Biomedical subjects

T Hiramatsu

Publications and source records attributed to T Hiramatsu.

At least 37 records · Page 2Linked to original sources

PubMed2000

Immune tolerance induced by polyethylene glycol-conjugate of protein antigen: clonal deletion of antigen-specific Th-cells in the thymus.

Polyethylene glycol (PEG) conjugates of protein antigens induce antigen-specific immune tolerance of helper T (Th)-cells. However, the mechanism of this Th-cell tolerance has remained unelucidated. Using transgenic mice with ovalbumin (OVA)-specific T-cell receptor (TCR) genes, we examined the response of OVA-specific Th-cells towards tolerogenic PEG-conjugate of OVA in vitro and in vivo. When stimulated with PEG--OVA in vitro, transgenic OVA-specific Th-cells proliferated and produced interleukin 2, the levels of which were comparable to those induced by unmodified OVA. In contrast, PEG--OVA administered into the circulation of transgenic mice induced unresponsiveness in peripheral OVA-specific Th-cells. Moreover, in the thymus of these transgenic mice, the frequency of immature CD4+CD8+ (double positive) thymocytes was reduced. A similar phenomenon was not observed in transgenic mice treated with unmodified OVA. As autoreactive T-cells are known to be clonally deleted at the immature double positive stage in the thymus. Th-cell tolerance induced by PEG--protein antigens is at least in part mediated by central tolerance in the thymus, and is likely caused by the markedly enhanced stability of PEG--protein conjugates in the circulatory system.

Animals↗

PubMed2000

Effect of cationic liposomes on intracellular trafficking and efficacy of antisense oligonucleotides in mouse peritoneal macrophages.

We have investigated the intracellular fate and antisense effect of oligonucleotide/cationic liposome complexes using phosphorothioate oligonucleotides (S-Oligo) targeted to inducible nitric oxide synthase in mouse peritoneal macrophages. Confocal laser microscopic analysis revealed that, after application of fluorescein isothiocyanate (FITC)-labeled S-Oligo alone, the intracellular localization of fluorescence exhibited a punctate pattern in the cytoplasm, suggesting that the oligonucleotides were mainly confined to the endosomal and/or lysosomal compartments. In the case of complexation with Lipofectin and DMRIE-C liposomes, cellular uptake of FITC-S-Oligo was not greatly enhanced and the fluorescence localization in the cells was similar to that of FITC-S-Oligo alone. LipofectAMINE slightly enhanced cellular uptake of FITC-S-Oligo; however, the intracellular localization profile of FITC-S-Oligo remained largely unchanged. The antisense effect was slightly enhanced by LipofectAMINE under only very limited experimental conditions. It was concluded that cationic liposomes are not a potential carrier for S-Oligo in peritoneal macrophages because of their inability to promote the release of S-Oligo from the endosomal compartments to the cytosol over a non-toxic concentration range.

Animals↗

PubMed2000

[Pulmonary outflow tract reconstruction with autologous tissue during the Ross procedure: right ventricular characteristics in mid-term follow-up].

BACKGROUND: The Ross procedure requires the interposition of prosthetic or homograft extracardiac conduits to establish ventricle-pulmonary artery connection (RV-PA). These materials usually require multiple reoperations because of conduit failure. To avoid the re-replacement of currently available conduits, usage of autologous tissue may be preferable to reconstruct RV-PA connection during the Ross procedure, especially in the pediatric age group. METHOD: Ten patients (mean age 8.7 years, range 2-23) with congenital aortic valve disease underwent the Ross procedure between June, 1996 and July, 1998. To establish RV-PA continuity, autologous aortic wall including aortic valve with a gusset of pericardial tissue was used in six patients, rolled pericardial conduit with fresh pericardial bicuspid valve in three and one direct anastomosis of pulmonary posterior wall onto the right ventricle with a fresh pericardial monocusp valved patch. All patient's postoperative courses were uneventful. All patients were followed up (mean follow-up period: 21.6 +/- 6.6 months) and postoperative right ventricular characteristics, cardio-thoracic ratio (CTR) on chest X-ray and pulmonary valve function were evaluated. RESULTS: Postoperative right ventricular end-diastolic volume, right ventricular ejection fraction and right ventricular end-diastolic pressure did not change significantly (RVEDV: 128 to 113% of normal, RVEF: 56.4 to 51.5%, RVEDP: 5.9 to 10.1 mmHg). Pulmonary regurgitation during follow-up was mild in six patients and moderate in four. However, CTR decreased significantly over time (preop.: 56.5% postop.: 58.5%, late period: 53.4%). CONCLUSION: Our results support the concept of the reconstruction of pulmonary outflow tract without foreign materials during the Ross procedure. Longer follow-up are necessary to define the possible limitation of this technique.

Adult↗

PubMed2000

Pharmacologic intervention with angiotensin II and kininase inhibitor enhanced efficacy of radioimmunotherapy in human colon cancer xenografts.

UNLABELLED: Induced hypertension and kininase inhibition can enhance tumor targeting of radiolabeled monoclonal antibody (MAb) by altering tumor circulation. This study investigated the effect of this manipulation on the antitumor efficacy of radioimmunotherapy (RIT). METHODS: Mice bearing human colon cancer xenografts were administered 2.0 microg/kg/min of angiotensin II (AT-II) for 1 h and 30 microg of a kininase inhibitor, enalapril maleate, before the administration of 3.7 MBq (131)I-A7, an IgG1 against 45-kDa glycoprotein on colorectal cancer, and tumor growth was observed thereafter. The mechanism of the manipulation effect was investigated by estimation of the tissue absorbed dose and radioluminography of tumors. RESULTS: The pharmacologic manipulation with AT-II and enalapril improved the tumor quadrupling time (Tq) of 3.7 MBq RIT from 24.3 +/- 2.75 d to 33.1 +/- 2.83 d (P < 0.05). Addition of this manipulation made 3.7 MBq RIT as effective as 9.25 MBq RIT alone (Tq, 37.2 +/- 2.97 d). Dose estimation showed that the manipulation increased the tumor absorbed dose 1.55-fold without affecting the doses to normal tissues. Uniform intratumoral distribution in the manipulated tumors was shown by radioluminography. CONCLUSION: Larger and more uniform tumor radiation produced by this pharmacologic manipulation can benefit RIT with (131)I-MAb.

Angiotensin II↗

PubMed2000

Management of suspected nosocomial infection: an audit of 19 hospitalized patients with septicemia caused by Bacillus species.

From April to August of 2000, Bacillus spp. were detected in the blood culture of 29 patients in a hospital in Japan. Of these patients, 19 had clinical signs of septicemia; positive culture in the remaining 10 patients was attributed to contamination with skin flora at the site of puncture. Of the 18 strains evaluated, 15 were Bacillus cereus, 2 were Bacillus subtilis, and one was Bacillus licheniformis. The only hospital death observed was that of a patient who had no clinical signs of septicemia at the time of blood sampling. That death is now considered attributable to the underlying neoplasm. The hospital committee for prevention of nosocomial infection concluded after a critical review of the patient records that the cause of septicemia in most cases had been contaminated intravenous lines. To control the situation, the committee recommended the use of a new skin disinfectant, and medical personnel were advised to avoid infusion pauses with interruption of intravenous lines and to replace the caps for the stopcocks with new ones each time the caps were removed. These measures were rigorously observed in addition to the conventional measures for preventing catheter sepsis, and the incidence of septicemia due to the Bacillus spp. declined dramatically thereafter.

Adult↗

PubMed1999

Combination radioimmunotherapy with local hyperthermia: increased delivery of radioimmunoconjugate by vascular effect and its retention by increased antigen expression in colon cancer xenografts.

Hyperthermia (HT) may increase tumor targeting of a radiolabeled antibody by its effects on tumor vasculature and antigen expression. Expression of a 45-kDa glycoprotein antigen on LS180 colon cancer cells was 2.7-fold enhanced 2 days after heating at 43 degrees C for 1 h. Preferential tumor accumulation of 125I-A7 recognizing this antigen was doubled and the antitumor effect of 131I-A7 was significantly improved by HT. Hyperthermia also increased tumor uptake of an irrelevant antibody but its radioactivity was rapidly cleared. These results indicate that HT increased the initial delivery of an antibody to a tumor by its vascular effect, and radioactivity was retained in tumors by increased specific binding, resulting in a better radioimmunotherapy outcome.

Animals↗

PubMed1999

Efficacy, toxicity and mode of interaction of combination radioimmunotherapy with 5-fluorouracil in colon cancer xenografts.

PURPOSE: The feasibility of radioimmunotherapy (RAIT) combined with 5-fluorouracil (5-FU) was examined in colon cancer xenografts. The mode of interaction of the two treatments was also investigated. METHODS: Mice bearing human colon cancer were treated with a combination of 4.63 MBq (L-RAIT) or 9.25 MBq (H-RAIT) (131)I-A7, an IgG1 against 45-kDa glycoprotein, and 5-FU at a dose of 30 mg kg(-1)day(-1) for 5 days. Myelotoxicity was monitored by blood cell counts and intestinal toxicity was assessed by the dosimetry. The results were compared with those of a single-modality therapy. RESULTS: The combination of 5-FU with H-RAIT enhanced the antitumor effect, improving the tumor quadrupling time from 25.3 +/- 9.59 days to 31.3 +/- 8.32 days (P < 0.05) and inducing tumor regression in 7 out of 10 mice, compared to 3 out of 9 mice treated with H-RAIT alone. The efficacy of L-RAIT was also improved by the combination. Analysis of the dose/response relationship showed an additive interaction of the two modalities. The combination of 5-FU with RAIT induced slightly more severe myelotoxicity than a single-modality treatment, but blood cell counts recovered similarly. Dose estimation suggested that RAIT does not increase the intestinal toxicity of 5-FU. CONCLUSION: The combination of two modalities would be feasible for the treatment of colon cancer, increasing antitumor effect with minor effect on toxicity.

Animals↗

PubMed1999

Time course of endothelin-1 and adrenomedullin after the Fontan procedure.

BACKGROUND: The endothelium-derived vasoconstrictor endothelin (ET)-1 might contribute to the physiology of blood flow regulation and play a role in cardiovascular disease. Adrenomedullin (AM) is a potent vasodilator peptide that has major effects on cardiovascular function and has multiple biologic effects involved in cardiovascular homeostasis. Although pulmonary vascular resistance is known to be one of the most important factors to determine the indications for a Fontan procedure, the time course of the plasma cytokine before and after the Fontan procedure is not known. METHODS: Sixteen patients were divided into two groups, 8 patients (1 to 14 years) who had the Fontan procedure (atriopulmonary connection) and 8 age-matched controls who had biventricular repair with normal central venous pressure. Plasma ET-1 and adrenomedullin levels were measured in both groups immediately before cardiopulmonary bypass, immediately after cardiopulmonary bypass, and 6 and 24 hours after cardiopulmonary bypass. A thermodilution catheter was inserted during the operation, and mean pulmonary arterial pressure, pulmonary wedge pressure, and cardiac output were measured, and pulmonary vascular resistance was calculated at the same time points. Correlation between the plasma ET-1 levels and pulmonary vascular resistance data were obtained in the Fontan group. RESULTS: Plasma ET-1 levels in the Fontan group were elevated after operation and were higher than the control group at 6 and 24 hours after cardiopulmonary bypass. Plasma adrenomedullin in the Fontan group was lower than in the control group at 6 and 24 hours after cardiopulmonary bypass. A significant positive correlation was obtained between the plasma ET-1 and pulmonary vascular resistance data (r = 0.475). CONCLUSIONS: Imbalance between increased ET-1 and relatively decreased adrenomedullin after cardiopulmonary bypass in the Fontan procedure could contribute to dominant effects of ET-1, which might induce vasoconstriction after the Fontan procedure. ET-1 might play an important role in maintaining vasoconstriction after the Fontan procedure.

Adolescent↗

PubMed1999

The long-term results of commissure plication annuloplasty for congenital mitral insufficiency.

BACKGROUND: Mitral valve repair in the pediatric population remains demanding because of a diversity of apparatus anomalies and the young age of the patients. METHODS: We reviewed our clinical results for mitral valve repairs for congenital mitral insufficiency. Forty-nine consecutive patients aged 2 months to 34 years (mean, 4.4 years) had mitral valve repair between June 1984 and December 1996. Forty-one patients (83.7%) had associated cardiac anomalies. The predominant pathologies for the regurgitations were chordal anomalies in 34 patients (69%), annular dilatation in 8 (16%), and leaflet anomalies in 7 (14%). Mitral valve repair included commissure plication annuloplasty in 43 patients (88%), modified DeVega in 11, cleft closure in 5, plication of the anterior leaflet in 3, triangular resection of the anterior leaflet in 2, chordal shortening in 1, and placement of artificial chordae in 1. Several combined techniques were required in 19 patients. RESULTS: There were no early or late deaths. The follow-up period was from 6 to 166 months (mean, 88.4 months). Forty-seven patients (95.9%) were in New York Heart Association class I. The long-term echocardiographic studies showed that 2 of 30 patients without reoperation had moderate regurgitation. The actuarial freedom from reoperation was 85.6% (95% confidence limits, 72.8%, 98.4%) at 13 years. Five patients (10.2%) required valve replacement from 13 days to 75 months after the valve repair. Two patients had cerebral ischemic events as a result of cardiomegaly and atrial fibrillation. CONCLUSIONS: Valve repair for congenital mitral insufficiency gave adequate results in combination with commissure plication annuloplasty and other techniques with excellent long-term functional status.

Adolescent↗

PubMed1999

Theophylline induces apoptosis of the IL-3 activated eosinophils of patients with bronchial asthma.

In bronchial asthma, eosinophils are upregulated and their survival is suggested to be prolonged by the action of some cytokines such as Interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF). We find here that the survival of eosinophils in the peripheral blood of patients with asthma is correlated with the serum levels of IL-3 but not of IL-5 and GM-CSF. Interestingly, theophylline is revealed to induce apoptosis of the prolonged survival eosinophils by IL-3, as judged by morphological changes and nucleosomal DNA fragmentation. During the apoptosis, caspase-3 in eosinophils stimulated by IL-3 is activated by theophylline. The substrate of caspase-3, poly (ADP-ribose) polymerase (PARP), is cleaved in the eosinophils after theophylline treatment. These results suggest that theophylline is able to induce apoptosis of the IL-3 activated eosinophils in patients with bronchial asthma, and that its clinical effectiveness may be due to the reduction of inflammatory cells in the airway.

Journal Article↗

PubMed1999

Early response of tumour to radiotherapy should be assessed by both uptake and retention of single photon tracers: in vitro analysis with 201Tl-chloride, 99Tcm-sestamibi and 99Tcm-tetrofosmin in human bladder cancer cells and human leukocytes.

The uptake and retention of single photon tracers in irradiated tumour cells was observed in an attempt at the early evaluation of the effect of radiation. T24 human bladder cancer cells were exposed to a single dose of 10 Gy or 20 Gy or a fractionated dose of 10 Gy (2 Gy for 5 days). The uptake of 201Tl chloride, 99Tcm-sestamibi and 99Tcm-tetrofosmin was observed by incubating in vitro for 60 min. The retention of the tracers was observed at 60 min after changing the incubation medium for a tracer-free medium. Uptake per culture well of all tracers in the cells exposed to 20 Gy declined as viable cell number decreased, but uptake per cell increased progressively. Uptake per cell of all tracers in the cells exposed to either a single dose or a fractionated dose of 10 Gy also increased, while a delay in growth was observed. The retention of these tracers decreased during this period and recovered thereafter. A binding assay with purified human leukocytes indicated that assessment with 99Tcm-sestamibi and 99Tcm-tetrofosmin is influenced by inflammatory cells. In conclusion, the effect of radiation may be underestimated if assessed by tracer uptake alone because of the increase in tracer uptake in viable irradiated cells. Observation of the retention of tracers may provide additional information.

Humans↗

PubMed1999

[A case of Bentall's operation for an 11-year-old patient with Marfan syndrome].

An 11-year-old girl who was diagnosed to have Marfan syndrome in her infancy, visited us with complaints of easy fatigability and chest discomfort. She was pointed out to have acute development of annuloaortic ectasia with severe aortic regurgitation and mild mitral regurgitation. She underwent replacement of the ascending aorta and aortic valve using composite graft with prosthetic valve (Bentall's operation) and circular annuloplasty of the mitral valve. Bentall's operation for infants and children is remarkably rare because in this generation, acute development of aortic dilatation leading rupture and dissection is quite infrequent while main death is caused by mitral regurgitation.

Aorta↗

PubMed1998

Hemodynamic effects of human atrial natriuretic peptide after modified Fontan procedure.

BACKGROUND: Reduction of pulmonary vascular resistance and maintenance of urine output are important after the modified Fontan procedure. Atrial natriuretic peptide (ANP) has the effects of a vasodilator (including the pulmonary arteries) and a physiologic diuretic, and newly synthesized human ANP is available. We measured plasma ANP levels before and after the Fontan procedure and examined the effects of human ANP on hemodynamic parameters after the Fontan procedure. METHODS: Eight patients, aged 2 to 15 years, underwent the Fontan procedure (atriopulmonary connection). Blood samples were taken before and 3 hours after operation, and plasma ANP levels were measured by radioimmunoassay. The correlation between central venous pressure and ANP was examined. Human ANP was infused intravenously at a dosage of 0.1 microg x kg(-1) x min(-1) for 1 hour after the Fontan procedure under controlled ventilation and another blood sample was obtained. Urine volume and central venous pressure were measured, and pulmonary vascular resistance and the cardiac index were calculated by the thermodilution catheter method before and after human ANP infusion. One hour after human ANP infusion was discontinued, the evaluation was repeated. No other diuretics were given and the infusion rates of catecholamine were kept constant during these measurements. RESULTS: Plasma ANP levels before and after the Fontan procedure were 29.1 and 54.9 pg/mL, respectively, and a positive correlation was obtained between central venous pressure and plasma ANP levels (r = 0.661, p < 0.05). Human ANP infusion significantly decreased central venous pressure and pulmonary vascular resistance, and increased urine volume and the cardiac index, whereas the plasma ANP level was elevated to 617.5 pg/mL. Systemic blood pressure did not change significantly. CONCLUSIONS: Atrial natriuretic peptide is secreted in response to elevated central venous pressure after the Fontan procedure, but its concentration might not be sufficient. Human ANP can be a therapeutic choice after the Fontan procedure as a physiologic diuretic and a pulmonary vasodilator.

Adolescent↗

PubMed1998

Atrial septal displacement for repair of anomalous pulmonary venous return into the right atrium.

BACKGROUND: In the repair of anomalous connection of the pulmonary veins to the right atrium, the use of a baffle of pericardium to divert the pulmonary venous blood into the left atrium could cause pulmonary venous obstruction as a result of thickening of the pericardial patch. Anomalous pulmonary venous drainage to the right atrium caused by malposition of the atrial septum primum can be repaired by displacing the shifted septum primum to the normal position. METHODS: In 5 patients with total (n=2) or partial (n=3) anomalous pulmonary venous drainage into the right atrium, the septum primum was shifted toward the left atrium and the pulmonary veins drained into the anatomic right atrium despite their normal connection with the posterior wall of the left atrium. This method consisted of incision of the posterior edge of the atrial septum primum and displacement of the incised atrial septum between the anomalous pulmonary veins and both venae cavae. No patch was used. RESULTS: Postoperative echocardiography showed a wide pathway from the pulmonary veins to the left atrium with no stenotic portions. No atrial arrhythmias occurred after the operation. CONCLUSIONS: This technique may be advantageous because it allows for future growth of the route of the pulmonary venous pathway and avoids postoperative supraventricular arrhythmias.

Arrhythmias, Cardiac↗

PubMed1998

Determination of the pH difference across a cell membrane using a methylammonium-selective membrane electrode.

A method was developed for determining pH differences across cell membranes using a methylammonium-selective membrane electrode, based on monitoring of the pH gradient-induced uptake of methylammonium in situ. The methylammonium electrode was constructed using calix[6]arene-hexaacetic acid hexaethyl ester as a neutral carrier and bis(2-ethylhexyl) sebacate as a membrane solvent in a poly(vinyl chloride) membrane matrix. This electrode exhibited a near-Nernstian response to methylammonium in the concentration range 2 x 10(-5)-1 x 10(-2) M with a slope of 58 mV per concentration decade in a buffer solution of 150 mM choline chloride-10 mM TRIS-HCl (pH 7.5). The limit of detection was 5 x 10(-6) M. In experiments using liposomes, the uptake of methylammonium into liposomes occurred effectively when the pH of the outside suspension medium was alkaline, and the determination of changes in methylammonium concentrations in the outer medium was quantitatively related to changes in the pH differences across the liposomal membrane. The transmembrane pH differences in Escherichia coli cells were also determined by this method.

Cell Membrane↗

PubMed1998

Rhenium-186-mercaptoacetyltriglycine-labeled monoclonal antibody for radioimmunotherapy: in vitro assessment, in vivo kinetics and dosimetry in tumor-bearing nude mice.

Stability and immunoreactivity of 186Re-labeled monoclonal antibody were examined, and its in vivo kinetics was investigated in tumor-bearing Balb/c nu/nu female mice to assess the feasibility of using it in radioimmunotherapy (RIT). A murine IgG1, A7, against a 45 kD glycoprotein in human colon cancer was radiolabeled with 186Re by using a chelating method with a mercaptoacetyltriglycine (MAG3). 186Re-MAG3 complex was conjugated to A7 after esterification of 186Re-MAG3 with tetrafluorophenol (TFP). The efficiency of 186Re-MAG3-TFP production and the labeling efficiency of A7 were 51-59% and 57-60%, respectively. Immunoreactivity of purified 186Re-MAG3-A7 was 68.2% at infinite antigen excess. In 0.9% NaCl at 4 degrees C, the radioactivity (12.7 MBq/mg, 3.55 MBq/ml) dissociated with time from 186Re-MAG3-A7 as a small molecular weight moiety because of autoradiolysis. The addition of ascorbic acid, 5 mg/ml, as a radioprotectant or storage at -80 degrees C could effectively prevent the radiolysis of 186Re-MAG3-A7 for 7 days. Immunoreactivity of 186Re-MAG3-A7, 6.70 MBq/mg (6.66 MBq/ml), stored in the presence of ascorbic acid was well retained up to 8 days after the preparation. In colon cancer xenografted mice, 31.0% of the injected dose/g of 186Re-MAG3-A7 had accumulated in the tumors at 24 h postinjection. Estimated radiation dose to tumors was 14.9 cGy/37 kBq up to 8 days postinjection which was 12-fold greater than the whole-body radiation dose. These in vivo characteristics were superior to those of A7 labeled with radioiodine, affording greater therapeutic ratios than 131I-A7. Because of the better image quality of 186Re-MAG3-A7 as well as more favorable dosimetry, 186Re-MAG3-A7 would be a better choice for RIT of colon cancer than 131I-A7. These results indicated the feasibility of RIT with 186Re-MAG3-A7, though the prevention of radiolysis of the labeled antibody should be considered.

Animals↗

PubMed1998

A putative multisubunit Na+/H+ antiporter from Staphylococcus aureus.

We cloned several genes encoding an Na+/H+ antiporter of Staphylococcus aureus from chromosomal DNA by using an Escherichia coli mutant, lacking all of the major Na+/H+ antiporters, as the host. E. coli cells harboring plasmids for the cloned genes were able to grow in medium containing 0.2 M NaCl (or 10 mM LiCl). Host cells without the plasmids were unable to grow under the same conditions. Na+/H+ antiport activity was detected in membrane vesicles prepared from transformants. We determined the nucleotide sequence of the cloned 7-kbp region. We found that seven open reading frames (ORFs) were necessary for antiporter function. A promoter-like sequence was found in the upstream region from the first ORF. One inverted repeat followed by a T-cluster, which may function as a terminator, was found in the downstream region from the seventh ORF. Neither terminator-like nor promoter-like sequences were found between the ORFs. Thus, it seems that the seven ORFs comprise an operon and that the Na+/H+ antiporter consists of seven kinds of subunits, suggesting that this is a novel type of multisubunit Na+/H+ antiporter. Hydropathy analysis of the deduced amino acid sequences of the seven ORFs suggested that all of the proteins are hydrophobic. As a result of a homology search, we found that components of the respiratory chain showed sequence similarity with putative subunits of the Na+/H+ antiporter. We observed a large Na+ extrusion activity, driven by respiration in E. coli cells harboring the plasmid carrying the genes. The Na+ extrusion was sensitive to an H+ conductor, supporting the idea that the system is not a respiratory Na+ pump but an Na+/H+ antiporter. Introduction of the plasmid into E. coli mutant cells, which were unable to grow under alkaline conditions, enabled the cells to grow under such conditions.

Amino Acid Sequence↗

PubMed1998

Persistent distension and enhanced diffusive extravasation of tumor vessels improved uniform tumor targeting of radioimmunoconjugate in mice administered with angiotensin II and kininase inhibitor.

Induced hypertension with angiotensin II (AT-II) and the inhibition of kininase with enalapril maleate may increase the tumor targeting of radiolabeled monoclonal antibodies (MAbs). We previously found that short-period infusion of 2.0 microg/kg/min of AT-II enhanced tumor targeting of MAb without an impact on normal tissue distribution. In this study, we aimed to optimize the manipulation with these agents, and examine the possible mechanism of their effects on MAb distribution. Effect of the manipulation on tissue circulation was assessed in mice bearing colon cancer xenografts by 201Tl and 99mTc-human serum albumin (HSA) as markers of tissue blood flow and tissue blood volume and/or vascular permeability. A dose finding study of enalapril ranging from 3 to 300 microg showed that 30 microg of enalapril in combination with AT-II infusion produced the best improvement in tumor uptake of 99Tc-HSA without altering 201Tl distribution, suggesting that the increase of vascular permeability was caused by enalapril. AT-II infusion for longer than 1 h affected renal blood flow and caused subcutaneous edema. Tumor uptake of (111)In-A7, a murine IgG1, was 1.62-fold improved 72 h postinjection (P < 0.001) and intratumoral distribution became uniform with 2.0 microg/kg/min of AT-II for 1 h and 30 microg of enalapril. Vessels in manipulated tumors were distended even 48 h after the cessation of AT-II infusion. In conclusion, it was suggested that persistent distension of tumor vessels and the increase of diffusive extravasation of MAb caused by short-period-induced hypertension and inhibition of bradykinin degradation produced favorable effect for the MAb distribution in tumors.

Angiotensin II↗