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PubMed2003

Gene therapy for pituitary tumors: from preclinical models to clinical implementation.

Gene therapy, which entails the use of nucleic acids as drugs, is a new approach to treat disease. Gene therapy has been successfully implemented in several preclinical animal models, including several paradigms of experimental pituitary tumors. In spite of these successes, several critical issues need to be addressed before gene therapy can become a clinical reality for the treatment of pituitary tumors. These include the development of safer and more effective gene delivery vectors, the uncovering of novel therapeutic targets, the development of molecular switches which will allow turning therapeutic transgene expression "on" and "off" as and when it is needed, and the ability to scale up the vector preparations devoid of any putative contaminants. There are still many basic science developments that must take place in order to allow this new therapeutic technology to make its way successfully into the clinical arena to treat pituitary disease. We envisage these developments taking place within the next five years, gene therapy for pituitary tumors will then form part of the armamentarium available to better treat and manage pituitary tumors.

Adenoviridae↗
PubMed1987

Preclinical modeling of changes in drug kinetics caused by acute renal failure in rats.

The rates of total and extrarenal elimination of amikacin, cefoperazone, ceftriaxone, gentamicin, mesocain, theophylline, tobramycin, and polyfructosane-S were determined in rats with intact kidneys and in those after bilateral nephrectomy. While the values of the elimination constants of the tested drugs were markedly higher in the rats than in man, the ratio of nonrenal and total elimination constants, expressing the fraction of drugs eliminated extrarenally, is close to the value found in man. These findings suggest that the model might be useful in preclinical drug testing and can help in the prediction of changes in the kinetics of drugs caused by renal failure.

Acute Kidney Injury↗
PubMed2003

The Wayne State University Waldenstrom's Macroglobulinemia preclinical model for Waldenstrom's macroglobulinemia.

The Wayne State University Waldenstrom's Macroglobulinemia xenograft model in mice with severe combined immune deficiency (WSU-WM-SCID) is the only preclinical animal model available for this disease. It is based on a permanent, EBV- IgMlambda cell line (WSU-WM) established from a patient with a 10-year history of Waldenstrom's macroglobulinemia (WM). These cells are CD5(-)CD10(+)CD19(+)CD20(+)CD22(+) and have t(8;14) (q24;32), t(12;17) (q24;q21), 2p-. WSU-WM cells also express DNA topoisomerase II (alpha and beta), and are bcl(2)(+)bcl(XL)(+)bax(-). Although the tumor has aggressive biological behavior with c-myc-IgH rearrangement, it has retained the salient features of WM. The breakpoint on 8q24 is downstream of c-myc exon 3, which is not usual for Burkitt-type breakpoints. WSU-WM cells also express both secretory (s(u)) and membrane (m(u)) IgM mRNA and secrete IgM in culture supernatant. Histiologically, WSU-WM-SCID xenograft tumors have lymphoplasmacytoid morphology. These features indicate biological, but not histological evolution. The WSU-WM-SCID is a model of a more aggressive and resistant WM usually seen toward the late stages of disease. It is, therefore, a particularly useful tool in developing new therapeutic strategies for the more aggressive WM, including targeted therapy, which exploits unique molecular characteristics of tumor cells.

Animals↗
PubMed2005

QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome.

Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements. In this study, we investigated effects of moxifloxacin on the hERG current in HEK-293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model. Moxifloxacin inhibited the hERG current with an IC50 of 35.7 microM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg(-1), with mean serum Cmax of 8.52 and 22.3 microg ml(-1), respectively. In the wedge preparation, moxifloxacin produced a concentration-dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after-depolarizations were observed in one of five experiments at 30 microM and five of five experiments at 100 microM. The arrhythmogenic potential was also concentration-dependent, and 100 microM ( approximately 18-fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP). Our data indicated a good correlation among the concentration-response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well-behaved pharmacokinetic profile and other dose-limiting effects.

Action Potentials↗
PubMed1990

[Preclinical modeling of the possible effect of acute uremia on drug resorption in the gastrointestinal tract].

The authors investigated in experiments on rats the course of serum concentrations of sulfisoxazole (S) and acetylsulfisoxazole (AS) in normal rats and in rats after bilateral nephrectomy after intra gastric administration of S. Serum concentrations of S and AS during the first three hours following administration did not differ significantly or were very close. During the subsequent hours the serum concentrations of S and AS in uraemic animals were significantly higher than in controls. The value of the absorption constant in the uraemic animals was on average higher and the absorption half-life lower than in controls. The assembled results suggest that in acute uraemia in rats the intestinal reabsorption of S and its metabolism in the liver are not reduced. The findings support the idea that the model used could be useful in preclinical research of drugs used in the treatment of acute uraemia.

Acute Disease↗
PubMed1994

Preclinical models for the evaluation of targeted therapies of metastatic disease.

It has been estimated that approx 60-70% of cancer patients harbor overt or subclinical metastases at diagnosis, and it is the eradication of such systemic disease that largely determines survival. Preclinical tumor model systems employed to evaluate potential new treatment strategies should aim to represent the process and patterns of metastasis of their clinical counterparts as closely as possible. Severe combined immune-deficient (SCID) and nu/nu mice have been extensively used as hosts for the growth of human tumor cell lines and in some cases fresh tumor material. However, in most instances the resulting neoplasms fail to metastasize, and the aberrant immune systems of such animals has limited their use mainly to passive therapies of localized disease. Recently, the development of specially selected tumor variants and the use of appropriate orthotopic sites for implantation has provided several models in which dissemination can be demonstrated. Where the gene coding for a potential target antigen has been cloned, and where its overexpression or mutation is associated with malignancy (e.g., c-erbB-2, H-ras), transgenic mice may yield tumors that will develop in these immunocompetent hosts. In some cases such tumors exhibit metastasis. A third approach is to transfect human genes of interest into appropriate rodent tumors expressing the desired metastatic phenotype. These various approaches are compared with particular reference to mammary carcinoma biology.

Animals↗
PubMed2002

Botulinum neurotoxin serotypes A and B preparations have different safety margins in preclinical models of muscle weakening efficacy and systemic safety.

This preclinical study compared the muscle weakening efficacy, duration, and safety margin of the recently approved botulinum toxin type B (BTX-B; Myobloc/Neurobloc) to botulinum toxin type A (BTX-A; BOTOX((R))). Mice received a single hind limb intramuscular injection of BTX-B (1-150U/kg) or BTX-A (1-120U/kg). An observer who was masked to treatment assessed the magnitude and duration of muscle weakening efficacy on a 0-4 scale using the digit abduction scoring assay. Safety margins were determined as the ratio of the IM median lethal dose to the IM dose that produced half-maximal muscle weakness in the DAS. BTX-A produced muscle weakness at lower doses than BTX-B (IM ED(50): 6.2+/-0.6 vs. 20.8+/-1.4U/kg, respectively) (p<0.0001). BTX-A at 29U/kg and BTX-B at 67U/kg produced comparable peak DAS scores of approximately 4 indicating maximal muscle weakness. At these doses, the duration of BTX-A was longer, with a return to baseline by day 36 compared to a return to baseline by day 14 with BTX-B. The mean dose that was lethal in 50% of mice was lower for BTX-A than BTX-B (81.4+/-3.5 vs. 104.6+/-1.9U/kg, respectively) (p<0.001) and the safety margin was higher (13.9+/-1.7 vs. 5.4+/-0.3, respectively (p<0.001). These results indicate that the BTX-A:BTX-B dose ratio for muscle weakening efficacy is different from the ratio for systemic effects following IM injections and suggest that no single dose ratio is adequate to compare these preparations. The in vivo differences found are consistent with the different clinical profiles reported for these two products.

Animals↗
PubMed2006

Preclinical model to test human papillomavirus virus (HPV) capsid vaccines in vivo using infectious HPV/cottontail rabbit papillomavirus chimeric papillomavirus particles.

A human papillomavirus (HPV) vaccine consisting of virus-like particles (VLPs) was recently approved for human use. It is generally assumed that VLP vaccines protect by inducing type-specific neutralizing antibodies. Preclinical animal models cannot be used to test for protection against HPV infections due to species restriction. We developed a model using chimeric HPV capsid/cottontail rabbit papillomavirus (CRPV) genome particles to permit the direct testing of HPV VLP vaccines in rabbits. Animals vaccinated with CRPV, HPV type 16 (HPV-16), or HPV-11 VLPs were challenged with both homologous (CRPV capsid) and chimeric (HPV-16 capsid) particles. Strong type-specific protection was observed, demonstrating the potential application of this approach.

Animals↗
PubMed2026

Are there any common effects in preclinical models of micro- and nanoplastic (MNP) exposure? A systematic review.

Micro- and nanoplastics (MNPs) are emerging contaminants detected in food sources and the marine food chain, raising concerns about human health. Although no causal relationship has been established between MNP exposure and specific diseases, growing evidence suggests adverse developmental, behavioral, cognitive and biochemical effects. This systematic review synthesized evidence from common preclinical neurotoxicology models, including C. elegans, D. rerio, D. melanogaster, in vitro systems and rodents, to identify convergent developmental, behavioral and biochemical outcomes. The protocol was preregistered in OSF, followed PRISMA-P guidelines, applied PICOS criteria, and assessed methodological quality using the European Commission's ToxRTool. Overall, 185 studies were included. Consistent findings showed impaired survival and disrupted development across all models. Behavioral alterations affecting anxiety, memory, learning, sociability and locomotor activity were also consistently reported. In addition, numerous studies identified disruptions in the serotonergic (5-HT) system, including changes in neurotransmitter levels, transporters and metabolic enzymes. Despite methodological heterogeneity, these findings indicate that MNP exposure produces reproducible neurodevelopmental and neurochemical alterations across experimental models. Future studies should improve methodological harmonization, strengthen cross-model comparability and identify robust biomarkers and key mechanisms underlying MNP-induced neurotoxicity, facilitating translation to human health risk assessment frameworks.

Animals↗
PubMed2004

Increased brain tumor resection using fluorescence image guidance in a preclinical model.

BACKGROUND AND OBJECTIVES: Fluorescence image-guided brain tumor resection is thought to assist neurosurgeons by visualizing those tumor margins that merge imperceptibly into normal brain tissue and, hence, are difficult to identify. We compared resection completeness and residual tumor, determined by histopathology, after white light resection (WLR) using an operating microscope versus additional fluorescence guided resection (FGR). STUDY DESIGN/MATERIALS AND METHODS: We employed an intracranial VX2 tumor in a preclinical rabbit model and a fluorescence imaging/spectroscopy system, exciting and detecting the fluorescence of protoporphyrin IX (PpIX) induced endogenously by administering 5-aminolevulinic acid (ALA) at 4 hours before surgery. RESULTS: Using FGR in addition to WLR significantly increased resection completeness by a factor 1.4 from 68+/-38 to 98+/-3.5%, and decreased the amount of residual tumor post-resection by a factor 16 from 32+/-38 to 2.0+/-3.5% of the initial tumor volume. CONCLUSIONS: Additional FGR increased completeness of resection and enabled more consistent resections between cases.

Aminolevulinic Acid↗
PubMed2002

Preclinical models of lymphatic disease: the potential for growth factor and gene therapy.

The human disease states that are characterized by functional lymphatic insufficiency currently lack a cure. Molecular approaches may ultimately provide a therapeutic window to reverse the stigmata of both primary and secondary lymphatic insufficiency. To harness the potential therapeutic power of lymphangiogenesis, testing the safety and efficacy of the treatment response will be necessary. This, in turn, necessitates the availability of suitable preclinical animal models of the disease processes in question, along with suitable research tools to permit an assessment of the response to applied therapies. An ideal model would reproducibly and inexpensively replicate the untreated disease of human lymphedema. It would closely simulate the biology, as we understand it, of the human disease, and would replicate both the pathogenesis of the disease, including its natural history and the temporal patterns of its clinical expression. In this way, one might aspire to make valid predictions about the human applicability of therapy by extrapolation from observations in animal models. In addition to the availability of suitable animal models, the required investigative tools must also be available. In the context of lymphangiogenesis, to assess the therapeutic response, one must certainly possess the ability to recognize newly developed lymphatic vasculature. Sophisticated immunohistochemical and imaging techniques make this increasingly feasible. Initial experimental observations indicate that growth factor and gene therapy with VEGF-C holds promise for the treatment of both primary and secondary forms of lymphedema.

Animals↗
PubMed2026

Evaluation of metabolic, reproductive, and gut microbiota alterations in a comparative study of different preclinical models of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a multifaceted, complex metabolic and endocrine disease where gut flora is considered an important factor in causing PCOS. This study aimed to identify a suitable PCOS model that contributes to gut microbial dysbiosis and metabolic and hormonal disturbances. Prepubertal SD rats were administered with normal control (NC), dihydrotestosterone (DHT), DHT with fructose (F), DHT+ high fat diet (HFD) for 91&#x2009;days, dehydroepiandrosterone (DHEA), DHEA with fructose, DHEA with HFD for 30&#x2009;days, sodium valproate (SV), sodium valproate with fructose, and sodium valproate with HFD for 21&#x2009;days. The estrous cycles were assessed over this timeframe. At the end of the experiment, superoxide dismutase and uterine and ovarian morphology were evaluated, along with hormone levels, lipid profiles, and 16S rRNA genomic sequencing. All models exhibited PCOS characteristics, including hormonal imbalances, insulin resistance (p&#x2009;&#x2264;&#x2009;.001), multiple follicular cysts on ultrasonography, and histological alterations. Gut microbial dysbiosis was observed across all PCOS-induced groups; however, the DHT alone group showed more pronounced alterations in microbial composition than the other experimental groups. Specifically, the DHT alone group exhibited reduced abundance of Firmicutes and increased abundance of Proteobacteria. Among the evaluated models, the DHT-only model showed more pronounced metabolic, hormonal, reproductive, and gut microbial alterations and may serve as a suitable model for PCOS research.

Animals↗
PubMed2001

A preclinical model for experimental chemotherapy of human head and neck cancer.

We developed a mouse model in a representative human derived head and neck cancer cell line for preclinical studies to evaluate antitumor response, tumor-free survival and host toxicity of alkylating agents, antimetabolites, platinum analogs and taxanes alone or in combination. Ninety athymic NMRI mice were inoculated with human derived oral squamous cell carcinoma cells growing on the hind paw to an average volume of 180 +/- 80 mm3. Animals were stratified according to tumor volume into 10 groups (n=6-10) and treated with ifosfamide (65 mg/kg b.w.), docetaxel (24 mg/kg b.w.), cisplatin (2 mg/kg b.w.), carboplatin (6 or 10 mg/kg b.w.), methotrexate (1 mg/kg b.w.), and fluorouracil (15 mg/kg b.w.) intravenously in single agent or combination (ifosfamide plus docetaxel or ifosfamide plus carboplatin) treatment schedules or controls. Tumor volume was measured 3 times per week for 60 days. The average tumor volume, the overall survival time and the response rates (CR, PR) of the treated animals were compared with the data obtained from untreated controls and statistically evaluated. Untreated tumors showed rapid and exponential tumor growth. Single agent therapies with ifosfamide, cisplatinum, and docetaxel lead to significant tumor regression and improved overall survival. Low dose carboplatin monotherapy induced significant tumor growth delay, but not significant tumor regression. Most impressive tumor-free survival was achieved by combination treatment with ifosfamide and docetaxel. This preclinical study demonstrates an animal model capable of differentiating various chemotherapy regimens.

Animals↗
PubMed2004

A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia.

PURPOSE: Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation therapy and chemotherapy. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. The purpose of this study was to develop and characterize a rodent tumor model with a reporter gene construct that would be transactivated by the hypoxia-inducible molecular switch, i.e., the upregulation of HIF-1. METHODS: The reporter gene construct is the herpes simplex virus 1-thymidine kinase (HSV1-tk) fused with the enhanced green fluorescent protein (eGFP) under the regulation of an artificial hypoxia-responsive enhancer/promoter. In this model, tumor hypoxia would up-regulate HIF-1, and through the hypoxia-responsive promoter transactivate the HSV1-tkeGFP fusion gene. The expression of this reporter gene can be assessed with the 124I-labeled reporter substrate 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodouracil (124I-FIAU), which is phosphorylated by the HSV1-tk enzyme and trapped in the hypoxic cells. Animal positron emission tomography (microPET) and phosphor plate imaging (PPI) were used in this study to visualize the trapped 124I-FIAU, providing a distribution of the hypoxia-induced molecular events. The distribution of 124I-FIAU was also compared with that of an exogenous hypoxic cell marker, 18F-fluoromisonidazole (FMISO). RESULTS: Our results showed that 124I-FIAU microPET imaging of the hypoxia-induced reporter gene expression is feasible, and that the intratumoral distributions of 124I-FIAU and 18F-FMISO are similar. In tumor sections, detailed radioactivity distributions were obtained with PPI which also showed similarity between 124I-FIAU and 18F-FMISO. CONCLUSION: This reporter system is sufficiently sensitive to detect hypoxia-induced transcriptional activation by noninvasive imaging and might provide a valuable tool in studying tumor hypoxia and in validating existing and future exogenous markers for tumor hypoxia.

Adenocarcinoma↗
PubMed2003

Predictions from a preclinical model: studies of aromatase inhibitors and antiestrogens.

We have developed a tumor model for studying the effects of aromatase inhibitors and antiestrogens in vivo. The model simulates postmenopausal breast cancer patients with estrogen-dependent tumors. This model utilizes human estrogen-dependent breast cancer cells transfected with the aromatase gene (MCF-7(CA)), which are inoculated in Matrigel s.c. into ovariectomized nude mice. The estrogen receptor-positive cells produce sufficient estrogen by aromatization to stimulate their proliferation and the formation of tumors in the mice. Using several different strategies, we have compared the aromatase inhibitors (letrozole and anastrozole) with antiestrogens (tamoxifen and fulvestrant). Aromatase inhibitors were more effective than tamoxifen and were more effective alone than when combined with antiestrogens. In addition, letrozole had a longer duration of effect than tamoxifen. The possibility of delaying the development of resistance to antiestrogens and aromatase inhibitors was investigated by alternating letrozole with tamoxifen every 4 weeks. However, although alternating treatment proved more effective than tamoxifen alone (tumors doubled in 16 weeks), tumors doubled in volume at about 18 weeks when treatment began with tamoxifen. When treatment started with letrozole and alternated with tamoxifen, tumors doubled in volume in about 22 weeks. However, tumors of mice treated with letrozole alone did not double in size until 35 weeks. These results demonstrate that this aromatase inhibitor is more effective and has a longer duration of response as a single agent than tamoxifen or in combination with tamoxifen.

Animals↗
PubMed1998

Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models.

UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2-0.3 microM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human alpha1-acidic glycoprotein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in "real time" with phase I studies.

Adult↗
PubMed2001

Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease.

Hepatocyte growth factor (HGF) exclusively stimulates the growth of endothelial cells without replication of vascular smooth muscle cells, and acts as a survival factor against endothelial cell death. Recently, a novel therapeutic strategy for ischemic diseases using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. We have previously reported that intra-arterial administration of recombinant HGF induced angiogenesis in a rabbit hindlimb ischemia model. In this study, we examined the feasibility of gene therapy using HGF to treat peripheral arterial disease rather than recombinant therapy, due to its disadvantages. Initially, we examined the transfection of 'naked' human HGF plasmid into a rat hindlimb ischemia model. Intramuscular injection of human HGF plasmid resulted in a significant increase in blood flow as assessed by laser Doppler imaging, accompanied by the detection of human HGF protein. A significant increase in capillary density was found in rats transfected with human HGF as compared with control vector, in a dose-dependent manner (P < 0.01). Importantly, at 5 weeks after transfection, the degree of angiogenesis induced by transfection of HGF plasmid was significantly greater than that caused by a single injection of recombinant HGF. As an approach to human gene therapy, we also employed a rabbit hindlimb ischemia model as a preclinical study. Naked HGF plasmid was intramuscularly injected in the ischemic hindlimb of rabbits, to evaluate its angiogenic activity. Intramuscular injection of HGF plasmid once on day 10 after surgery produced significant augmentation of collateral vessel development on day 30 in the ischemia model, as assessed by angiography (P < 0.01). Serial angiograms revealed progressive linear extension of collateral arteries from the origin stem artery to the distal point of the reconstituted parent vessel in HGF-transfected animals. In addition, a significant increase in blood flow was assessed by a Doppler flow wire and the ratio in blood pressure of the ischemic limb to the normal limb was observed in rabbits transfected with HGF plasmid as compared with rabbits transfected with control vector (P < 0.01). Overall, intramuscular injection of naked human HGF plasmid induced therapeutic angiogenesis in rat and rabbit ischemic hindlimb models, as potential therapy for peripheral arterial disease.

Animals↗