Biomedical subjects

N Oku

Publications and source records attributed to N Oku.

At least 73 records · Page 4Linked to original sources

PubMed1997

Tumor cells with organ-specific metastatic ability show distinctive trafficking in vivo: analyses by positron emission tomography and bioimaging.

To elucidate the behavior of various metastatic tumor cells with different characteristics in the blood flow, we have developed a system to investigate real-time trafficking using positron emission tomography. In this study, positron-labeled cells, i.e., lung-metastatic B16BL6 melanoma and two sublines of liver-metastatic RAW117 large cell lymphoma, were injected i.v., and the trafficking of these cells was noninvasively determined. All sublines tested accumulated in the lungs immediately after injection, presumably because the lungs were the first organ passed through after i.v. injection. The elimination of RAW117 cells from the lungs, however, was fast compared with that of B16BL6 cells. The latter showed a release rate from the lungs of less than 1%/min, whereas that of RAW117 cells was greater than 2%/min. Reflecting the elimination from lungs, RAW117 cells accumulated in the liver in a time-dependent manner. Biodistribution of metastatic cells was also analyzed by whole-body autoradiography after injection of 5-[125I]iodo-2'-deoxyuridine-labeled cells, using a bioimaging analyzer system. The method is invasive; however, it enables a precise determination of the biodistribution of metastatic cells. Bioimaging analyzer system analysis also showed the organ-specific accumulation of these metastatic cells. Furthermore, colonized distribution of B16BL6 cells in the lungs and that of RAW117 cells in the liver were observed. The present data suggest that the trafficking of metastatic tumor cells greatly influences the organ specificity of cancer metastasis.

Animals↗

PubMed1997

DNA single-strand breaks in L-132 cells resulting from inhibition of repair polymerization shortly after exposure to dimethylarsinic acid.

DNA single-strand breaks due to the inhibition of repair polymerization in cultured human pulmonary epithelial (L-132) cells after exposure to dimethylarsinic acid (DMAA), a main metabolite of inorganic arsenics in mammals, were examined. The strand breaks were detected by an alkaline elution method with the use of inhibitors of DNA polymerase, aphidicolin (aph) and 2',3'-dideoxythymidine (ddT); the former inhibits DNA polymerases alpha, delta and epsilon, and the latter inhibits DNA polymerase beta. Generally, DNA polymerases delta and epsilon are thought to be associated with necleotide excision (long patch) repair and polymerase beta with base excision (short patch) repair. After exposure of the L-132 cells to 10 mM DMAA, the breaks occurred in a time-dependent manner during incubation for 1-6 h under the inhibition of aph-sensitive polymerases with 50 micrograms/ml aph plus 10 mM hydroxyurea (HU) for the last 1 h of the DMAA exposure. Also, when DNA polymerase beta was inhibited with 10 mM ddT plus 1 microM methotrexate (MTX), the exposure of L-132 cells to 10 mM DMAA for 6 h significantly induced DNA single-strand breaks. An experiment of the co-treatment with both aph and ddT suggested that in the DNA repair process, aph-sensitive polymerases, probably polymerases delta and/or epsilon, and polymerase beta, functioned independently on different lesions induced after exposure to DMAA.

Animals↗

PubMed1997

Cell-nuclear accumulation of 72-kDa stress protein induced by dimethylated arsenics.

The induction and subsequent intracellular distribution of the 72-kDa heat shock (stress) protein (Hsp72) by exposure of cultured human alveolar (L-132) cells to dimethylarsinic acid (DMAA), a main metabolite of inorganic arsenics in mammals, were examined. A significant induction of Hsp72 in the cells was observed by exposure to 10mM DMAA for 6 h. The induction was similar to the case by arsenite for 6 h or by heat treatment at 42 degrees C for 3h. However, the nuclear distribution of Hsp72 differed greatly between DMAA and 42 degrees C treatment or arsenite exposure, i.e., Hsp72 induced by exposure to DMAA accumulated not only in the nucleoli but also in the nucleoplasm, whereas that by 42 degrees C or arsenite exposure did not accumulate in the nucleoplasm. Furthermore, the Hsp72 accumulated in the nucleus by DMAA exposure hardly diffused with the addition of ATP, suggesting that the DMAA-induced Hsp72 strongly binds to some macromolecules in the nucleus. The fact that Hsp72 induced by DMAA exposure accumulated in the nucleus of the cells may reflect a protective response toward the nucleus-specific damaging action of dimethylarsenics.

Adenosine Triphosphate↗

PubMed1997

Application of long-circulating liposomes to cancer photodynamic therapy.

Photodynamic therapy (PDT) as a cancer treatment is notable for its quite low side effects in comparison with those of chemotherapy and radiotherapy. However, the accumulation of porphyrin derivatives used in PDT into tumor tissues is rather low. Since long-circulating liposomes are known to accumulate passively into tumor tissues, we liposomalized a porphyrin derivative, benzoporphyrin derivative monoacid ring A (BPD-MA), and used these liposomes to investigate the usefulness of PDT for tumor-bearing mice. BPD-MA was liposomalized into glucuronate-modified liposomes, which are known to be long-circulating. These liposomes were injected i.v. into Balb/c mice bearing Meth A sarcoma, and tumor regression and survival time were monitored after irradiation with laser light. Tumor regression and complete curing of tumor (80% cure rate by the treatment with 6 mg/kg BPD-MA) were observed when long circulating liposomalized BPD-MA was injected and laser-irradiated. In contrast, only a 20% cure rate was obtained when the animals were treated with BPD-MA solution or BPD-MA entrapped in conventional liposomes. These results suggest that a long-circulating liposomal formulation of photo-sensitive agents is useful for PDT.

Animals↗

PubMed1997

Comparison of iodine-123-iomazenil SPECT and technetium-99m-HMPAO-SPECT in Alzheimer's disease.

UNLABELLED: This study was designed to elucidate a central type of benzodiazepine (Bz) receptor distribution in patients with Alzheimer's disease using SPECT with [123I]iomazenil (IMZ). METHODS: Eight patients with probable Alzheimer's disease were studied. Benzodiazepine receptor imaging was performed 15 min (early) and 180 min (delayed) after intravenous administration of 167 MBq IMZ, sequentially, using hexamethylpropylene amine oxime (HMPAO) SPECT to evaluate regional cerebral perfusion. RESULTS: Early IMZ-SPECT depicted areas of reduced uptake in sites of decreased cerebral blood flow (CBF), but each area of decreased uptake was extended wider than the area of hypoperfusion. Delayed IMZ-SPECT images demonstrated a similar pattern of decreased area of CBF; the affected region in Bz receptor bindings, however, was clearer and broader compared with that in either HMPAO-SPECT or early IMZ-SPECT. In comparison with the uptakes for the normal cerebral hemisphere (ratio to the contralateral cerebellum) in patients with unilateral cerebral infarction as a control group (n = 4), the patients with Alzheimer's disease showed distinctive bilateral frontal or parietal defects (p < 0.05). CONCLUSION: Brain SPECT using IMZ may be more sensitive than CBF images in patients with Alzheimer's disease.

Alzheimer Disease↗

PubMed1997

Intra-individual differences between technetium-99m-HMPAO and technetium-99m-ECD in the normal medial temporal lobe.

UNLABELLED: Regional distributions of 99mTc-hexamethyl propyleneamine oxime (99mTc-HMPAO) and 99mTc-ethyl cysteinate dimer (99mTc-ECD) were compared in the normal brain. METHODS: Six paid, healthy volunteers (mean age 26 yr) had high-resolution neuroperfusion SPECT using both 99mTc-HMPAO and 99mTc-ECD on separate days. RESULTS: Regional distribution of the two tracers differed. Technetium-99m-HMPAO accumulated more in the thalamus, frontal lobe, temporal lobe and cerebellum than 99mTc-ECD, which accumulated more in the occipital and parietal lobes. There was a considerable difference in the accumulation of the two tracers in the medial temporal lobe. The percent accumulations of 99mTc-HMPAO and 99mTc-ECD in the medial temporal lobe compared with the mean global cerebral cortical accumulation were 93.9% +/- 2.4% and 83.1% +/- 4.1% (mean +/- s.d.), respectively. CONCLUSION: The results suggest that 99mTc-HMPAO and 99mTc-ECD require specific and separate criteria for diagnosing temporal lobe pathologies, such as dementia and temporal lobe epilepsy.

Adult↗

PubMed1997

Hemodynamic aspect of cerebral watershed infarction: assessment of perfusion reserve using iodine-123-iodoamphetamine SPECT.

UNLABELLED: The mechanism whereby watershed (WS) infarcts develop remains controversial, although a hemodynamic cause is usually assumed. The aim of this study was to investigate the relationship between the site of WS infarcts and the hemodynamic status of the cerebral circulation. METHODS: From among 96 consecutive patients with angiographically confirmed unilateral major cerebral artery obstruction (occlusion or > 70% stenosis), we investigated 29 patients with supratentorial WS infarcts on magnetic resonance imaging. The regional cerebral blood flow and perfusion reserve were quantified using the split-dose [123I]iodoamphetamine SPECT method, coupled with intravenous injection of 1 g of acetazolamide. Seven patients had a cortical WS infarct between the superficial branches of the anterior and middle cerebral arteries (MCAs) or between the middle and posterior cerebral arteries (Group C), and 22 had a deep WS infarct between the superficial branches and deep penetrating arteries of the MCA (Group D). Moreover, the patients in Group D were classified into two subgroups, i.e., Type A (n = 12), with lesions lying in the centrum semiovale above the level of the lateral ventricles, and Type B (n = 10), with lesions lying in the corona radiata adjacent to the lateral ventricles. RESULTS: Comparison of the Type of WS infarct with the clinical course of onset showed that sudden onset was more frequent in Group C than in Group D (p < 0.05). The perfusion reserve in the affected MCA territory in Group D (20.1% +/- 15.6%) was significantly lower than that in Group C (43.8% +/- 10.8%; p < 0.01) and that in 20 hemispheres (10 control subjects) without a major arterial lesion (54.7% +/- 16.4%; p < 0.01). Among the Group D patients, the patients with Type A infarcts showed a significantly lower perfusion reserve compared with those with Type B infarcts (p < 0.05). CONCLUSION: Patients with deep WS infarcts, especially Type A infarcts, showed severe hemodynamic impairment, whereas patients with cortical WS infarcts showed preserved perfusion reserve which appeared to be secondary to the embolism. The mechanism of development of WS infarcts is multifactorial, and distinguishing among these WS infarcts and from other types of infarct is important, because different pathogenic mechanisms require different therapeutic strategies.

Acetazolamide↗

PubMed1996

Sulphatide binds to human and animal influenza A viruses, and inhibits the viral infection.

We found, by using a virus overlay assay, that influenza A virus isolates bind to sulphatide (HSO3-Gal beta 1-->1'Cer), which has no sialic acid residue, and that the infection of Madin-Darby canine kidney cells with the human influenza virus A/Memphis/1/71 (H3N2) is inhibited by sulphatide. A/Memphis/1/71 (H3N2) causes obvious haemagglutination and low-pH haemolysis of asialoerythrocytes reconstituted with sulphatide. All influenza A virus isolates from the species of animals so far tested bound to sulphatide. The sulphatide-binding specificity of the isolates was different from the viral sialyl-linkage specificity. Influenza A virus isolates also bound to galactosyl ceramide (GalCer; Gal beta 1-->1'Cer), as well as sulphatide, in the virus overlay assays. In contrast, the influenza virus did not bind to N-deacyl, a derivative of sulphatide, glucosyl ceramide or the other neutral glycolipids tested. These results indicate that the linkage of galactose, or sulphated galactose, to ceramide is important for viral binding.

Animals↗

PubMed1996

Effect of serum protein binding on real-time trafficking of liposomes with different charges analyzed by positron emission tomography.

Liposomes have been used as carriers of various materials and as tools for gene transfer: for the latter purpose, positively charged liposomes are usually used. To evaluate the stability in the presence of serum and the in vivo behavior of such liposomes as well as those aspects of neutral and negatively charged liposomes, we investigated liposomal agglutinability in the presence of serum, serum protein binding to these liposomes, and real-time liposomal trafficking by a non-invasive method using positron emission tomography (PET). Liposomes composed of dipalmitoylphosphatidylcholine, cholesterol without or with charged lipid were prepared in the presence of mannitol, and the turbidity change in the presence of serum was determined. Turbidity increase was not observed for so-called long-circulating liposomes, i.e., liposomes modified with glucuronic acid or with poly(ethylene glycol), or for negatively charged liposomes containing dicetyl phosphate (DCP), phosphatidylglycerol, or phosphatidylserine. On the contrary, a significant turbidity increase was observed when positively charged liposomes modified with stearylamine, stearyltrimethylammonium chloride or 1,2-dimyristyloxypropyl-3-dimethylhydroxyethyl bromide (DMRIE), which is known as a component of liposomes for gene transfer, were used. These liposomes were found to have bound a high amount of serum proteins after separation of unbound serum proteins by use of a spin column. The liposomal trafficking in vivo was determined for three kinds of liposomes, i.e., liposomes with DMRIE, those with DCP, and those without charged lipids. These liposomes were prepared in the presence of 2-[18F]fluoro-2-deoxy-D-glucose ([2-18F]FDG), and the [2-18F]FDG-labeled liposomes were administered to mice to perform PET scans. Positively charged liposomes containing DMRIE showed high accumulation in the liver compared with neutral and negatively charged liposomes. Since DMRIE-liposomes tended to aggregate in the presence of serum, and to be associated with serum protein, these characteristics may lead to the high uptake of DMRIE-liposomes by the liver.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1996

Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor-cell arrest in lungs followed by extravasation.

Our study demonstrates that synthetic sialyl Lewis X (SLex) as a ligand for selectins and fibronectin-derived RGDS peptide analogue [Ar(DRGDS)3] inhibits lung metastases produced by i.v. co-injection of B16-BL6 melanoma cells. To investigate the inhibitory mechanisms in a living animal, we performed positron-emission tomography (PET) analysis after i.v. injection of [2-18F]2-fluoro-2v-deoxy-D-glucose-labeled tumor cells with or without liposomal SLex or Ar(DRGDS)3. The real-time PET measurement for the first 120 min, started immediately after injection, showed that tumor-cell arrest, i.e., accumulation in the target organ (lung) was remarkably inhibited by liposomal SLex, but not inhibited by Ar(DRGDS)3 or liposomal Me-SLex, which is not recognized by selectins. In contrast, Ar(DRGDS)3 inhibited the invasion of B16-BL6 cells into reconstituted basement membrane (Matrigel) following tumor arrest, whereas SLex- or Me-SLex-entrapped liposomes did not affect tumor invasion. In the metastatic processes containing tumor-cell lodgement and arrest in the target organ followed by extravasation (invasion), SLex resulted in the inhibition of initial arrest of tumor cells, presumably tumor-endothelium interaction, while Ar(DRGDS)3 achieved inhibition of tumor invasion into basement membrane at later steps of the cascade, consequently leading to inhibition of metastasis. Thus, tumor-cell arrest in lungs in the metastatic processes must be precisely and properly controlled by different adhesion molecules at different stages, which are similar to those observed in leukocyte-endothelium interaction.

Amino Acid Sequence↗

PubMed1996

Antitumor activity of vincristine encapsulated in glucuronide-modified long-circulating liposomes in mice bearing Meth A sarcoma.

Liposomes modified with the uronic acid derivative palmityl-D-glucuronide (PGlcUA) have a long circulation time and tend to accumulate in the tumors of tumor-bearing mice. Taking advantage of this character, we investigated the therapeutic effect of vincristine (VCR) encapsulated in liposomes containing PGlcUA (dipalmitoylphosphatidylcholine/cholesterol/PGlcUA = 4:4:1 as a molar ratio) on tumor-bearing mice. VCR was loaded into liposomes by a remote loading method, and then free or liposomal VCR was injected intravenously into BALB/c mice bearing Meth A sarcoma implanted subcutaneously 5 days before hand. Single-dose administration of VCR (3.0 mg/kg) in PGlcUA-liposomes significantly suppressed tumor growth, and prolonged the survival time (T/C = 1.37). Furthermore, two-dose administration of the liposomes cured one third of the animals. The therapeutic effect of PGlcUA-liposomes was greater than that of control liposomes containing dipalmitoylphosphatidylglycerol instead of PGlcUA. PGlcUA-liposomes might thus be a useful tool for delivering antitumor agents to tumor tissues.

Animals↗

PubMed1996

In vivo trafficking of long-circulating liposomes in tumour-bearing mice determined by positron emission tomography.

Various kinds of long-circulating liposome, such as ganglioside GM1-, polyethyleneglycol- (PEG-), and glucuronide-modified liposomes, have been developed for passive targeting of liposomal drugs to tumours. To evaluate the in vivo behaviour of such long-circulating liposomes, we investigated the liposomal trafficking, especially early trafficking just after injection of liposomes, by a non-invasive method using positron emission tomography (PET). Liposomes composed of dipalmitoylphosphatidylcholine, cholesterol, and modifier, namely, GM1, distearoylphosphatidylethanolamine (DSPE)-PEG or palmityl-D-glucuronide (PGlcUA), were labelled with [2-18F]-2-fluoro-2-deoxy-D-glucose ([2-18F]FDG), and administered to mice bearing Meth A sarcoma after having been sized to 100 nm. A PET scan was started immediately after injection of liposomes and continued for 120 min. PET images and time-activity curves indicated that PEG liposomes and PGlcUA liposomes were efficiently accumulated in tumour tissues time dependently from immediately after injection. In contrast, GM1 liposomes accumulated less in the tumour as was also the case for control liposomes that contained dipalmitoylphosphatidylglycerol (DPPG) instead of a modifier. Long-circulating liposomes including GM1 liposomes, however, remained in the blood circulation and avoided liver trapping compared with control DPPG liposomes. These data suggest that PGlcUA and PEG liposomes start to accumulate in the tumour just after injection, whereas GM1 liposomes may accumulate in the tumour after a longer period of circulation.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1996

Liposomal Arg-Gly-Asp analogs effectively inhibit metastatic B16 melanoma colonization in murine lungs.

Analogs of a synthetic peptide having the L-arginine-L-glycine-L-aspartic acid (RGD) sequence have been found to decrease metastatic colonization. To enhance the metastasis-suppressing efficacy of these analogs, we sought to stabilize these analogs and to prolong their circulation time by incorporating them into a liposomal formulation. Various structures of RGD analogs grafted to hydrophobic groups were synthesized and then incorporated into liposomes. Liposomes composed of distearoylphosphatidylcholine, cholesterol, dipalmitoylphosphatidylglycerol and appropriate RGD analogs were injected intravenously along with B16BL6 murine melanoma cells into mice. Liposomal RGD (0.6 mumol of the analog equivalent to ca. 200 micrograms RGD peptides) inhibited lung colonization up to 76%. This dose is an order of magnitude lower than that for comparable inhibition reported for free RGD. Multi-dose administration of liposomal RGD (0.15 mumol of the analog) also inhibited the spontaneous lung metastasis of cells from a primary tumor site of B16BL6 cells subcutaneously implanted into the footpad of mice. Taken together, our data indicate that liposomal RGD may serve as a useful anti-metastatic agent.

Amino Acid Sequence↗

PubMed1996

Dimethylarsenics reveal DNA damage induced by superoxide anion radicals.

We previously reported that DNA single-strand breaks (ssb) induced by exposure to dimethylarsinic acid (DMAA) were enhanced by the presence of paraquat (PQ), a superoxide anion radical 0 -(2)-producing agent, in cultured human alveolar type II (L-132) cells in vitro. In the present study, we examined the effect of sequential exposure of the cells to PQ and then DMAA under conditions causing no ssb by each alone, and observed a remarkable occurrence of ssb. The result suggests that 0 -(2) caused DNA damage, which became detectable as ssb by the treatment using DMAA. The DNA damage induced by the exposure to PQ alone was different from that by DMAA; PQ-induced damage was fully repaired after 24 h, while DMAA-induced damage was repaired only partially, and aphidicolin, an inhibitor of repair-serving DNA polymerases alpha, delta and/or epsilon, inhibited only the latter repair but not the former. These findings indicate that the DMAA treatment may be an effective tool to reveal DNA damage induced by 0 -(2), which to date has not been sufficiently clarified.

Aphidicolin↗

PubMed1996

Differential effect of UV-B and UV-C on DNA damage in L-132 cells.

Ultraviolet radiation is known to induce skin cancer. The induction of DNA damage caused by UV-B and UV-C was investigated using cultured L-132 cells. DNA strand breaks assayed by the alkaline elution procedure occurred in a dose-dependent manner, the extent of the strand breaks were inversely well correlated with the number of viable L-132 cells after 24 h incubation. About a 10-fold dose of UV-B irradiation was required to induce a similar degree of strand breaking to that induced by UV-C. Similarly about a 10-fold dose of UV-B was required to produce a similar amount of pyrimidine dimers, such as cyclobutane-type dimers and pyrimidine-(6-4)-pyrimidone photoproducts, which were determined by ELISA using the specific monoclonal antibody, to that produced by UV-C. Strand breaks induced by UV-B, however, were not fully repaired in viable cells remaining after incubation of cells for a longer period of time, although UV-C-induced strand breaks were repaired in a time-dependent manner. Furthermore, an experiment with a cell-free system, where the induction of strand breaks by repair enzymes did not take place, indicated that UV-B caused significantly more direct DNA strand breaks than that caused by one-tenth the dose of UV-C. The data shown here suggest that UV-B-induced DNA damage is mediated, at least in part, via a different mechanism from the UV-C induced one.

Antibodies, Monoclonal↗

PubMed1996

Effect of freeze-thawing on phospholipid/surfactant mixed bilayers.

The effect of freeze-thawing of egg phosphatidylcholine (PC) and octyl glucoside (OG) on vesicle growth and on liposomal formation by the subsequent removal of the OG was investigated. When increasing concentrations of OG were mixed with PC vesicles of 10 or 20 mM PC, vesicle growth was observed until the ratio of OG/PC reached about 3.0, and then micellization occurred at a higher concentration of OG, as determined by turbidity change and microscopic observation. On the other hand, a marked increase in turbidity was observed after freeze-thawing of the samples when the OG/PC ratio was less than 3.0. The frozen and thawed mixed bilayer composed of OG/PC = 2 formed closed vesicles having solute-trapping ability as determined by fluorescence microscopy. Interestingly, the trapping volume of liposomes generated after removal of OG from freeze-thawed samples was higher for those from mixed micelles than for those from mixed vesicles composed of OG and PC. When increasing concentrations of OG were mixed with PC vesicles of 0.8 or 2 mM PC, micellization started when the OG was at about its critical micelle concentration (cmc), although marked turbidity was observed when the OG/PC ratio was 2.0 after freeze-thawing. These data suggest that freeze-thawing affects the bilayer-micelle transition and liposomal formation after removal of OG even at concentrations of detergent lower than its cmc.

Detergents↗

PubMed1996

[Evaluation of 123I-iomazenil SPECT in patients with ischemic cerebrovascular disease: comparative study with 123I-IMP SPECT].

Clinical evaluation of 123I-iomazenil, a new imaging agent for central-type benzodiazepine receptors with SPECT, was performed in patients with ischemic cerebrovascular disease. We investigated 15 patients with angiographically-proven severe occlusive lesions (occlusion or > 70% stenosis) in the unilateral carotid system. 123I-iomazenil SPECT images were compared with cerebral blood flow (CBF) images and the cerebral perfusion reserve, which were measured using the "split dose 123I-IMP SPECT method" before and after the intravenous injection of 1 g of acetazolamide. For the detection of ischemic lesions, CBF images were superior to 123I-iomazenil images based on visual analysis. Regarding the count ratio of the affected MCA territory to the non-affected (L/N), 123I-IMP was lower than 123I-iomazenil in most of the cases. In five patients showing "crossed cerebellar diaschisis" by 123I-IMP, asymmetry of the cerebellar accumulation was observed in only one patient with 123I-iomazenil, which was less prominent than with 123I-IMP. There was no significant correlation between the L/N ratio with 123I-iomazenil and the cerebral perfusion reserve in the affected MCA territory. However, in some cases showing a decreased L/N ratio (< 90%) with 123I-iomazenil, a decreased CBF with normal perfusion reserve and cerebral hemi-atrophy were observed with 123I-IMP and MRI, which suggested the influence of neuronal loss due to chronic ischemia. These results indicate that 123I-iomazenil SPECT, which provides new information regarding neuronal loss due to ischemic damage to the brain, is useful for the evaluation of ischemic cerebrovascular disease.

Adult↗

PubMed1995

Real-time PET analysis of metastatic tumor cell trafficking in vivo and its relation to adhesion properties.

Although a number of studies have indicated that highly metastatic cells tend to adhere more to target endothelium in vitro than low or non-metastatic cells, direct evidence about the correlation between cellular adhesiveness and organ disposition of the cells has not been obtained. Using positron emission tomography (PET), we have developed a novel technique that enables the non-invasive detection of the real-time tumor cell trafficking. The present study shows the correlation between trafficking of murine large cell lymphoma RAW117 and the adhesion properties of the cells in vitro. Cells accumulated in the liver time-dependently, and accumulation of RAW117-H10, liver metastatic subline cells, was more intense than that of RAW117-P, the parental cells, indicating that the metastatic potential is correlated with the in vivo accumulation of the cells in the target tissue. To examine whether the adhesion properties of the cell membrane determine the cell trafficking, we performed PET analysis after altering the adhesion properties on the cell membrane by means of cellular protein kinase C modulation, since the modulation of this enzyme is known to alter the surface adhesion molecules, i.e., those of the integrin superfamily. The treatment of RAW117-P with 12-O-tetradecanoylphorbol 13-acetate, which caused augmentation of adhesion to hepatic sinusoidal microvessel endothelial cells (HSE) in vitro, enhanced the hepatic accumulation of the cells in vivo. On the contrary, treatment of RAW117-H10 with the protein kinase C inhibitor H-7, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, which reduced the adhesion activity of the cells to HSE, suppressed their accumulation in the liver, although the suppression was observed only during the first 30 min after administration of the cells. These data suggest that the adhesion properties of metastatic lymphoma cells are critical for the accumulation of these cells in the target tissue.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗