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Biomedical subjects

M Inaba

Publications and source records attributed to M Inaba.

At least 55 records · Page 3Linked to original sources
PubMed1991

Mechanism for resistance to 5-fluorouracil in P388 leukemia cells.

In order to assess mechanisms for acquired resistance to 5-fluorouracil (5-FU) of P388 cells on a cellular basis, we compared sensitivities of P388 and its 5-FU-resistant subline (P388/5-FU) cells to 5-FU, 5-fluorouridine (FUrd) and 5-fluoro-2'-deoxyuridine (FdUrd). P388/5-FU cells exhibited an approximately 10-fold resistance to 5-FU and 170-fold cross-resistance to FUrd but not to FdUrd when they were exposed to each agent for 5 h in vitro. 5-FU-induced growth inhibition was hardly reversed with thymidine, suggesting its ribonucleic acid (RNA)-directed effect. This was supported by the fact that similar amounts of 5-FU were incorporated into cellular RNA in P388 and P388/5-FU when these cells were incubated with equitoxic concentrations of 5-FU. Furthermore, incorporation of 5-FU and FUrd into cellular RNA in P388/5-FU cells were significantly lower than in P388 cells when cells were exposed to them at the same concentration. These results suggest a major action of 5-FU is directed toward RNA in these cells at least under the present experimental condition, and 5-FU resistance of this cell line is closely associated with reduced uridine kinase activity among various enzymatic changes previously observed.

Animals↗
PubMed1991

Design and synthesis of antitumor compounds based on the cytotoxic diterpenoids from the genus Rabdosia.

Two active sites responsible for antitumor activity, an oxirane ring and an alpha-methylene-cyclopentanone moiety, have been extracted from studies on the structure-activity relationship of the cytotoxic diterpenoids isolated from Rabdosia shikokiana. Series of the simplified cyclopentanone derivatives containing both of the two active sites in the molecule have been synthesized and evaluated for cytotoxicity against P 388 cells. The compounds possessing both of two active sites displayed cytotoxicity at a concentration of 1 microgram/ml, while those possessing a single active site showed no activity.

Animals↗
PubMed1991

Cryoglobulinemia in a horse.

Cryoglobulin was isolated from a horse which had glomerulo-nephritis and a history of swelling and skin ulcers of the limbs in the winter. The isolated cryoglobulin showed a single peak on a gel permeation chromatography column with an apparent molecular mass (Mr) of 180,000 which could be divided into two gamma bands by cellulose acetate electrophoresis. Immunoelectrophoretic analysis revealed that the cryoglobulin formed two precipitation lines with anti-horse IgG. Spur formation was observed when the cryoglobulin and the IgG purified from a normal healthy horse were cross-reacted with anti-horse IgG on a double diffusion gel. In addition, sodium dodecyl sulfate-polyacrylamide gel electrophoresis under the reduced conditions showed that the isolated cryoglobulin consisted of two doublets of polypeptides with Mr values of 52,000 and 50,000, and 31,000, and 30,000, corresponding to the heavy chain and the light chain of the horse IgG molecules, respectively. These results suggest that the isolated cryoglobulin might consist of two different IgG molecules, and that the manifestations such as foot swelling with skin ulcers and renal failures were all induced by the cryoglobulin in the serum.

Animals↗
PubMed1991

Effect of dietary calcium on serum BGP (osteocalcin).

The present study was designed to clarify the effects of dietary calcium (Ca) intake on serum BGP (osteocalcin) levels. Twelve women with a mean age of 21.2 years participated in the study. After one week of normal Ca intake (mean +/- SE, 535 +/- 2 mg/day), a low-Ca diet (163 +/- 1 mg/day) was given for one further week. Additional asparagine Ca (3 g as Ca/day) was also given to half of the subjects. Serum total and ionized Ca concentrations as well as BGP, PTH and 1,25(OH)2D3 were measured at the end of each period. Amounts of Ca and hydroxyproline excreted in urine were also determined. The plasma level of ionized Ca was significantly increased without any change in total Ca in either group. Low and high Ca intake decreased and increased urinary Ca excretion by 28% and 56%, respectively. Serum levels of BGP and 1,25(OH)2D3 were significantly augmented along with a transient increase in urinary hydroxyproline excretion after Ca deprivation. These results suggest that serum BGP is increased after one week of Ca restriction in healthy subjects.

Adult↗
PubMed1991

Effects of arginine vasopressin on blood pressure and renal prostaglandin E2 in rabbits.

The role of arginine vasopressin (AVP) in blood pressure regulation in humans and animals is still controversial. The present study was designed to investigate the effects of AVP on blood pressure and the excretion of sodium and prostaglandin (PG) E2 in rabbits. AVP dissolved in 0.01 M acetic acid was infused subcutaneously at a rate of 0.86 ng/kg/min with a miniosmotic pump into 12 New Zealand white rabbits (2.7-3.4 kg), while 10 controls were given vehicle alone. AVP infusion resulted in a 3.5-fold rise in the level of plasma AVP (21.8 +/- 4.4 (SEM) pg/ml) as compared with controls, associated with a significant decrease in the urine volume and urinary excretion of sodium. The PGE2 excretion was increased 1.8-fold after AVP infusion. In the chronic AVP-infused group, blood pressure was not significantly increased, but the acute vascular response to AVP was significantly attenuated without any changes in the vasopressor response to angiotensin II. Preadministration of V1-antagonist completely abolished the vasopressor action of AVP, but not that of angiotensin II, in either group. These results suggest that circulating AVP within physiological range of concentrations may stimulate renal PGE2 synthesis and attenuate the vascular response through vascular V1 receptors without affecting the baroreflex, which may be attenuated through V2 receptors.

Angiotensin II↗
PubMed1991

Effects of slow-release nifedipine on nighttime blood pressure.

With the advent of long-acting or slow-release antihypertensive drugs, we should be aware of a fall in nighttime blood pressure (BP) as well as daytime blood pressure. In the present study, casual BPs at the physician's office as well as ambulatory BP was recorded every hour throughout 24 hours with a noninvasive automated BP monitoring device in 24 essential hypertensives treated with slow-release nifedipine. Administration of slow-release nifedipine (20-40 mg, b.i.d.) decreased not only casual BPs but also ambulatory mean BP during the whole day or daytime (6 am to 10 pm). Slow-release nifedipine at 10 mg in the morning did not affect casual BPs at the office. However, mean BP obtained by ambulatory BP monitoring during the daytime was significantly attenuated. In addition, a profound fall in mean BP amounting to more than 20 mmHg during the night in some of the patients was observed during treatment with slow-release nifedipine not only at 20-40 mg (b.i.d.) but also at 10 mg once a day. These results suggest that we have to take into consideration the possibility that long-acting hypotensive agents may cause a great fall in nighttime BP during sleep, especially in the elderly.

Adult↗
PubMed1991

Clinical significance of ambulatory blood pressure monitoring. Evaluation of severity of hypertension, efficacy of treatment and effects on nighttime blood pressure.

Blood pressure (BP) obtained by the physician in his office and ambulatory BP recorded every hour throughout 24 hours with a noninvasive automated BP monitoring device were compared in 10 normotensives and 162 hypertensives. Casual BPs significantly correlated with averages in ambulatory BPs (ABPs) throughout the whole day, day (7 am - 10 pm) and night (0-5 am). However, it was noted that 6 of 10 normotensives and all of the moderate to severe hypertensives had ABPs of more than 150/90 mmHg at least once during the 24-hour period. The incidence of ABPs greater than 150/90 mmHg among all readings was higher in untreated and treated hypertensives with diastolic BPs in the office of more than 105 mmHg, and, when checked along with the clock time, higher not only in the morning but also in the evening. On the other hand, one-third or one-fifth of treated hypertensives with diastolic office BPs less than 90 mmHg or between 90 and 105 mmHg respectively had ABPs less than 150/90 mmHg throughout the whole day. When the effect of nicardipine (60 mg, t.i.d.) or slow-release nifedipine (27.3 +/- 3.0 mg, b.i.d.) on minimum BP during the night was analyzed, long-acting nifedipine decreased BP throughout the night to levels not significantly different from normotensive controls, whereas short-acting nicardipine did not affect nighttime BPs. These results suggest that simple ABP monitoring throughout the day gives us useful information to evaluate the severity of hypertension and the efficacy of antihypertensive medication as well as to avoid overtreatment with long-acting hypotensive agents resulting in a great fall in BP during sleep.

Blood Pressure Determination↗
PubMed1991

Effects of uremic serum on 1,25-dihydroxyvitamin D3-induced differentiation of a human promyelocytic leukemia cell line, HL-60.

The mechanism by which resistance to 1,25 dihydroxyvitamin D3 (1,25-(OH)2D3) occurs in patients with chronic renal failure was studied. This agent induces differentiation and 1,25-(OH)2D3-24-hydroxylase activity in the mitochondria of the human promyelocytic leukemia cell line, HL-60, via a steroid-hormone receptor mechanism. HL-60 cells were cultured in RPMI 1640 medium supplemented with 10% normal or uremic serum. Treatment of these cells with 10(-8)M 1,25-(OH)2D3 for 5 days in a medium containing 10% uremic serum from 4 patients with chronic renal failure resulted in a maturation of the cells amounting to 30.3 +/- 18.7% (mean +/- SD) and 32.5 +/- 11.2%, as obtained by NBT reduction assay and NSE assay, respectively. These values were significantly lower than those obtained with 10% serum from 3 normal controls (66.6 +/- 12.8%, 58.3 +/- 10.9%, p less than 0.02). The treatment of HL-60 cells with 1,25-(OH)2D3 in a mixture of 5% normal plus 5% uremic serum caused cell differentiation to an extent similar to that in 10% uremic serum, which suggests the presence of a substance(s) having 1,25-(OH)2D3-inhibitory activity in the uremic serum. Exposure of HL-60 cells to uremic serum significantly impaired their responsiveness to 1,25-(OH)2D3 as assessed by the induction of the cell's ability to hydroxylate the C-24 position of 1,25-(OH)2[3H]D3. The mechanism by which uremic serum confers an impaired cellular response to 1,25-(OH)2D3 seemed to be due, in part, to a decrease in 1,25-(OH)2D3 receptor levels. A significant positive correlation was observed between intracellular cAMP levels and 1,25-(OH)2D3-induced HL-60 cell maturation. In summary, the mechanism by which uremic serum confers 1,25-(OH)2D3 resistance upon HL-60 cells seemed to be due to the presence of 1,25-(OH)2D3-inhibitory activity in uremic serum, which may modulate cellular responsiveness to 1,25-(OH)2D3 by such mechanisms as reducing 1,25-(OH)2D3 receptor levels in the cells, in part through alteration in cAMP metabolism.

Adult↗
PubMed1991

[Pharmacokinetic approach to the improvement of clinical predictability in the preclinical test for antitumor agents].

Clinical predictability of preclinical test for antitumor agents has not been significantly improved even after the use of a human tumor/nude mouse model. Such different antitumor activities between preclinical and clinical tests probably due to the fact that therapeutic used in both tests usually each maximum tolerated dose (MTD), are pharmacokinetically not equivalent. Therefore, we introduced a new concept of "clinically equivalent dose (CED)", which can reproduce in the nude mouse the blood level of a given drug observed with human patients received its therapeutic dose. Treatment of human tumors implanted in the nude mice with CEDs of several drugs exhibited much better correlation with their clinical efficacies than those with MTDs. The feasibility of use of CED predicted by animal scale-up procedure as a therapeutic dose in the preclinical test was discussed.

Animals↗
PubMed1990

Granulocyte-macrophage colony-stimulating factor enhances macrophage accessory function in con A-stimulated T-cell proliferation.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported to augment various macrophage (M phi) functions, including antigen presentation in the antibody-producing response. We investigated the augmentative effect of GM-CSF on M phi A-cell activity in concanavalin A-stimulated T-cell proliferation. Pretreatment with GM-CSF of peritoneal M phi enhanced the T-cell proliferative response. This effect of GM-CSF was dose dependent and GM-CSF supplementation was needed at the beginning of M phi culture. We observed that GM-CSF induced M phi spreading and firm attachment accompanied with enlargement of the cytoplasm, but could not induce de novo expression of Ia antigen. GM-CSF treatment enabled M phi to produce more interleukin (IL)-1 and IL-6 upon stimulation with lipopolysaccharides or polyinosinic-polycytidylic acid, but was unable to stimulate M phi directly. This was confirmed by Northern blot analysis. These results indicate that GM-CSF augments M phi A-cell activity through the enhancement of the capacity of M phi to produce IL-1 and IL-6.

Animals↗
PubMed1990

Inhibition of tumor cell proliferation by natural suppressor cells present in murine bone marrow.

Natural suppressor (NS) cells, which are Thy-1-, immunoglobulin-, and nonadherent cells with relatively low density (1.063 to 1.075 g/ml), inhibit not only the proliferation of spleen cells which have been stimulated by allogeneic cells or mitogens but also the proliferation of tumor cell lines. Cell-to-cell contact is not necessary for NS cells to exert NS activity. Being radioresistant, DNA synthesis is not necessary for NS cells to suppress proliferation. However, protein synthesis is necessary, since puromycin blocks NS cell activity. In addition, NS cells were found to secrete a factor which inhibits DNA synthesis. Of the various cytokines tested, interleukin 3 and granulocyte-macrophage colony-stimulating factor enhance NS activity. These results suggest that NS cells play an important role in the suppression of not only immune responses but also tumor growth.

Animals↗
PubMed1990

Analyses of thrombocytopenia in idiopathic thrombocytopenic purpura-prone mice by platelet transfer experiments between (NZW x BXSB)F1 and normal mice.

Male (NZW x BXSB) F1 (W/B F1) mice, which develop lupus nephritis, myocardial infarction, and thrombocytopenia, showed reduced platelet lifespan (PLS) and increased platelet-associated antibody (PAA) values. There were statistically significant correlations between the increase in PAA values and either the reduction in PLS or the decrease in platelet counts. This and the results of platelet transfer experiments between old male W/B F1 mice and either female W/B F1 or normal BALB/c mice indicate that PAAs on the platelet surface play a crucial role in the destruction of platelets in W/B F1 mice. The mechanism of thrombocytopenia observed here appears similar to that of human idiopathic thrombocytopenic purpura (ITP). Therefore, we think that W/B F1 mice are a potentially useful animal model for investigating the effectiveness and mode of action of therapeutic agents in human ITP, and that they may provide additional information on the basic mechanisms of this autoimmune phenomenon.

Animals↗
PubMed1990

Enrichment of natural suppressor activity in a wheat germ agglutinin positive hematopoietic progenitor-enriched fraction of monkey bone marrow.

Natural suppressor (NS) activity, the capacity of unprimed cells to suppress immunologic responses, is present in mouse, rabbit, and human bone marrow (BM). In this study we characterize NS activity in bone marrow cells of the rhesus monkey. Greatest NS activity was found in low-density cells (1.0600 to 1.0655 g/mL) obtained by density centrifugation on a discontinuous Percoll gradient. NS activity was further enriched when cells were separated by affinity for wheat germ agglutinin (WGA). Cells with high affinity to WGA demonstrated potent NS activity, whereas cells with low affinity to WGA had no NS activity. A significant relationship between NS activity and hematopoietic activity was demonstrated using in vitro assays of colony formation (CFU-GM and CFU-MIX). NS activity was not affected by treatment with monoclonal antibodies (MoAbs) to human Fc gamma receptors (Leu, 11a,b,c) or treatment with MoAbs to monkey natural killer cells. These findings extend our prior observations by showing that cells with NS activity, which apparently have WGA receptors, are present not only in murine BM but also in monkey bone marrow, and suggest that such cells may be involved in immunoregulation by primitive cells of BM.

Animals↗
PubMed1990

Two novel molecular isoforms of band 4.2 in Japanese Sika deer (Cervus nippon yesoensis, Heude) erythrocytes.

Two molecular isoforms of band 4.2 were identified in erythrocyte membranes from 25 Japanese Sika deer (Ceryus nippon yesoensis, Heude) based on specific immunorecognition with anti-human band 4.2. These two variants, designated 4.2/78 and 4.2/76, had respective relative molecular weights (Mr) of 78,000 and 76,000 on sodium dodecyl sulfate-polyacrylamide electrophoresis gels and showed similar profiles after limited proteolysis, exhibiting identity in primary structure. 25 adult Sika deer could be divided into two groups according to the 4.2/78:4.2/76 ration, indicating a genetic control in the expression of the molecular isoforms of band 4.2. Both polypeptides were completely retained in cytoskeletal protein-depleted membranes and could be removed by alkaline extraction, suggesting that both proteins contribute to the association of membrane proteins.

Animals↗
PubMed1990

24-homologated 1,25-dihydroxyvitamin D3 compounds: separation of calcium and cell differentiation activities.

A series of 24-homologated 1,25-dihydroxyvitamin D3 compounds have been chemically synthesized and studied with regard to their activity in inducing differentiation of human promyelocyte HL-60 cells to monocytes and in calcium mobilizing activity in vitamin D deficient rats. Homologation of 1,25-dihydroxyvitamin D3 or its delta 22 analogue by one or two carbons increases by 10-fold and three-carbon homologation reduces by half the activity in causing differentiation of HL-60. On the other hand, homologation causes a substantial decrease in in vivo calcium mobilization activity. The addition of each carbon at the 24-position decreases binding to the HL-60 receptor or rat intestinal receptor by 5-10-fold so that binding affinity of the trihomo compound for the receptors is 130 times less that of 1,25-dihydroxyvitamin D3. Thus, binding affinity for the receptor cannot account for the preferential activity of the 24-homologated compounds in inducing cell differentiation.

Animals↗
PubMed1990

Functional analyses of thymic CD5+ B cells. Responsiveness to major histocompatibility complex class II-restricted T blasts but not to lipopolysaccharide or anti-IgM plus interleukin 4.

The function of thymic B cells in several standard in vitro assays was investigated. Thymic B cells, 75% of which were CD5+, showed a poor responsiveness to the mitogens LPS or anti-mu plus IL-4. Both proliferation and antibody formation were much lower in thymic than splenic B cell cultures. However, CD5- B cells purified using a cell sorter responded well to B cell stimulants, whereas purified CD5+ thymic B cells did not, indicating that CD5+ thymic B cells were unresponsive to B cell growth factor or LPS. Thymic B cells could be activated polyclonally by direct interaction with alloreactive T blasts, as manifested by DNA synthesis and antibody formation. These findings indicate that CD5+ thymic B cells may not be stimulated via sIg and IL-4, but require instead direct interaction with T blasts.

Animals↗
PubMed1990

Antitumor activity of a derivative of mitomycin, 7-N-[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]mitomycin C (KW-2149), against murine and human tumors and a mitomycin C-resistant tumor in vitro and in vivo.

The antitumor activity of a mitomycin derivative, 7-N-[2[[2-(gamma-glutamylamino)ethyl]dithio]ethyl]mitomycin C (KW-2149), was evaluated in murine and human tumor models, including a mitomycin C (MMC)-resistant tumor in vitro and in vivo. KW-2149 showed a profound effect against i.p. inoculated P388 leukemia on both a single and an intermittent administration schedule. Against s.c. implanted colon adenocarcinoma 38 (colon 38). KW-2149 was as effective as MMC in ILS% and in tumor growth inhibition on a single-administration schedule. Both compounds were similarly effective when an intermittent schedule was used. KW-2149 showed activity against human tumor xenografts and was effective in two of four non-small-cell lung carcinomas but was not effective against three gastric adenocarcinomas on the single-administration regimen. The activity of KW-2149 against gastric adenocarcinoma was inferior to that of MMC on a single-administration schedule. However, the antitumor activity of KW-2149 was higher on an intermittent schedule than on a single-administration regimen. The antitumor activity of KW-2149 against human tumor xenografts was similar to that of MMC on an intermittent schedule, and the former drug was effective against both gastric adenocarcinomas and both non-small-cell lung carcinomas. KW-2149 was more effective than MMC against a subline of P388 leukemia that is resistant to MMC in vitro as well as in vivo.

Adenocarcinoma↗