Biomedical subjects

M Niwa

Publications and source records attributed to M Niwa.

At least 127 records · Page 7Linked to original sources

PubMed1998

Transport of fragmented DNA in apical dendrites of gerbil CA1 pyramidal neurons following transient forebrain ischemia.

Transport of fragmented DNA in apical dendrites of the CA1 pyramidal neurons of gerbil hippocampus is observed in the apoptotic process following transient forebrain ischemia. The time-course of specific DNA fragmentation was examined after the ischemic insult by in situ nick-end-labeling method and fluorescence detection technique by DAPI. Although the role of the fragmented DNA movement is unclear, the transport mechanism of fragmented DNA is still active in the late phase of apoptotic process.

Animals↗

PubMed1998

The increase in angiotensin type-2 receptor mRNA level by glutamate stimulation in cultured rat cortical cells.

The changes in the angiotensin type-2 (AT2) receptor mRNA level during glutamate neurotoxicity in cultured rat cortical cells are examined to assess the possible involvement of AT2 receptor in cell injury. The day 10-14 cortical neurons were exposed to glutamate at a toxic concentration of 100 microM for 15 min. The viability of the culture was reduced by 60% after 24 h. AT2 receptor mRNA was then increased 2-fold after exposure to glutamate, while the maximum increase was observed in a dose-dependent manner (50-1000 microM) 3 h after glutamate stimulation. AT2 receptor binding also increased 3-12 h after glutamate exposure. The results suggest that the increase in the AT2 receptor preceded to some extent the insult of the cell after exposure. The increase in the mRNA level was suppressed by MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, thus indicating the possible involvement of NMDA receptor. The increase in the mRNA level was also antagonized by N-nitro L-arginine methyl-ester, a nitric oxide synthase inhibitor. The hemoglobin, a nitric oxide trap, inhibited the increase in the mRNA level. These results suggest that the increase in the mRNA level is associated with the nitric oxide synthesis by glutamate exposure. The viability of cortical cells after glutamate stimulation was partially restored by the AT2 receptor antagonist and by the antisense oligonucleotide for the AT2 receptor. The present results thus suggest that the AT2 receptor may in some way be related to one of the processes in cell injury caused by glutamate.

Angiotensin II↗

PubMed1998

Morphology of single primary spindle afferents of the intercostal muscles in the cat.

A reconstruction was made of the trajectory of primary spindle afferents from the intercostal muscles in the spinal cord of the cat. Intraaxonal recordings were performed from the primary spindle afferents that were identified by their response to lung inflation and stimulus threshold to activate the action potentials. The afferents were stained by using intraaxonal injection of horseradish peroxidase (HRP). Results were obtained mainly from internal intercostal Ia fibers, which entered the spinal cord and bifurcated into ascending and descending branches. The ascending branches could be traced up to 10.7 mm, and the descending branches could be traced up to 7.3 mm. The ascending branches extended to the next segment. Collaterals ranging from one to six were given off from these branches. The distances between adjacent collaterals ranged from 0.9 mm to 4.7 mm. Each collateral had similar morphological characteristics. The collaterals entered the dorsal horn and ran toward lamina IX through the medial half of the gray matter. Fine branches and boutons were given off in laminae V, VII, VIII, and IX. The aggregations of these branches were found in lamina VII, mainly in the region of Clarke's column and in the ventral and ventrolateral regions thereof and in lamina IX, mainly in the nucleus lateromedialis. Most terminals did not contact the somata of target neurons in all laminae in which terminals were found. However, a few terminals were found to contact large neurons in lamina IX. In addition to these aggregates, there were some terminals scattered throughout the ventral horn. Thus, it was concluded that single intercostal Ia afferents project to the region of Clarke's column, to the intercostal motor nucleus, and to the intermediate regions.

Afferent Pathways↗

PubMed1998

A heat shock-related protein, p20, plays an inhibitory role in platelet activation.

Some low molecular mass heat shock proteins (HSPs) appear to act as molecular chaperones, but their exact physiological roles have not been fully elucidated. We reported previously that a 20-kDa protein (p20), which is classified as a low molecular mass HSP, is present at high levels in skeletal and smooth muscles. In the present study, we investigated a physiological role of p20 on platelet function in vitro and ex vivo. p20 inhibited platelet aggregation using human platelets dose-dependently induced by botrocetin. On the other hand, HSP27, the other type of low molecular mass HSP, did not affect platelet aggregation. When p20 (300 microg/kg) was injected intravenously as a bolus in hamsters, platelet aggregation ex vivo induced by botrocetin was also significantly inhibited. In order to further investigate the inhibitory effect by p20 on platelet activation, we performed platelet aggregation induced by thrombin or ADP using human platelets. p20 markedly prevented platelet aggregation induced by thrombin, but not ADP. These findings suggest that p20 can act intercellularly to regulate platelet functions. Our results may provide the basis for a novel defensive system to thrombus formation.

Adenosine Diphosphate↗

PubMed1998

Relationship between magnitude of hypothermia during ischemia and preventive effect against post-ischemic DNA fragmentation in the gerbil hippocampus.

Protective effect of hypothermia against DNA fragmentation in hippocampal CA1 field after transient forebrain ischemia in gerbils was evaluated by changing the magnitude of hypothermia. Inhibition of DNA fragmentation was proportional to the magnitude of hypothermia. The result indicates that, in terms of susceptibility to ischemia, hippocampal CA1 neurons are sensitive to a relatively small decrement of temperature, with temperatures </=35 degreesC being critical for the prevention of apoptotic process following transient forebrain ischemia.

Animals↗

PubMed1998

Involvement of H2O2 production in cisplatin-induced nephrotoxicity.

The purpose of this study was to elucidate the involvement of H2O2 production in cisplatin-induced nephrotoxicity. The S3 cells were more sensitive than OMCT cells in cell viability and H2O2 production during cisplatin treatment. The cytotoxicity and H2O2 production induced by cisplatin were terminated by treatment with catalase. In conclusion, we emphasize the importance of the hydroxy radical in cisplatin nephrotoxicity.

Animals↗

PubMed1998

Pioglitazone enhances splanchnic glucose uptake as well as peripheral glucose uptake in non-insulin-dependent diabetes mellitus. AD-4833 Clamp-OGL Study Group.

To evaluate the effect of pioglitazone on insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) patients, a double-blind placebo-controlled trial was carried out with 30 NIDDM patients. Twenty-one subjects, three on diet alone and 18 on sulfonylurea (SU), orally received 30 mg pioglitazone once daily for 12 weeks. Nine subjects, one on diet alone and eight on SU, received a matching placebo once daily for 12 weeks. Euglycemic (5.2 mmol/l) hyperinsulinemic (1200 pmol/l) clamp combined with an oral glucose load (OGL) was performed before and after 3-month treatment with pioglitazone or placebo to determine insulin-stimulated glucose disposal and splanchnic glucose uptake (SGU). No significant differences existed in the patients' characteristics, including age and body mass index, between the two study groups. The pioglitazone treatment increased the mean glucose infusion rate (GIR) prior to OGL from 8.2 +/- 2.2 to 9.2 +/- 2.0 mg/kg.min (mean +/- SD, P = 0.003) and increased the SGU rate from 28.5 +/- 19.4 to 59.4 +/- 27.1% (P = 0.010). The placebo treatment produced no significant changes in either GIR or SGU after treatment. A significant difference (P = 0.042) was observed in change of SGU between the pioglitazone and placebo treatment groups. In conclusion, the results indicate that pioglitazone is effective for ameliorating insulin resistance in NIDDM by enhancing SGU as well as peripheral glucose uptake.

Blood Glucose↗

PubMed1998

Effects of several agents on UVB- and UVA plus systemic fluoroquinolone-induced erythema of guinea pig skin evaluated by reflectance colorimetry.

The aim of this study was to clarify the mechanisms underlying the erythema of guinea pig skin induced by ultraviolet (UV) irradiation alone and in combination with a systemic fluoroquinolone (FQ). The effects of several drugs which may modify the actions of some inflammatory mediators and radicals possibly released in the inflamed site on the erythema were examined and compared in an objective and quantitative way by measuring the change in color of the irradiated skin, determined as the change in chroma (C*) with use of reflectance colorimetry. After confirming that the C* value increased in an irradiation dose-dependent manner and reached a plateau 1-2 h after irradiation of UVB alone or UVA coadministered with an FQ, Y-26611 (10 mg/kg, i.p.), guinea pigs were pretreated with indomethacin, butylated hydroxytoluene (BHT) or beta-carotene before, or treated with H1- or H2-receptor antagonist, superoxide dismutase or N omega-nitro-L- arginine methyl ester after UV irradiation, and their inhibitory effects against erythema were evaluated. It was suggested that there are some substantial differences between UVB- and UVA plus FQ-induced erythemas. Although histamine makes little contribution to both types of erythema, metabolites of arachidonic acid catalyzed by cyclooxygenase contribute more to UVB-induced erythema, whereas superoxides take more part in UVA plus FQ-induced erythema. Furthermore, nitric oxide seems to participate in both types of erythema; however, the pretreatment with BHT or beta-carotene was ineffective against both erythemas. From these results, interventions should be directed to powerfully scavenging radicals for prevention and treatment of UV plus FQ-induced phototoxicity.

4-Quinolones↗

PubMed1998

Involvement of protein kinase C activation in endothelin-1-induced secretion of interleukin-6 in osteoblast-like cells.

We previously reported that endothelin-1 (ET)-1 stimulates phospholipase D (PLD) independently of phosphoinositide hydrolysis in osteoblast-like MC3T3-E1 cells. In the present study, we examined the effect of ET-1 on the secretion of interleukin-6 (IL-6) and the involvement of protein kinase C (PKC) activation in the IL-6 secretion in these cells. ET-1 significantly stimulated IL-6 secretion time-dependently up to 72 h. The stimulative effect was dose-dependent in the range between 1 nM and 1 microM. BQ123, a selective antagonist of endothelinA (ETA) receptor, inhibited the ET-1-induced IL-6 secretion. On the contrary, BQ788, a selective antagonist of endothelinB (ETB) receptor, had no effect. 12-O-Tetradecanoylphorbol-13-acetate (TPA), a PKC-activating phorbol ester, significantly stimulated IL-6 secretion. However, 4 alpha-phorbol 12,13-didecanoate, a PKC-nonactivating phorbol ester, did not affect IL-6 secretion. The effect of a combination of ET-1 and TPA on IL-6 secretion was not additive. Calphostin C, a specific PKC inhibitor, significantly inhibited the ET-1-induced IL-6 secretion. Both ET-1- and TPA-induced IL-6 secretion were reduced in PKC downregulated MC3T3-E1 cells. These results strongly suggest that ET-1 stimulates IL-6 secretion via ETA receptor in osteoblast-like cells and that PKC activation is involved in the ET-1-induced IL-6 secretion.

Animals↗

PubMed1998

Endothelin-1 binding to endothelin receptors in the rat anterior pituitary gland: interaction in the recognition of endothelin-1 between ETA and ETB receptors.

1. 125I-Endothelin (ET)-1 binding to the rat anterior pituitary gland was saturable and single, with a Kd of 71 pM and a Bmax of 120 fmol/mg. 2. When 1.0 microM BQ-123 (ETA antagonist) was added to the incubation buffer, the binding parameters were 8.3 pM and 8.0 fmol/mg, whereas 10 nM sarafotoxin S6c (ETB agonist) exerted little change in these binding parameters (Kd, 72 pM; Bmax, 110 fmol/mg). 3. ETB receptor-related compounds such as sarafotoxin S6c, ET-3, IRL1620, and BQ-788 competitively inhibited 125I-ET-1 binding, only when 1.0 microM BQ-123 was present in the incubation buffer. 4. Thus, the ETB receptor is capable of binding ET-1 when the ETA receptor is being occupied by BQ-123. A collaboration mechanism between the ETA and the ETB receptor may function in the recognition of ET-1, a typical "bivalent" ligand.

Animals↗

PubMed1998

Nicardipine normalizes elevated levels of antioxidant activity in response to xanthine oxidase-induced oxidative stress in hypertensive rat heart.

It has been reported that the production of oxygen radicals mediated by xanthine oxidase (XO) is stimulated in hypertensive cardiovascular endothelium, suggesting involvement of oxidative stress in pathogenesis of hypertension. In this study we estimated the effect of nicardipine, a calcium blocker, on the oxidative stress and antioxidant activities in left ventricles from spontaneously hypertensive rat (SHR) and stroke-prone SHR (SHRSP). The activity of XO increased 3.5-fold in SHR and 6.2-fold in SHRSP compared to that in normal controls (WKY). Interestingly, the levels of glutathione (GSH) and the activity of its synthesizing enzyme (gamma-glutamylcysteine synthetase, gamma-GCS) elevated concomitantly in SHR and SHRSP: the level of GSH increased 1.2-fold in SHR and 1.3-fold in SHRSP. The activity of gamma-GCS was elevated 1.5-fold in SHR and 2.4-fold in SHRSP, accompanying an increase in the expression of its mRNA. Treatment of these rats with nicardipine, for 4 weeks improved blood pressure, from 176 +/- 10 to 140 +/- 8 mmHg in SHR, and from 201 +/- 11 to 167 +/- 5 mmHg in SHRSP, respectively, and decreased wet weight of heart, levels of GSH, and the activities of XO and gamma-GCS. Nicardipine reduced the expression of gamma-GCS mRNA. Collectively, these results suggest that reactive oxygen species produced by XO in hypertensive rat heart cause induction of the expression of gamma-GCS and nicardipine plays a role in reducing the oxidative stress in hypertensive heart.

Animals↗

PubMed1998

Inhibitory effects of propofol on intracellular signaling by endothelin-1 in aortic smooth muscle cells.

BACKGROUND: Blood pressure decreases when propofol is administered. However, the exact mechanism underlying the vascular effects of propofol has not yet been elucidated. Endothelin produced by vascular endothelial cells is a potent vasoactive peptide that elicits prolonged contraction of vascular smooth muscle cells. The effects of propofol on endothelin-1-induced intracellular signaling in an aortic smooth muscle cell line, A10 cells, were examined. METHODS: Cultured A10 cells were pretreated with propofol for 20 min and then stimulated with endothelin-1. The effect of propofol on the endothelin-1-induced Ca2+ influx into A10 cells was evaluated by measuring intracellular 45Ca2+. The effects of propofol on the endothelin-1-induced activation of phosphatidylinositol-hydrolyzing phospholipase C and phosphatidylcholine-hydrolyzing phospholipase D were evaluated by measuring the formation of inositol phosphates and choline, respectively. The effect of propofol on endothelin-1 binding to its receptor was determined by an [125I] endothelin-1-binding assay. RESULTS: Propofol inhibited the endothelin-1-induced Ca2+ influx, but this was significant only at supuraclinical concentrations. The endothelin-1-stimulated formation of inositol phosphates was significantly suppressed by propofol. However, propofol had no effect on the formation of inositol phosphates induced by NaF, an activator of heterotrimeric guanosine triphosphate (GTP)-binding proteins. Propofol inhibited the endothelin-1-induced formation of choline. Propofol had no effect on the binding of endothelin-1 to its receptor. CONCLUSIONS: These results suggest that propofol inhibits endothelin-1-induced intracellular signaling in vascular smooth muscle cells. The inhibitory effect of propofol might be exerted at a point between the endothelin-1 receptor and its GTP-binding protein. However, because all significant effects are observed at high concentrations, clinical relevance is unclear.

Anesthetics, Intravenous↗

PubMed1998

Protective effect of apoptosis-inhibitory agent, N-tosyl-L-phenylalanyl chloromethyl ketone against ischemia-induced hippocampal neuronal damage.

Delayed neuronal death in the gerbil hippocampal CA1 sector occurs 48 to 72 hours after severe forebrain ischemia. DNA fragmentation is observed in the hippocampal CA1 neurons at around that time. We show here that an inhibitor of proteolytic process of apoptosis, N-tosyl-L-phenylalanyl chloromethyl ketone (TPCK), protected hippocampal neuronal damage by inhibition of the DNA fragmentation in a dose-dependent manner and that TPCK induced an apoptosis-regulating molecule, Bcl-2 protein, in the surviving neurons. These results suggest the prevention of apoptosis-related DNA fragmentation by TPCK may be an attractive therapeutic strategy for preserving hippocampal neurons from ischemic insult.

Animals↗

PubMed1998

Effect of GR144053, a fibrinogen-receptor antagonist, on thrombus formation and vascular patency after thrombolysis by tPA in the injured carotid artery of the hamster.

The antithrombotic effect of GR144053, which inhibits platelet aggregation by binding to the fibrinogen receptor (glycoprotein IIb/IIIa), was investigated in vitro and in vivo by using hamsters. This compound inhibited the platelet aggregation induced by adenosine diphosphate (ADP; 2.5 microM) with a mean inhibitory concentration (IC50) value of 2.2 +/- 0.4 x 10(-5) M. Vascular injury was inflicted in one carotid artery by using a modified catheter to produce endothelial denudation. In the control group, arterial blood flow was interrupted 4.4 +/- 2.3 min (n = 12) after the injury. When GR144053 continuously infused intravenously at doses of 0 (saline) 0.1, 0.3, and 1.0 mg/kg/h (n = 8, each), the time that elapsed before the vessel became completely obstructed was prolonged in a dose-dependent manner. In separate experiments, reperfusion could be obtained by continuous infusion of tissue-type plasminogen activator (tPA; 0.52 mg/kg) starting 30 min after the initiation of thrombus formation. When GR144053 (0.3 and 1.0 mg/kg/h) was infused in addition to tPA, the incidence of reperfusion and the later patency of the reperfused artery were much improved as compared with tPA alone. The bleeding time at the end of tPA infusion was significantly prolonged in the presence of the highest dose of GR144053. Next, neointima formation was evaluated 2 weeks after the vascular injury. When GR144053 (0.3 mg/kg/h) was continuously infused i.v. by an implanted osmotic pump for 14 days, the neointimal area was significantly reduced. In separate hamsters, the proliferating index of smooth muscle cells (SMCs) by using bromodeoxyuridine (BrdU) was investigated, and treatment with both tPA and GR144053 significantly decreased the SMC proliferation index in vivo. However, in the in vitro experiments using a hamster SMC line, GR144053 did not have an inhibitory effect on SMC proliferation. These findings suggest that GR144053 inhibits platelet activation on the injured artery and improves vascular patency after thrombolysis with tPA, which furthermore results in suppression of neointima formation.

Animals↗

PubMed1998

Pharmacokinetics and safety of a new parenteral carbapenem antibiotic, biapenem (L-627), in elderly subjects.

The pharmacokinetics and tolerability of a new parenteral carbapenem antibiotic, biapenem (L-627), were studied in healthy elderly volunteers aged 65 to 74 years (71.6 +/- 2.7 years [mean +/- standard deviation], n = 5; group B) and > or = 75 years (77.8 +/- 1.9 years, n = 5; group C), following single intravenous doses (300 and 600 mg), and compared with those of healthy young male volunteers aged 20 to 29 years (23.0 +/- 3.5 years, n = 5; group A). The agent was well tolerated in all three age groups. Serial blood and urine samples were analyzed for biapenem to obtain key pharmacokinetic parameters by both two-compartment model-dependent and -independent methods. The maximum plasma concentration and area under plasma concentration-versus-time curve (AUC) increased in proportion to the dose in all three groups. Statistically significant age-related effects for AUC, total body clearance, and renal clearance (CLR) were found, while elimination half-life (t1/2 beta) and percent cumulative recovery from urine of unchanged drug (% UR) remained unaltered (t1/2 beta, 1.51 +/- 0.42 [300 mg] and 2.19 +/- 0.64 [600 mg] h [group A], 1.82 +/- 1.14 and 1.45 +/- 0.36 h [group B], and 1.75 +/- 0.23 and 1.59 +/- 0.18 h [group C]; % UR, 52.6% +/- 3.0% [300 mg] and 53.1% +/- 5.1% [600 mg] [group A], 46.7% +/- 7.4% and 53.0% +/- 4.8% [group B], and 50.1% +/- 5.2% and 47.1% +/- 7.6% [group C]). A significant linear correlation was observed between the CLR of biapenem and creatinine clearance at the dose of 300 mg but not at 600 mg. The steady-state volume of distribution tended to be decreased with age, although not significantly. Therefore, the age-related changes in parameters of biapenem described above were attributable to the combination of decreased lean body mass and lowered renal function of the elderly subjects. However, the magnitude of those changes does not necessitate dosage adjustment in elderly patients with normal renal function for their age.

Adult↗

PubMed1998

Palmitoylation of human thyrotropin receptor: slower intracellular trafficking of the palmitoylation-defective mutant.

We here show that the epitope-tagged human TSH receptor (TSHRmyc) is covalently modified with palmitic acid by thioesterification. Side-directed mutagenesis identified Cys699 in the C-terminal cytoplasmic tail of the receptor as the putative palmitoylation site. Mutation of Cys699 to Ala results in the nonpalmitoylated receptor (TSHRmycC699A) in which high affinity TSH binding, Gs coupling, homologous desensitization and TSH-induced internalization are unaffected. In contrast, abolition of palmitoylation appears to decrease the rate of the intracellular trafficking of the receptor. However, since most of TSHRmycC699A seems to be fully processed finally and the receptor number of TSHRmycC699A on the cell surface is comparable to that of TSHRmyc, our results suggest that abolition of palmitoylation delays the cell surface expression of TSHR, but does not trap the receptor intracellularly, although another possibility for proteolytic degradation of either the 95 kDa or the 100 kDa mutant receptor can not be excluded. Thus, post-translational modification of TSHR by palmitoylation may provide a novel mechanism of enhancing the rate of intracellular trafficking of the receptor.

Amino Acid Sequence↗

PubMed1998

Expression profile of receptor-type protein tyrosine kinase genes in the human thyroid.

Protein tyrosine kinases (PTKs) play a role in regulating the growth and differentiated functions of thyroid cells and are probably involved in tumorigenesis of papillary-type thyroid carcinoma. To better understand the roles of PTKs in the physiology and pathophysiology of the thyroid, we analyzed the expression profile of receptor-type PTKs in normal human thyroid tissues. Highly conserved regions in the catalytic domains of receptor-type PTKs were amplified by RT-PCR using degenerate oligonucleotide primers. Nucleotide sequencing of about 100 clones identified 21 PTKs, including 16 receptor type and 5 nonreceptor type; no novel PTK was identified. Insulin-like growth factor I receptor, platelet-derived growth factor receptor (PDGFR), TrkE, Axl, epidermal growth factor receptor, etc., appear to be the most abundant receptor-type PTKs in the thyroid; many of which (PDGFR, TrkE, Axl, etc.) have never previously been demonstrated to be expressed in the thyroid. The expression of messenger RNAs (mRNAs) for PDGFR, axl, and trkE in normal thyroid cells was confirmed by Northern blot analysis, and interestingly, the expression levels of PDGFR and trkE mRNAs were decreased in all three thyroid carcinoma cell lines examined (FRO, WRO, and NPA), whereas axl mRNA and protein were overexpressed in 2 of 3 thyroid carcinoma cell lines (FRO and WRO) compared with that in normal tissue. The axl gene was, however, neither amplified nor rearranged. The biological activity of the ligand for Axl, the product of growth arrest-specific gene 6 (Gas6), was then evaluated, demonstrating modest mitogenic activity in thyroid carcinoma cells overexpressing Axl. Furthermore, gas6 mRNA was expressed in FRO cells. Thus, we here identify a variety of PTKs expressed in the thyroid gland, many of which may participate in the regulation of thyroid cell function. Variable expression levels of some PTKs in normal and cancerous cells suggest that there may be an imbalance and disarray of phosphorylation events in thyroid carcinoma cells. Furthermore, Gas6 is identified as a novel growth factor for thyroid carcinoma cells overexpressing Axl receptor tyrosine kinase.

Amino Acid Sequence↗

PubMed1998

Retrovirus-mediated suicide gene/prodrug therapy targeting thyroid carcinoma using a thyroid-specific promoter.

To develop gene therapy targeting thyroid carcinoma, the recombinant retrovirus (LNTGTK) carrying herpes simplex virus thymidine kinase (HSV-TK) gene under the control of thyroglobulin (TG) promoter was constructed and its efficacy was investigated in 3 thyroid cell lines; a differentiated normal rat thyroid cell line (FRTL5), malignant rat thyroid carcinoma cells derived from FRTL5 (FRTC) and a human anaplastic thyroid carcinoma cell line (FRO). TG mRNA was detected by Northern blot analysis in FRTL5 cells and by RT-PCR in FRTC cells when cultured with 2 U/L TSH and its expression levels were decreased by TSH withdrawal. However, either methods revealed no TG expression in FRO cells. In vitro cytotoxic assays demonstrated TG expression status-dependent cell killing by transduction of LNTGTK followed by ganciclovir (GCV) treatment. Thus, LNTGTK transduction increased the GCV sensitivity approximately 13,000- and approximately 160-folds in the presence of TSH and approximately 4- and approximately 27-folds in the absence of TSH in FRTL5 and FRTC cells, respectively. In contrast, there was no difference in the GCV cytotoxicity between parental and transduced FRO cells. Significant growth inhibition, but not complete eradication, of transduced FRTC cells was observed in in vivo subcutaneous tumor models of nude mice. These results demonstrate that retrovirus-mediated transduction of HSV-TK gene under the control of the TG promoter confers the GCV sensitivity selectively to TG-expressing thyroid cells. This system may therefore be feasible for gene therapy targeting TG-expressing thyroid carcinomas.

Animals↗