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PubMed1992

Interactions between Trichomonas vaginalis and vaginal flora in a mouse model.

To study the role of vaginal flora and pH in the pathogenesis of Trichomonas vaginalis, an intravaginal mouse model of infection was established. By employing this model, the vaginal flora and pH of mice could be monitored for changes caused by the parasite. As a baseline, the endemic vaginal flora of BALB/c mice was examined first and found to consist mainly of Staphylococcus aureus and Enterococcus species (32-76%). Lactobacilli and enteric bacilli were moderate (16-32%) in their frequency of isolation, and the prevalence of both anaerobic species and coagulase-negative staphylococci was low (4-16%). Vaginal pH was recorded at 6.5 +/- 0.3. Estrogenization, which was required for a sustained T. vaginalis infection, did not significantly alter vaginal flora; however, a slight rise in the number of bacterial species isolated per mouse and a drop in vaginal pH (6.2 +/- 0.5) were observed. Trichomonas vaginalis-infected mice did not appear to show significant changes in vaginal flora although vaginal pH was slightly increased. This mouse model could have applications in both immunologic and pathogenic studies of T. vaginalis and, with further modifications, aid in the study of protist-bacterial interactions.

Animals↗
PubMed2004

Osteogenic differentiation of recombinant adeno-associated virus 2-transduced murine mesenchymal stem cells and development of an immunocompetent mouse model for ex vivo osteoporosis gene therapy.

Gene therapy for osteopenic conditions including osteoporosis is a potential alternative to pharmacotherapy for cost effectiveness, long-term viability, and the ability to enhance bone mass by anabolic approaches. Increased understanding of mesenchymal stem cell (MSC) lineage differentiation during osteogenesis, and of the molecular pathways involved in bone cell production, provides an opportunity for the advancement of gene therapy approaches for osteopenic conditions. The potential of MSCs in osteoblast differentiation and the relative ease of MSC isolation and culturing offer a promising resource for the development of ex vivo gene therapy for bone defects. In an effort to develop ex vivo gene therapy for osteoporosis, we used gene-modified MSCs in a preclinical mouse model to determine the efficiency of transduction of murine MSCs by recombinant adeno-associated virus 2 (AAV) vectors carrying reporter genes and determined their osteogenic potential after recombinant AAV-mediated expression of bone morphogenic protein 2, known to induce osteoblast differentiation. Although surgical ovariectomy is believed to induce progressive bone loss in mouse models, similar to an osteoporosis-like phenotype in humans, several factors, including hormonal alteration and dietary habits, significantly affect both the onset and progression of the disease. Thus, in the present study, we determined the influence of these factors and developed an immunocompetent mouse model of osteoporosis with degenerative bone loss as in the human pathology.

Alkaline Phosphatase↗
PubMed2005

Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which results from selective loss of upper and lower motor neurons. Mouse models of ALS, such as one carrying the G93A mutant of the human Cu-Zn superoxide dismutase gene[SOD1(G93A)], develop motor neuron pathology and clinical symptoms similar to those observed in ALS patients. There is compelling evidence that both direct and indirect glutamate toxicity contribute to the pathogenesis of motor neuron degeneration. However, the therapeutic effect of various glutamate receptor antagonists has not been clearly demonstrated. Memantine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It has been shown to protect neurons against NMDA- or glutamate-induced toxicity in vitro and in animal models of neurodegenerative diseases. In the current study, we have examined the therapeutic efficacy of memantine in an ALS mouse model carrying a high copy number of SOD1(G93A). Memantine treatment significantly delayed the disease progression and increased the life span of SOD1(G93A) mice, from 121.4 +/- 5.5 to 129.7 +/- 4.5 days (P = 0.032). Furthermore, NMDA receptor subunits were reliably detected in the spinal cord of SOD1(G93A) mice and their expression levels were similar to those in the wild-type littermate control. Therefore, the neuroprotective effect of memantine in SOD1(G93A) mice is most probably due to the inhibition of spinal cord NMDA receptors. In view of the long-term usage of memantine for dementia patients, with excellent tolerance and safety, these data suggest that memantine may be used in ALS patients alone or in combination with other therapies to prolong survival.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Placental perfusion MR imaging with contrast agents in a mouse model.

PURPOSE: To quantitatively analyze placental perfusion by using magnetic resonance (MR) imaging with contrast agents in a mouse model. MATERIALS AND METHODS: Study was conducted according to French law and in full compliance with National Institutes of Health recommendations for animal care. Thirty-six pregnant Balb/c mice at 16 days of gestation were injected intravenously with either a conventional or macromolecular gadolinium chelate, and 1.5-T single-section T1-weighted two-dimensional fast spoiled gradient-echo sequential MR imaging was then performed for 14 minutes. Images were analyzed qualitatively, and parametric map analysis was performed in the resultant 25 mice included in the study. Signal intensity was measured in maternal left ventricle (input function), placenta, and fetus on all images. After converting signal intensity into contrast agent tissue concentrations, a three-compartment model was developed with compartmental and numeric modeling software. Placental perfusion was calculated for conventional (n = 12) and macromolecular (n = 13) gadolinium chelates. Finally, placental and fetal gadolinium concentrations were assayed by means of atomic emission spectrophotometry (n = 15). Perfusion values and placental and fetal gadolinium concentrations for conventional and macromolecular chelates were compared by using an unpaired t test. RESULTS: Based on a constant transfer parameter, estimated placental perfusion did not differ between procedures with conventional and macromolecular gadolinium chelates (0.99 mL/min/g +/- 0.5 [standard deviation] and 1.28 mL/min/g +/- 0.6, respectively, P = .22). Likewise, mean placental gadolinium concentrations did not differ after injection of conventional and macromolecular chelates. In contrast, mean fetal gadolinium concentration was 9.83 micromol/L after conventional chelate injection and below detection limit after macromolecular chelate injection. CONCLUSION: Placental perfusion can be calculated by using dynamic contrast-enhanced MR imaging, as shown in this mouse model.

Animals↗
PubMed1997

Adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy leads to systemic activity against spontaneous and induced metastasis in an orthotopic mouse model of prostate cancer.

It is critical to develop new therapies, such as gene therapy, which can impact on both local and metastatic prostate cancer progression. We have developed an orthotopic mouse model of metastatic prostate cancer using a cell line (RM-1) derived from the mouse prostate reconstitution (MPR) model system. This mouse model closely simulates the anatomical and biological milieu of the prostate and allows for realistic testing of experimental gene therapy protocols. Adenovirus (ADV)-mediated transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene in conjunction with ganciclovir (GCV) in this model led to significant suppression of growth and of spontaneous metastasis at 14 days post-tumor inoculation. Longer-term studies produced a significant survival advantage and a continued suppression of metastatic activity for treatment animals despite regrowth of the primary tumor. Challenge by injection of tumor cells into the tail vein following excision of treated and control s.c. primary tumors resulted in 40% reduction in lung colonization in the treatment group, indicating the possible production of systemic anti-metastatic activity following a single in situ treatment with ADV/HSV-tk + GCV in this model system.

Adenoviridae↗
PubMed1996

Cremophor EL reversed multidrug resistance in vitro but not in tumor-bearing mouse models.

Cremophor EL (CreEL), a polyethylene castor oil used as a vehicle for cyclosporin A and taxol, reverses P-glycoprotein-mediated drug resistance. The vehicle in an i.v. dosage form of PSC 833, [3'-keto-Bmt1]-[Val2]-cyclosporin, contains CreEL and has been presumed to have the potentiation of the reversal activity of PSC 833. To examine this possibility, we compared reversal activities of CreEL and PSC 833 against multidrug resistance (MDR) in vitro and in vivo. Both CreEL and PSC 833 inhibited P-glycoprotein-mediated efflux of [3H]vincristine from adriamycin-resistant myelogenous leukemia K562. The sensitization of multidrug-resistant cell lines to anticancer drugs by CreEL and PSC 833 was selective to MDR-related agents, suggesting a specific interference of the P-glycoprotein function by the two MDR modulators. The concentration-dependent activity of the modulators demonstrated that CreEL is at least 100 times less potent than PSC 833. The in vivo reversal effects of CreEL alone and PSC 833 in the vehicle were investigated in multidrug-resistant tumor-bearing mouse models. In vincristine-resistant P388 leukemia-bearing mice, neither i.v. nor i.p. administration of CreEL even at 1440 mg/kg enhanced the antitumor activity of adriamycin. The in vivo negligible activity of CreEL was confirmed in an HCT-15-bearing athymic mouse model. In contrast, PSC 833 significantly enhanced the antitumor activity of adriamycin in the in vivo models. The reversal activity of CreEL restricted to in vitro leads us to conclude that the vehicle containing CreEL did not potentiate the activity of PSC 833 in the tumor-bearing mouse models.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Classification of proliferative pulmonary lesions of the mouse: recommendations of the mouse models of human cancers consortium.

Rapid advances in generating new mouse genetic models for lung neoplasia provide a continuous challenge for pathologists and investigators. Frequently, phenotypes of new models either have no precedents or are arbitrarily attributed according to incongruent human and mouse classifications. Thus, comparative characterization and validation of novel models can be difficult. To address these issues, a series of discussions was initiated by a panel of human, veterinary, and experimental pathologists during the Mouse Models of Human Cancers Consortium (NIH/National Cancer Institute) workshop on mouse models of lung cancer held in Boston on June 20-22, 2001. The panel performed a comparative evaluation of 78 cases of mouse and human lung proliferative lesions, and recommended development of a new practical classification scheme that would (a) allow easier comparison between human and mouse lung neoplasms, (b) accommodate newly emerging mouse neoplasms, and (c) address the interpretation of benign and preinvasive lesions of the mouse lung. Subsequent discussions with additional experts in pulmonary pathology resulted in the current proposal of a new classification. It is anticipated that this classification, as well as the complementary digital atlas of virtual histological slides, will help investigators and pathologists in their characterization of new mouse models, as well as stimulate further research aimed at a better understanding of proliferative lesions of the lung.

Animals↗
PubMed1992

Mouse model for Pneumocystis carinii pneumonia that uses natural transmission to initiate infection.

Animal models for Pneumocystis carinii, for the most part, have been limited to immunosuppressed rats and ferrets, while a dependable mouse model has been more difficult to develop. A P. carinii mouse model has now been established with several strains of mice, including C3Heb/FeJ, C3HeN, BALB/c, DBA/2N, and BALB/c nu/nu (athymic). In lieu of using invasive methods for initiating P. carinii infections, mice harboring P. carinii transmitted the disease to mice without latent infection via short-term cohabitation. After the exposure period, the seed mice were sacrificed to confirm the presence of acute P. carinii pneumonia. Acute infections in recipient mice developed at approximately 7 to 8 weeks, while control unseeded littermates remained uninfected. All recipient mice and their littermates were maintained in isolation hoods to eliminate the possibility of exposure to other sources of P. carinii. This approach allows investigators to consistently transmit P. carinii to mice and to select the strain of mouse desired for use in a particular study. The results presented here suggest that more attention should be given to the potential for patient-to-patient transmission of P. carinii in immunocompromised patients such as those with AIDS.

Animals↗
PubMed2001

Transgenic mouse models of Alzheimer's disease.

Recent advances in the understanding of the genetic basis of Alzheimer's disease have enabled the production of transgenic mouse models of the disease. Utilizing both cDNA- and genomic-based approaches, these mouse models for Alzheimer's disease have already provided valuable insights into the pathogenesis of the disease and potential therapeutic interventions.

Alzheimer Disease↗
PubMed2004

Improved efficacy of gene therapy approaches for Pompe disease using a new, immune-deficient GSD-II mouse model.

Glycogen storage disease type II (GSD-II) is a lysosomal storage disorder in which the lack of human acid-alpha glucosidase (hGAA) activity results in massive accumulations of glycogen in cardiac and skeletal muscle fibers. Affected individuals die of cardiorespiratory failure secondary to the skeletal and/or cardiac muscle involvement. Recombinant hGAA enzyme replacement therapy (ERT) is currently in clinical trials and, although promising, ERT may be limited by large-scale production issues and/or the need for frequent infusions. These limitations could be circumvented or augmented by gene therapy strategies. Previous findings in our lab demonstrated that hepatic targeting of a modified adenovirus vector expressing human GAA was able to correct the glycogen accumulation in multiple affected muscles in the GAA-KO mice, by virtue of high-level, hepatic secretion of hGAA. However, although the vector persisted and expressed hGAA for 6 months in the liver, plasma hGAA was not detectable beyond 10 dpi (days postinjection), and reaccumulation of glycogen was observed. Two possibilities may have contributed to this phenomenon, the shut down of the CMV promoter and/or the onset of high levels of anti-hGAA antibodies. In order to test these and other possibilities, we have now developed an immune-deficient mouse model of GSD-II by interbreeding GAA-KO mice with severe combined immune-deficient (SCID) mice, generating double knockout, GAA-KO/SCID mice. In this new mouse model, we evaluated the efficacy of an [E1-, polymerase-] AdhGAA vector, in the absence of anti-hGAA antibody responses. After intravenous injection, GAA detection in the plasma was prolonged for at least 6 months secondary to the lack of anti-hGAA antibody production in all of the treated mice. GAA-KO/SCID mice treated with high doses of viral vector demonstrated longer durations of glycogen correction in both skeletal and cardiac muscles, relative to mice injected with lower doses of the vector. Notably, within 2 weeks of vector injection, muscle strength and coordination was normalized, and the improved muscle function persisted for at least 6 months. In summary, this new mouse model of GSD-II now makes it possible to assess the full potential for efficacy of any GAA-expressing vector (and/or ERT) contemplated for use in GSD-II gene therapy, without the negative influence that anti-hGAA antibodies entail.

Animals↗
PubMed2000

The effects of N-6 polyunsaturated fatty acid supplementation on the lipid composition and atherogenesis in mouse models of atherosclerosis.

Despite numerous studies, the precise role of dietary n-6 polyunsaturated fatty acids in the pathogenesis of atherosclerosis remains controversial. It has been shown that feeding an n-6-enriched diet resulted in decreased atherosclerosis in African green monkeys and was associated with a reduction in LDL levels. However, other authors reported that n-6 supplementation increased the oxidative stress and the susceptibility of LDL to undergo in vitro oxidation, thus potentially enhancing atherosclerosis. The present study was designed to investigate the effect of dietary supplementation of n-6 polyunsaturated fats (safflower oil), as compared with a saturated fat-rich diet (Paigen), on the blood lipid profile and atherosclerosis in two mouse models. In the first experiment, female C57BL/6 mice (n=23-30 per group) were fed a cholate containing Paigen diet, a safflower oil-rich diet (with cholate), or normal chow for 15 weeks. No significant differences between the high fat diet groups were evident with respect to total cholesterol, LDL, HDL or triglyceride levels. The extent of aortic sinus fatty streaks did not differ significantly between the two groups. In the second experiment, LDL-receptor-deficient (LDL-RD) mice (n=20-30 per group) were randomized into similar dietary regimens. Mice consuming a safflower oil-enriched diet developed significantly less atherosclerosis, in comparison with Paigen diet-fed mice. A reduction in LDL levels, although not of a similar magnitude as the reduction in atherosclerosis, was evident in the safflower oil-fed mice when compared to the Paigen diet-fed littermates. In both mouse models of atherosclerosis, LDL isolated from the plasma of mice on the n-6 polyunsaturated diet was rendered slightly more susceptible to oxidation in vitro, as indicated by a shorter lag period for diene formation. Thus, the effects of n-6 fatty acids on the lipoprotein composition and other potential influences may have contributed to the anti-atherogenic effect in the LDL-RD mouse model.

Animals↗
PubMed1996

A comparison of a CB17 scid mouse model and the tetrazolium-dye assay using human haematological tumour cell lines.

Haematological tumours in the CB17 scid mouse produce a disseminated blood-borne disease analogous to that seen in humans. The CB17 scid mouse model has been applied to study the efficacy of chemotherapeutic agents on tumours. Using three human tumour-cell lines of haemopoietic origin (CCRF-CEM, Raji, HS-Sultan), we established disseminated tumours in scid mice and studied the in vivo response of these tumours to four chemotherapeutic agents (daunorubicin, idarubicin, ifosfamide, etoposide). The in vitro drug-resistance profiles of the same cell lines to these drugs were also determined by the tetrazolium-dye (MTT) assay. Differences were found in the patterns of resistance and sensitivity of the cell lines in the in vivo and in vitro systems tested. Since the scid mouse model determines the in vivo response of both host and tumour to cytotoxic agents, it may be more valid than the other models in determining drug resistance of haematological malignancies.

Animals↗
PubMed2002

Mouse models for the genetic dissection of atopy.

Atopic disorders are complex traits with a significant contribution of heritability. Several mouse models for atopic phenotypes such as allergen-induced and intrinsic asthma, atopic dermatitis and immediate cutaneous hypersensitivity have been used to systematically dissect the genetics of these diseases. Many of the chromosomal regions identified in genome-wide screens colocalize with linkage regions of autoimmune phenotypes suggesting common regulatory genes in combination (or addition) to disease-specific genes. Moreover, many of these regions correspond to regions found in the human system, thus strengthening the likelihood of a gene contributing to the phenotype. The role of individual candidate genes has been vigorously pursued in genetically modified mice by destruction or overexpression of the candidate gene. The complex interactions of multiple contributing genes may further be elucidated in randomly mutated mouse strains. Thus mouse models can contribute largely to the elucidation of disease genes.

Animals↗
PubMed1996

Defining inoculation conditions for the mouse model of ascending urinary tract infection that avoid immediate vesicoureteral reflux yet produce renal and bladder infection.

A satisfactory mouse model of ascending urinary tract infection (UTI) must avoid inoculation-induced vesicoureteral reflex (VUR) yet still produce kidney and bladder infection in a substantial proportion of mice. To define inoculation conditions that would satisfy both these conditions, mice were evaluated for VUR immediately after inoculation under a variety of conditions and were assessed for kidney and bladder infection 48 h after inoculation. Elimination of VUR required a slowed infusion rate, a reduced inoculum volume (25 microliter), and use of less traumatic methods for euthanasia and organ harvest. Bladder and kidney infection were highly prevalent at 48 h among mice inoculated under VUR-free conditions with either of 2 wild type Escherichia coli strains. Together with reports from other investigators, these findings indicate that satisfactory experimental conditions for the mouse model of ascending UTI can be defined empirically but may be laboratory-specific.

Animals↗
PubMed1998

Inactivation of two haemolytic toxin genes in Aeromonas hydrophila attenuates virulence in a suckling mouse model.

The contribution of two unrelated Aeromonas hydrophila beta-haemolytic toxins to virulence was assessed in a suckling mouse model. The first haemolysin gene, isolated from an A. hydrophila A6 cosmid bank, encoded a potential gene product of 621 amino acids and a predicted molecular size of 69.0 kDa. The inferred amino acid sequence showed 89% identity to the AHH1 haemolysin of A. hydrophila ATCC 7966, and 51% identity to the HlyA haemolysin of Vibrio cholerae EI Tor strain O17. The second haemolysin gene (designated aerA), which encodes aerolysin, a pore-forming toxin, was partially cloned by PCR for the purpose of mutant construction. This PCR product was a 1040 bp fragment from the C-terminal region of aerA. It is proposed that the 69.0 kDa V. cholerae-HlyA-like haemolysin gene be termed hlyA to contrast with the aerA terminology for the aerolysin. A suicide vector was used to inactivate both the hlyA and aerA genes in A. hydrophila A6. When assessed in the suckling mouse model, only the hlyA aerA double mutant showed a statistically significant reduction in virulence--a 20-fold change in LD50 (Scheffe test, P < 0.05). Cytotoxicity to buffalo green monkey kidney cell monolayers and haemolysis on horse blood agar were eliminated only in the hlyA aerA double mutants. This is the first report of cloning and mutagenesis of two unrelated haemolytic toxin genes in the same strain of a mesophilic aeromonad. For A. hydrophila, a two-toxin model provides a more complete explanation of virulence.

Aeromonas hydrophila↗
PubMed2000

Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease.

We investigated a transgenic mouse model of sickle cell disease, homozygous for deletion of mouse beta-globin and containing transgenes for human beta(S) and beta(S-antilles) globins linked to the transgene for human alpha-globin. In these mice, basal cGMP production in aortic rings is increased, whereas relaxation to an endothelium-dependent vasodilator, A-23187, is impaired. In contrast, aortic expression of endothelial nitric oxide synthase (NOS) is unaltered in sickle mice, whereas expression of inducible NOS is not detected in either group; plasma nitrate/nitrite concentrations and NOS activity are similar in both groups. Increased cGMP may reflect the stimulatory effect of peroxides (an activator of guanylate cyclase), because lipid peroxidation is increased in aortae and in plasma in sickle mice. Despite increased vascular cGMP levels in sickle mice, conscious systolic blood pressure is comparable to that of aged-matched controls; sickle mice, however, evince a greater rise in systolic blood pressure in response to nitro-L-arginine methyl ester, an inhibitor of NOS. Systemic concentrations of the vasoconstrictive oxidative product 8-isoprostane are increased in sickle mice. We conclude that vascular responses are altered in this transgenic sickle mouse and are accompanied by increased lipid peroxidation and production of cGMP; we suggest that oxidant-inducible vasoconstrictor systems such as isoprostanes may oppose nitric oxide-dependent and nitric oxide-independent mechanisms of vasodilatation in this transgenic sickle mouse. Destabilization of the vasoactive balance in the sickle vasculature by clinically relevant states may predispose to vasoocclusive disease.

Anemia, Sickle Cell↗
PubMed2005

Inhibition of cyclooxygenase-2 enhances myocardial damage in a mouse model of viral myocarditis.

To determine critical role of cyclooxygenase-2 (COX-2) for development of viral myocarditis, a mouse model of encephalomyocarditis virus-induced myocarditis was used. The virus was intraperitoneally given to COX-2 gene-deficient heterozygote mice (COX-2+/-) and wild-type mice (WT). We examined differences in heart weights, cardiac histological scores, numbers of infiltrating or apoptotic cells in myocardium, cardiac expression levels of COX-2, tumor necrosis factor-alpha (TNF-alpha), and adiponectin mRNA, immunoreactivity of COX-2, TNF-alpha, and adiponectin in myocytes, cardiac concentrations of TNF-alpha and adiponectin, prostaglandin E2 (PGE2) levels in hearts, and viral titers in tissues between COX-2+/- and WT. We observed significantly decreased expression of COX-2 mRNA and reactivity in hearts from COX-2+/- on day 8 after viral inoculation as compared with that from WT, together with elevated cardiac weights and severe inflammatory myocardial damage in COX-2+/-. Cardiac expression of TNF-alpha mRNA, reactivity, and protein on day 8 was significantly higher in COX-2+/- than in WT, together with reciprocal expression of adiponectin mRNA, reactivity, and protein in hearts. Significantly reduced cardiac PGE2 levels on day 8 were found in COX-2+/- compared with those in WT. There was no difference in local viral titers between both groups on day 4. Infected WT treated with a selective COX-2 inhibitor, NS-398, also showed the augmented myocardial damage on day 8. These results suggest that inhibition of COX-2 may enhance myocardial damage through reciprocal cardiac expression of TNF-alpha and adiponectin in a mouse model of viral myocarditis.

Adiponectin↗
PubMed2002

In situ transduction of cytosine deaminase gene followed by systemic use of 5-fluorocytosine inhibits tumor growth and metastasis in orthotopic prostate cancer mouse models.

OBJECTIVE: To investigate the antitumor and anti-metastatic effect of in situ transduction of adenovirus encoding cytosine deaminase (AdCD) followed by the systemic use of 5-fluorocytosine (5-FC) in the orthotopic (o.t.) prostate cancer mouse model. METHODS: The o.t. prostate cancer model of C57BL/6 mouse was developed by o.t. inoculation of RM-1 cells to the subcapsular area of the prostate gland. In situ transduction of the CD gene, followed by systemic use of 5-FC at a daily dosage of 300 mg/kg for 14 days, was performed two days later. RESULTS: Compared with mice treated with Adbeta-gal/5-FC, 5-FC and PBS, mice of the o.t. model receiving in situ treatment of AdCD/5-FC had significant prolongation of survival and suppression of local tumor growth. More importantly, pathological observations showed that metastatic activity occurred in all mice of the PBS, 5-FC and Adbeta-gal groups including metastasis to the iliac lymph node (10/10, 10/10, 10/10) and the lung (8/10, 7/10, 7/10). However, only two out of ten had iliac lymphatic metastasis in the AdCD/5-FC group with no systemic or preaotic lymphatic metastasis, suggesting a strong metastatic inhibitory effect. CONCLUSIONS: In situ transduction of AdCD followed by systemic use of 5-FC leads to the inhibitory effect on tumor growth and metastatic activity in the o.t. mouse model of prostate cancer. Clinically, it may be possible to treat metastatic or recurrent prostate cancer with a novel gene therapy using in situ injection techniques in future.

Adenoviridae↗