Biomedical subjects

J W Chang

Publications and source records attributed to J W Chang.

At least 37 records · Page 2Linked to original sources

PubMed2001

Highly diastereoselective Michael addition of alpha-hydroxy acid derivatives and enantioselective synthesis of (+)-crobarbatic acid.

[reaction: see text]. Michael addition of enolates of 2a and 2b to alpha,beta-unsaturated esters took place selectively on different faces (Si and Re, respectively) of the double bond to give the corresponding products 4 and 5, respectively, with >98% de. Subsequent hydrolysis of these Micheal adducts gives 3,4-disubstituted gamma-lactones with high enantiomeric excesses.

Journal Article↗

PubMed2001

Characteristics of Chinese suicide attempters admitted to a geropsychiatric unit.

PURPOSE: To investigate the characteristics for elderly Chinese suicide attempters in Taiwan and make comparisons with Western reports. METHODS: During a six-year period, patients admitted to a geropsychiatric unit as a result of a suicide attempt were investigated for factors related to the suicide attempt. RESULTS: Of the 722 admissions during this period, 55 (7.6%) were patients who had been admitted due to suicide attempt. The sex and age distributions for the suicide attempters were similar to those for other patients. The most common diagnoses were depressive disorders (56.4%), followed by delusional disorders (20.0%). A total of 121 suicide motives were cited for the 55 attempters, an average of 2.2 per person, with depressive symptoms commonly found on admission. During the first week of hospitalization, 53 attempters (96.4%) still exhibited suicidal ideation and six patients made a further suicide attempt, however, only three patients retained suicidal ideation on discharge. CONCLUSIONS: Our study confirms previous Western reports that depressive disorders are commonly manifested in elderly suicide attempters. There were differences in the motives and methods employed for the suicides, possibly due to cultural difference and/or sample source. Most of the suicide attempters exhibited a favourable response with hospitalization.

Age Factors↗

PubMed2001

Microvascular decompression of the facial nerve for hemifacial spasm in youth.

OBJECTS: The goal of this study was to investigate the differences between clinical findings in youth and in adulthood on microvascular decompression (MVD) of the facial nerve for the treatment of hemifacial spasm (HFS). METHODS: We retrospectively evaluated 855 patients who underwent MVD from January 1985 to July 1999. In our series of 33 young HFS patients, all patients had definite offending vessels. Interestingly, pathologic tortuous vertebral artery as a possible etiology was more rarely observed in young HFS patients (1/33 patients, 3.0%) than in adult patients (61/822 patients, 7.4%) (P < 0.05). We did not observe any atomical variations of the vessels or any arachnoidal thickening around the root entry zone and cerebellopontine cistern in youths. Furthermore, young HFS patients did not necessarily have poorer surgical outcomes than adult HFS patients. CONCLUSIONS: Our results suggest that the cause and progress of HFS are the same in youth as in adulthood, even though the pathogenesis of early onset remains unclear.

Adolescent↗

PubMed2001

Radiologically confirmed de novo glioblastoma multiforme and hippocampal sclerosis associated with the first onset of nonconvulsive simple partial status epilepticus.

The authors report a case of an unusual progression of glioblastoma multiforme in the temporal lobe associated with the first onset of nonconvulsive simple partial status epilepticus (SPSE), a rare form of status epilepticus. The patient underwent a left temporal craniotomy and the tumor was removed. Concurrently, the hippocampus was removed as well. The pathological diagnosis of the tumor and the hippocampus were glioblastoma multiforme and hippocampal sclerosis. The patient's postoperative course was uneventful.

Brain Neoplasms↗

PubMed2001

Efficient gene transfer of VSV-G pseudotyped retroviral vector to human brain tumor.

A retroviral vector constructed from the murine leukemia virus (MLV) can only express transgenes in cells undergoing mitosis, indicating its suitability as a delivery vehicle for cancer gene therapy. However, the transduction efficiency (TE) of retroviruses embedding endogenous envelope proteins in human cancer cells was found to be unsatisfactory. Recently, several research groups have demonstrated the feasibility of a retroviral vector pseudotyped with a vesicular stomatitis virus G (VSV-G) protein. In this study, the potential of VSV-G pseudotyped MLV-based retrovirus was examined as a delivery vehicle in a variety of human cancer cells including brain tumor cells in vitro and in vivo. The transduction efficiency of the 293T/G/GP/LacZ retrovirus in cell culture was superior in most cancer cells, particularly in brain tumor cells, compared with that of other retroviruses, such as PA317- or PG13-derived. The relative growth rate and phosphatidylserine expression level on the plasma membrane of target cells mainly influenced the transduction efficiency of VSV-G pseudotyped retrovirus, which suggested that both the relative growth rate and phosphatidylserine expression level were major determinants of TE. Furthermore, 293T/G/GP/LacZ could efficiently transduce human cancer cells regardless of the presence of chemical additives, whereas in other retroviruses, cationic chemical additives such as polybrene or liposomes were essential during virus infection. Finally, an average of 10% gene expression was routinely obtained exclusively in the tumor mass when 293T/G/GP/LacZ concentrated by simple ultracentrifugation was directly administrated to pre-established brain tumors in animal models (U251-N nu/nu mice or C6 Wistar rats). All told, the present study suggests that the VSV-G pseudotyped retrovirus is a suitable vector for brain tumor gene therapy.

Brain Neoplasms↗

PubMed2001

Ictal automatisms with preserved responsiveness in a patient with left mesial temporal lobe epilepsy.

PURPOSE: To describe the possible mechanism of ictal automatisms with preserved responsiveness (APRs) in a patient with left mesial temporal lobe epilepsy, which had not been reported previously. METHODS: Ictal EEGs recorded from bilateral foramen ovale electrodes with scalp-sphenoidal electrodes were analyzed in respect to the ictal semiology. RESULTS: The patient had a right hemispheric language dominance in the dextral. Electroclinical analysis revealed that the onset of oroalimentary automatisms coincided with the involvement of the left mesial and lateral temporal structures by spreading ictal discharges. The ictal discharge spreading was limited to the ipsilateral hemisphere throughout the seizure, which explained the intact consciousness and preserved responsiveness of the patient. CONCLUSIONS: This case suggests that APRs take place in seizures originating from the nondominant temporal lobe, during which ipsilateral mesial and lateral temporal structures are diffusely involved without spreading to the contralateral side.

Adolescent↗

PubMed2001

Outcome of renal transplantation in hepatitis B surface antigen-positive patients after introduction of lamivudine.

BACKGROUND: In end-stage renal disease patients with hepatitis B surface antigen (HBsAg), the risk of hepatic dysfunction after immunosuppression represents a large barrier in renal transplantation. Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication. We retrospectively investigated the outcome of HBsAg-positive renal transplantation recipients after lamivudine had become available. METHODS: From July 1994 to August 2000, seventeen HBsAg-positive patients (M:F=15:2) received renal allografts (13:4=living:cadaveric donors). Liver function tests at the time of transplantation were normal in all patients. Pre-transplant liver biopsies performed in 15 patients demonstrated minimal inflammatory histology, except in three patients showing pathological and clinical signs of active hepatitis. Lamivudine was started pre-operatively in these three subjects. Another seven patients were treated with lamivudine for post-operative hepatic dysfunction. The remaining seven patients did not develop hepatic dysfunction after transplantation. RESULTS: Lamivudine was initially effective in decreasing serum HBV DNA titres, and in normalizing hepatic enzymes. Lamivudine was well tolerated without significant side effects for 35.5+/-8.9 months after initiation of treatment. HBV DNA became negative in nine patients but remained positive in one patient. Among the nine patients with initial negative conversion of HBV DNA, two developed transient positive conversion of HBV DNA and two demonstrated persistent positive conversion. Among the patients with normal liver histology in the pre-transplant period, 41.6% (5/12) developed liver pathology progression after immunosuppression. All 17 patients had functioning grafts, except for one patient who developed relapsed IgA nephropathy. CONCLUSIONS: Our data showed relatively favourable outcomes in hepatitis B-positive renal transplant recipients receiving lamivudine treatment, even though two patients developed lamivudine resistance.

Adolescent↗

PubMed2001

The efficacy and safety of risperidone for the treatment of geriatric psychosis.

Risperidone is an atypical antipsychotic drug which has been suggested to be beneficial for the treatment of elderly patients with psychotic symptoms. In this study, we assessed the short-term efficacy and the safety of risperidone in geropsychiatric inpatients with psychotic symptoms. The sample population included 110 elderly inpatients with psychotic disorders. Assessment for drug efficacy using the Brief Psychiatric Rating Scale, Sandoz Clinical Assessment-Geriatric scale, and Clinical Global Impression scale was conducted at baseline and also at 4 weeks subsequent to risperidone treatment commencement. Subsequent to commencing risperidone treatment, 80 patients completed a 4-week therapeutic evaluation. Seventy (87.5%) of the 80 patients experienced mild to substantial improvement using the Clinical Global Impression scale. Adverse effects were monitored in all 110 patients. The most commonly detected adverse effects were weakness of legs or walking problems (43/110; 39.1%) and dizziness (32/110; 29.1%). Peripheral edema was noted in 18 (16.4%) patients. Risperidone, in low doses, appeared to have been effective in this sample of patients older than 65 years with psychotic symptoms. The mean dose (2.1 +/- SD 1.4 mg/day) applied was lower then that suggested for young patients and was related to the each specific patient diagnosis. Peripheral edema and walking problems were commonly observed adverse effects for these elderly patients, such problems having not been seen to the same extent in previous studies of young patients.

Aged↗

PubMed2001

Microvascular decompression for hemifacial spasm: a long-term follow-up of 1,169 consecutive cases.

We analyzed the records of 1,169 patients with hemifacial spasm (HFS) who underwent microvascular decompression (MVD) and were followed up for more than 6 months from January 1987. The mean follow-up duration was 23.8 months (6-145 months). Excellent surgical outcome was obtained in 90.5% and good in 4.5%, giving an overall success rate of 95.0%. There was statistically significant relationship between vertebral artery (VA) shift and side of symptom. Permanent facial weakness and hearing impairment were 1.4% and 2.3%, respectively. There were no anatomical differences at the root entry zone (REZ) and significant differences of surgical outcome in young HFS (34 patients). Factors such as type of offender, severity of compression on the facial nerve root, and the degree of decompression of the REZ on postoperative MRI did not correlate with surgical outcome.

Adult↗

PubMed2001

Gamma knife radiosurgery for metastatic brain tumors.

We reviewed our series of metastatic brain tumors treated by Gamma Knife Radiosurgery. From May 1992 to January 2001, 115 consecutive patients with 425 lesions were treated over 128 treatment sessions. Forty three patients were known to have died at the end of the recording period. The mean follow-up duration was 11.6 months and mean number of lesions was 3.5. The most common primary sites were lung and breast. Mean tumor volume was 4.2 cm(3) and mean margin dose was 16.2 Gy. 6-month, 1-year, and 18-month survival rates were 73.6, 58, and 46%, respectively. Multivariate analysis revealed that higher KPS scores, no evidence of extracranial metastasis, and controlled primary disease were significantly related to longer survival. Adjuvant whole brain irradiation did not significantly influence on the prolongation of survival time and local control of radiosurgically treated lesions.

Brain Neoplasms↗

PubMed2001

Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models.

This article reviews the mechanism of dopamine delivery in the CNS in order to determine the optimal set of genes for effective gene therapy in Parkinson's disease (PD). Systematic neurobiological investigation of the biochemical steps has revealed that tyrosine hydroxylase (TH), which has been used in earlier studies, functions only when the essential cofactor, tetrahydrobiopterin (BH1) is present. Transduction of the gene for GTP cyclohydrolase I, the first and rate-limiting step in BH1 synthesis, along with the TH gene, generated cells that are capable of producing L-DOPA spontaneously both in vitro and in vivo. When the aromatic L-amino acid decarboxylase (AADC) gene was added as a third gene, in an attempt to increase the conversion of L-DOPA to dopamine, feedback inhibition by the end product, dopamine, on TH activity resulted. To circumvent this problem, we employed a complementary strategy. Gene transfer of the vesicular monoamine transporter was combined with AADC and produced genetically modified cells that can convert L-DOPA to dopamine and store it for gradual release. This approach provided a means to regulate final dopamine delivery by controlling precursor doses and to achieve more sustained delivery of dopamine. Our investigation into determining the genes necessary for optimal dopamine delivery has been facilitated by in vivo biochemical assays using microdialysis. This technique has provided us with a clear and quantitative tool to compare the effects of various genes involved in dopamine synthesis and processing.

Animals↗

PubMed2000

Oncolytic potential of E1B 55 kDa-deleted YKL-1 recombinant adenovirus: correlation with p53 functional status.

YKL-1, E1B 55 kDa-deleted recombinant adenovirus vector, capable of harboring a transgene casette of up to 4.9 kb, was newly constructed by reintroducing E1A and E1B 19 kDa into E1/E3-deleted adenoviral vector with a homologous recombination in E. coli. Virus replication and cytotoxicity were dramatically attenuated in all 3 different types of normal human cells. In contrast, YKL-1 efficiently replicated and induced cytotoxicity in most cancer cells, especially Hep3B and C33A cells with an inactivating p53 mutation. However, both H460 and HepG2 exhibited intermediate sensitivity to YKL-1, which was between that of Hep3B or C33A and normal human cells. The YKL-1 and DNA damaging agent, camptothecin effectively induced p53 in H460 and HepG2 as well as in normal cells. Furthermore, YKL-1 effectively prohibited both Hep3B and C33A tumor growth in nu/nu mice in a dose-dependent manner. H/E staining and TUNEL assay indicated a largely distributed necrotic area and apoptosis on its periphery. This study, therefore, indicates that YKL-1, possesses promising potential as an oncolytic adenoviral vector, which acts partially in a p53-dependent manner.

Adenoviridae↗

PubMed2000

Regulation of encephalitogenic T cells with recombinant TCR ligands.

We have previously described recombinant MHC class II beta1 and alpha1 domains loaded with free antigenic peptides with potent inhibitory activity on encephalitogenic T cells. We have now produced single-chain constructs in which the peptide Ag is genetically encoded within the same exon as the linked beta1 and alpha1 domains, overcoming the problem of displacement of peptide Ag from the peptide binding cleft. We here describe clinical effects of recombinant TCR ligands (RTLs) comprised of the rat RT1.B beta1alpha1 domains covalently linked to the 72-89 peptide of guinea pig myelin basic protein (RTL-201), to the corresponding 72-89 peptide from rat myelin basic protein (RTL-200), or to cardiac myosin peptide CM-2 (RTL-203). Only RTL-201 possessed the ability to prevent and treat active or passive experimental autoimmune encephalomyelitis. Amelioration of experimental autoimmune encephalomyelitis was associated with a selective inhibition of proliferation response and cytokine production by Ag-stimulated lymph node T cells and a drastic reduction in the number of encephalitogenic and recruited inflammatory cells infiltrating the CNS. The exquisitely selective inhibition could be observed between molecules that differ by a single methyl group (the single amino acid residue difference between RTL-200 (threonine) and RTL-201 (serine) at position 80 of the myelin basic protein peptide). These novel RTLs provide a platform for developing potent and selective human diagnostic and therapeutic agents for treatment of autoimmune disease.

Adoptive Transfer↗

PubMed2000

Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells.

BACKGROUND: The p14(ARF) protein encoded by the INK4a/ARF locus promotes degradation of the MDM2 protein and thus prevents the MDM2-mediated inhibition of p53. Homozygous deletion of the INK4a/ARF locus is common in human mesothelioma and may result in the loss of p14(ARF) and the inactivation of p53. We designed this study to evaluate the biologic and potential therapeutic roles of p14(ARF) expression in mesothelioma cells. METHODS AND RESULTS: We constructed Adp14, an adenoviral vector carrying human p14(ARF) complementary DNA, and used it to transfect human mesothelioma cell lines H28, H513, H2052, and MSTO-211H. Overexpression of p14(ARF) led to increased amounts of p53 and the p21(WAF) proteins and dephosphorylation of the retinoblastoma protein. The growth rate of mesothelioma cells was inhibited markedly by infection with Adp14 compared with mock infection or infection with a control adenovirus vector, AdCtrl. Overexpression of p14(ARF) induced G(1)-phase cell cycle arrest and apoptotic cell death. Cytotoxicity assays showed that Adp14 had a statistically significantly (P =.002) greater effect on colon cancer (HCT116) cell lines containing two copies of the wild-type p53 gene than on p53-null cells, suggesting that functional p53 is a critical determinant of p14(ARF)-mediated cytotoxicity. CONCLUSIONS: The transfection of p14(ARF) into mesothelioma cells led to the overexpression of p14(ARF), which resulted in G(1)-phase arrest and apoptotic cell death. These results suggest that this gene therapy-based approach may be of use in the treatment of mesothelioma.

Adenoviridae↗

PubMed2000

Microvascular decompression of the facial nerve for the treatment of hemifacial spasm: preoperative magnetic resonance imaging related to clinical outcomes.

BACKGROUND: The objective of this study was to investigate the role of preoperative three dimensional short-range magnetic resonance angiography (3D-TOF MRA) in predicting the clinical outcomes following microvascular decompression for the treatment of hemifacial spasm. METHOD: Preoperative magnetic resonance (MR) imaging was performed on all patients with hemifacial spasm (564 cases) between January 1992 and September 1998. Of the 564 patients, 440 patients were included in this retrospective study. The presence of vascular contact, offenders, and anomalies in the vertebro-basilar system, were determined by 3D-TOF MRA prior to microvascular decompression of the facial nerve. The preoperative findings were compared with the surgical findings and clinical outcomes. Findings. A correlation was found between the clinical outcome (p < 0.01) and the presence of a vascular indentation at the root entry zone (REZ) of the facial nerve. A shift of the vertebrobasilar system to the symptomatic side was found in 214 (48.6%) patients with hemifacial spasm, compared to only 10 (13.5%) patients in the control group (p < 0.01). The unilateral vertebral artery was observed in 43 (9.8%) patients with hemifacial spasm and in 8 (10.8%) of the control patients. A hypoplasia of the artery was found in 8 (1.8%) patients with hemifacial spasm and in 1 (1.4%) control patient. The compressing offenders in the patients, discovered by MRI in conjunction with MRA, were as follows: 45.9% (202 patients) in the anterior inferior cerebellar artery (AICA), 34.8% (153 patients) in the posterior inferior cerebellar artery (PICA), 12.5% (55 patients) in the vertebral artery (VA) and 6.8% (30 patients) in multiple vessels. In contrast to the compressing offenders seen on the MRA, the offenders confirmed during surgery were as follows: 43% (189 patients) in the AICA, 36.4% (160 patients) in the PICA, 1.4% (6 patients) in the VA, 19% (84 patients) in multiple vessels, and 0.2% (1 patient) in the vein. In our long-term follow-up series of the 440 patients with hemifacial spasm, an excellent surgical outcome was obtained in 86.3% of cases and a good outcome was achieved in 6.4% (mean follow-up duration, 45.5 months). INTERPRETATION: Preoperative 3D-TOF MRA can identify the relationship between the facial nerve and adjacent vessels in patients with a hemifacial spasm and assist in preoperative planning. This study suggests that 3D-TOF MRA is useful for selecting appropriate patients for surgical treatment and, to some extent, as an additional role for predicting the clinical outcome.

Adult↗

PubMed2000

Role of calcium/calmodulin-dependent protein kinases in expression of Fos protein in the nucleus tractus solitarii after sustained hypertension.

We investigated the role of calcium/calmodulin-dependent protein kinases in the phosphorylation of cyclic AMP response element binding protein and subsequent induction of c-fos gene elicited by sustained hypertension in neurons of the nucleus tractus solitarii of anesthetized rats. Activation of glutamate receptors in the nucleus tractus solitarii significantly increased the number of neurons that were immunoreactive to phosphorylated cyclic AMP response element binding protein and Fos protein. Microinjection bilaterally into the nucleus tractus solitarii of the calcium/calmodulin-dependent protein kinase inhibitor, 1-[N,O-bis(5-isoquinolinesulfonyl-N-methyl-L-tyrosyl]-4-phenylpiperazine , appreciably blunted such an increase. This inhibitor also attenuated the augmented immunoreactivity for phosphorylated cyclic AMP response element binding protein or Fos protein in the same nucleus induced by sustained hypertension. These results were comparable to those observed after blockade of either N-methyl-D-aspartate or non-N-methyl-D-aspartate ionotropic glutamate receptors in the nucleus tractus solitarii. Reverse transcription-polymerase chain reaction further indicated that the calcium/calmodulin-dependent protein kinase blocker attenuated the expression of Fos protein induced by sustained hypertension in the nucleus tractus solitarii by suppressing the transcription of c-fos messenger RNA. The present results suggest that activation of calcium/calmodulin-dependent protein kinases may represent an important step in the cascade of intracellular events that leads to phosphorylation of cyclic AMP response element binding protein and subsequent induction of c-fos gene after activation of ionotropic glutamate receptors by baroceptive signals in the nucleus tractus solitarii.

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

PubMed2000

Phase II study of regimen of gemcitabine and cisplatin in advanced non-small cell lung cancer.

BACKGROUND: Cisplatin-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). Many novel drugs, including gemcitabine, navelbine, paclitaxel and docetaxel have been used in combination with cisplatin. Of these drugs, gemcitabine is reported to have a high response rate and acceptable toxicity. The aim of this study was to evaluate the efficacy and safety of the combination of gemcitabine and cisplatin. METHODS: Thirty-two patients with NSCLC, who met the selection criteria from June 1998 to January 1999, were enrolled. All of them were confirmed by histology and were in an advanced stage, i.e. stage IIIB with pleural effusion or stage IV. Cisplatin at a dose of 80 mg/m2 was given monthly on day 15, in combination with gemcitabine at a dose of 1000 mg/m2 administered on days 1, 8 and 15 of the 28-day cycle. RESULTS: Of the 32 assessable patients, two showed complete remission and 11 achieved partial remission. The overall response was 40.6% (95% CI, 24.8-56.4%). The median time to disease progression was 7.2 months (95% CI, 4.87-9.53 months). The major hematological toxicity was neutropenia. Seven patients (22.9%) developed grade 3 and 4 neutropenia, but none developed febrile neutropenia. One patient (3.1%) had grade 3 thrombocytopenia. One patient (3.1%) developed grade 3 anemia. Nausea and vomiting were seen in 12 patients (37.5%). CONCLUSIONS: The regimen of combined gemcitabine with cisplatin is safe and effective. With this combination, a lower dose of cisplatin seems to have an efficacy similar to that in previous reports.

Adult↗

PubMed2000

Combined antitumor effects of an adenoviral cytosine deaminase/thymidine kinase fusion gene in rat C6 glioma.

OBJECTIVE: In this study, we investigated the feasibility of a double-suicide gene/prodrug therapy, involving direct introduction of the herpes simplex virus Type 1 thymidine kinase (TK) gene and the Escherichia coli cytosine deaminase (CD) gene, via a recombinant adenoviral vector, and ganciclovir (GCV) and/or 5-fluorocytosine (5-FC) treatment, in a rat C6 glioma model. METHODS: Efficient gene transfer and transduction of C6 glioma cells via a recombinant adenovirus were evaluated by infecting cells with adenovirus bearing the beta-galactosidase gene and then staining cells with X-5-bromo-4-chloro-3-indolyl-13-D-galactoside. CD/TK expression in cells infected with adenovirus bearing the CD/TK gene (ad-CD/TK) was examined by immunoblotting analysis. For in vitro cytotoxicity experiments, the cells were infected with ad-CD/TK or ad-deltaE1 (as a control). After the addition of a variety of concentrations of GCV and 5-FC, either separately or in combination, cell viability was determined by staining the cells with crystal violet solution 6 days after infection. For in vivo antitumor experiments, 1x10(5) cells were stereotactically injected into the right caudate-putamen of female Wistar rat brains. At 3 days after implantation, 1x10(8) plaque-forming units of ad-CD/TK or ad-deltaE1 (as a control) were stereotactically injected into the tumors and GCV (25 mg/kg) and 5-FC (250 mg/kg), alone or in combination, were intraperitoneally administered. Animals were then killed, and tumor volumes were measured by determining the tumor area in every fifth section, using a light microscope. RESULTS: C6 glioma cells were efficiently transduced with recombinant adenoviral vector at multiplicities of infection of 200 or more. In vitro cytotoxicity of GCV and/or 5-FC, either alone or in combination, was exclusively observed in the cells transduced with ad-CD/TK. Obvious cytotoxicity (>50% inhibition) was observed in the presence of 5-FC at concentrations greater than 30 microg/ml or GCV at concentrations greater than 0.3 microg/ml at a multiplicity of infection of 100. Additionally, cytotoxicity in the presence of both GCV and 5-FC was greater than that after single-prodrug treatments, indicating additive effects of the prodrug treatments. In in vivo experiments, the tumor volumes of the rats treated with GCV or 5-FC alone after ad-CD/TK injection (59.1+/-4.6 and 57.4+/-7.1 mm3, respectively) were significantly smaller than that of the control rats (157+/-8.9 mm3, P<0.05). Furthermore, the tumor volume of the rats treated with GCV and 5-FC in combination was 14.7+/-1.8 mm3. CONCLUSION: These results demonstrated the efficient transduction of C6 glioma cells with a recombinant adenovirus and the additive effects of CD/TK fusion gene/GCV/5-FC treatment, compared with single-gene therapy with the TK or CD gene. Therefore, our data suggest that the direct administration of a double-suicide gene/prodrug therapy has great potential in the treatment of brain tumors.

Adenoviridae↗