these results strongly suggest that SL-1250 is, after being converted to SM-108, activated to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7) and that this SM-108 nucleotide blocks de novo synthesis of guanosine 5'-monophosphate by inhibiting IMP dehydrogenase.

Adenine Phosphoribosyltransferase↗
PubMed1982

Collateral sensitivity of 6-mercaptopurine-resistant sublines of P388 and L1210 leukemia to the new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate and 4-carbamoylimidazolium 5-olate.

Two new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250) and 4-carbamoylimidazolium 5-olate (SM-108), were investigated for their antitumor activities against 6-mercaptopurine (6-MP)-resistant sublines of P388 and L1210 leukemia. It was found that both resistant sublines exhibited collateral sensitivity instead of cross-resistance to these new antipurine drugs. Since more potent cytotoxic activities of these drugs against 6-MP-resistant cells were observed even in vivo cell culture systems, this collateral sensitivity was proved on a cellular basis. Biochemical studies revealed that 6-MP-resistant sublines of both P388 and L1210 leukemia are deficient in hypoxanthine-guanine phosphoribosyltransferase activity. In these cells, not only the activation of 6-MP to its nucleotide but also the synthesis of guanosine 5'-monophosphate via the salvage pathway seems to be severely restricted. However, SL-1250 and SM-108 can be activated to their nucleotide even in these 6-MP-resistant cells because the activation of these compounds is proceeded by adenine phosphoribosyltransferase. In conclusion, suppression of de novo purine synthesis with SL-1250 and SM-108 seems to be a very efficient means of killing these 6-MP-resistant cells, which lack a salvage pathway for guanosine 5'-monophosphate.

Animals↗
PubMed1982

Immunogenicity and amplifier cell production by tumor vaccines enhanced by concanavalin A.

The induction of immune resistance to L1210 murine leukemia by 3 types of L1210 vaccines was compared under conditions in which in vitro cell proliferation and transplantability to mice were completely suppressed. L1210 cells treated with glutaraldehyde plus concanavalin A (ConA) were more potent in inducing antitumor immunity than those treated with Vibrio cholerae neuraminidase or mitomycin C (MMC). This and the finding that cell-bound ConA enhanced the immunogenic potency of MMC- or formaldehyde-treated L1210 vaccines indicate that ConA endowed the cells with additional potency in inducing antitumor immunity. ConA-free and ConA-bound vaccine cells took up the same amount of anti-L1210 antibody, suggesting that cell-bound ConA did not increase tumor-associated antigen molecules on the tumor cell surface. However, adoptively transferred spleen cells of mice sensitized with ConA-bound, but not ConA-free, vaccine amplified the vaccine-induced antitumor immunity in the recipients. These donor spleen cells suppressed the in vitro proliferation of live L1210 cells no more than non-primed spleen cells, nor was their amplifying activity abrogated by treatment with anti-Lyt-2.1 antibody and rabbit sera as a source of complement. This indicated that cytotoxic T cells and/or their precursors were not involved in the observed amplification. This as well as the finding that their amplifying activity was completely abrogated by treatment with rabbit anti-mouse brain-associated T cell antigen antisera and rabbit sera as a source of complement, led us to conclude that amplifier T cell production, associated with vaccine-bound ConA, was responsible for the enhanced immunogenic potency of ConA-bound vaccines.

Animals↗
PubMed1982

Occurrence of drug resistance in human tumor implanted in nude mice.

A line of human breast tumor xenograft in nude mouse, MX-1, acquired resistance to vincristine or mitomycin C during multiple treatments; both drugs were effective against the parent line of this tumor. If the treatment was started when the tumor was smaller than 500 mm3 in size, MX-1 was responsive to the initial treatment with vincristine (0.8 mg/kg) or mitomycin C (3.4 mg/kg), and some animals survived with complete regression of the tumor. However, some of the recurrent tumors were able to tolerate multiple treatments with either of these agents, and finally acquired apparent resistance to the agent. On the other hand, when tumors larger than 5,000 mm3 were treated with vincristine, the occurrence of resistance was observed with much higher frequency than when small tumors were treated. Resistant tumors thus obtained exhibited significant refractoriness to each agent when they were reimplanted in new mice and treated in the same manner. This suggests that the occurrence of resistance can be ascribed to changes not in metabolic functions of the host animal but in the tumor cell populations.

Animals↗
PubMed1982

[Development of a new therapeutic method of brain infarction in the acute period: revascularization under the administration of mannitol and perfluorochemicals].

Ten cases were treated with systematic administration of mannitol followed by the blood substitute, perfluorochemicals, in the acute period of cerebral infarction in order to suppress the development of infarction and progressive deterioration. This chemotherapy was followed by reconstructive vascular surgery. There were 8 cases of cerebral infarction and 2 other cases in which cerebral vascular occlusion occurred during surgery. Due to this treatment, there were no cases of aggravated condition or death and at the time of follow-up examination after 2 months, and 8 of the ten patients returned to productive lives. We consequently believe that this therapeutic method may prove to be the effective means for treating cerebral infarction in the acute period. It is also thought that this method is applicable in surgical cases where long-term vascular occlusion is required.

Acute Disease↗
PubMed1982

4'-O-tetrahydropyranyladriamycin as a potential new antitumor agent.

Chemotherapy with 4'-O-tetrahydropyranyladriamycin (THP-ADM), a new derivative of Adriamycin, was equally or more effective against several experimental mouse tumors than it was with Adriamycin (ADM). When mice with P388 leukemia were given i.p. injections of THP-ADM or ADM daily for 9 consecutive days, the maximum increases in life span (ILSs) of the mice were 190 and 175%, respectively. Eight of 24 mice treated with THP-ADM were free of tumor, while one of 24 mice treated with ADM was free of tumor. A single i.p. injection of either drug was also effective; maximum ILS was 170% for mice treated with THP-ADM and 240% for those treated with ADM. Nine of 12 mice were found to be free of tumor. THP-ADM was equally or slightly more effective against P388 leukemia than was ADM when either drug was given i.v. The maximum ILS was 106% with THP-ADM and 77% with ADM when the drug was given for 9 consecutive days. Single i.v. injections of THP-ADM or ADM were almost equally (ILS, 100%) effective. Chemotherapy with THP-ADM was also very effective against L1210 leukemia. THP-ADM administered i.p. five times, every other day starting from Day 1, was more effective than ADM was against Lewis lung carcinoma, B16 melanoma, and colon adenocarcinoma 38 inoculated s.c. In the study with Lewis lung carcinoma, metastasis to the lungs was well suppressed by THP-ADM. ADM was more effective than was THP-ADM against colon adenocarcinoma 26. Because THP-ADM was more cytotoxic than or almost equally as cytotoxic as ADM against the established cell lines from the above mouse tumors, we suggest that THP-ADM is more efficiently transported into cultured cells.

Adenocarcinoma↗
PubMed1982

Enzyme catalyzation of the deacylation of N4-acyl derivatives of 1-beta-D-arabinofuranosylcytosine in the mouse liver microsome.

Enzymatic hydrolysis of acylamide of N4-acyl-1-beta-D-arabinofuranosylcytosine was studied. The highest enzyme activity among various homogenates from mouse tissues, as expressed by specific activity, was found in liver homogenate. More than 50% of the activity in the liver was found in the microsomal fraction. The hydrolysis products of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine by microsomal enzyme were identified stoichiometrically as 1-beta-D-arabinofuranosylcytosine and palmitic acid. The microsomal enzyme showed an optimum pH at 9.0 in Tris-HCl buffer. Michaelis constant for N4-palmitoyl-1-beta-D-arabinofuranosylcytosine was 2.5 X 10(-5) M. The enzyme did not require divalent cations for the reaction. Mn2+ and Co2+ at 1 mM strongly inhibited the reaction. The relative rates of hydrolysis of N4-palmitoyl-, N4-stearoyl-, N4-lauroyl-, N4-butyryl-, and N4-behenoyl-1-beta-D-arabinofuranosylcytosine were 100, 47.6, 31.3, 15.9, and 9.1, respectively. The enzyme might play an important role in the formation of 1-beta-D-arabinofuranosylcytosine from N4-acyl derivatives of 1-beta-D-arabinofuranosylcytosine.

Amidohydrolases↗
PubMed1982

Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors.

Some calcium antagonists and calmodulin inhibitors enhance the intracellular levels of vincristine and Adriamycin in vincristine- and Adriamycin-resistant P388 leukemia cells by inhibiting their outward transport. The high intracellular drug accumulation was directly related to the enhancement of the cytotoxicity of the antitumor agents, and the vincristine and Adriamycin resistance in these cells was circumvented.

Animals↗
PubMed1981

Effect of hydrophilic and hydrophobic microdomains on mode of interaction between block polymer and blood platelets.

ABA-type block copolymers composed of 2-hydroxyethyl methacrylate (HEMA), a hydrophilic monomer, and styrene (St), a hydrophobic monomer, were synthesized by the coupling reaction of telechelic oligomers used as prepolymers. These block copolymers may be represented as microphase-separated structures. It is therefore possible to change the balance between hydrophilicity and hydrophobicity in the level of an assembled order of macromolecules. In response to the relative composition of the copolymers, three typical morphological patterns were observed in electron microscopic photographs: dispersed domains of continuous St chains in the region of HEMA chains, alternate HEMA and St lamellae and finally, dispersed phases of continuous HEMA chains in the region of St chains. The effect of the hydrophilic and hydrophobic microdomains of the copolymers on the mode of interaction between polymers and platelets was studied by the microsphere column method. In the case of homopolymers and random copolymers, a significant degree of platelet adhesion and aggregation was observed. However, the degree of platelet adhesion and deformation was suppressed on the surfaces of the block copolymers containing 0.608 and 0.347 mole fractions of HEMA whose microdomains were hydrophilic-hydrophobic lamellae and isolated hydrophilic islands in hydrophobic areas, respectively. These results show that the microphase-separated structures were antithrombogenic and prevented platelet adhesion and deformation. On the basis of the results obtained, the interaction between platelets and polymer surfaces was described in terms of the effect of hydrophilic and hydrophobic microdomains.

Acrylates↗