Rat Model Of Cancer Research Articles

Diffusion Weighted Imaging Evaluated the Early Therapy Effect of Tamoxifen in an MNU-Induced Mammary Cancer Rat Model

PurposeTo assess the optimal time point of diffusion-weighted imaging (DWI) for early prognosis of breast cancer following tamoxifen therapy using a methylnitrosourea (MNU)-induced ER-positive breast-cancer model.MethodsTwo groups of Sprague-Dawley rats (n = 15 for group 1; n = 10 for group 2) were used. All animals (50 days old) were intravenously injected with MNU (50 mg/kg body weight) to induce ER-positive mammary tumors. When tumors were approximately 2 cm in diameter, DWI was performed on days 0, 3, and 7, and intratumoral apparent diffusion coefficient (ADC) values were measured. Therapy started on day 0 with tamoxifen (10 mg/kg diet) and continued for 4 weeks for group 1, but only 1 week for group 2, while tumor volume was measured by caliper twice weekly. All animals of group 2 were euthanized on day 7 after imaging, and Ki-67, TUNEL, ERα, and ERβ staining were performed on tumor tissue.ResultsDW images of MNU-induced mammary tumors were successfully obtained with minimal motion artifact. For group 1, ADC change for 3 days after therapy initiation (ADC3D) was significantly correlated with tumor-volume change until day 11, but the significant correlation between ADC change for 7 days (ADC7D) and the tumor-volume change was observed until day 18. Similarly, for group 2, either ADC7D or ADC3D was significantly correlated with the tumor-volume change, but the higher significance was observed for ADC7D. Furthermore, ADC7D was significantly correlated with apoptotic (TUNEL stained), proliferative (Ki-67 stained), and ERβ-positive cell densities, but ADC3D was not significantly correlated with any of those.ConclusionsADC7D might be a more reliable surrogate imaging biomarker than ADC3D to assess effectiveness of tamoxifen therapy for ER-positive breast cancer, which may enable personalized treatment. The significant correlation between ADC7D and ERβ-positive cell density suggests that ERβ may play an important role as a therapeutic indicator of tamoxifen.

Validation of suitable endogenous control genes for quantitative PCR analysis of microRNA gene expression in a rat model of endometrial cancer

BackgroundMicroRNAs are small RNA molecules that negatively regulate gene expression by translational inhibition or mRNA cleavage. The discovery that abnormal expression of particular miRNAs contributes to human disease, including cancer, has spurred growing interest in analysing expression profiles of these molecules. Quantitative polymerase chain reaction is frequently used for quantification of miRNA expression due to its sensitivity and specificity. To minimize experimental error in this system an appropriate endogenous control gene must be chosen. An ideal endogenous control gene should be expressed at a constant level across all samples and its expression stability should be unaffected by the experimental procedure.ResultsThe expression and validation of candidate control genes (4.5S RNA(H) A, Y1, 4.5S RNA(H) B, snoRNA, U87 and U6) was examined in 21 rat cell lines to establish the most suitable endogenous control for miRNA analysis in a rat model of cancer. The stability of these genes was analysed using geNorm and NormFinder algorithms. U87 and snoRNA were identified as the most stable control genes, while Y1 was least stable.ConclusionThis study identified the control gene that is most suitable for normalizing the miRNA expression data in rat. That reference gene will be useful when miRNAs expression are analyzed in order to find new miRNA markers for endometrial cancer in rat.

Abstract 1278: Obesity enhances benzo(a)pyrene-induced colon tumorigenesis in a PIRC rat model of colon cancer..

Abstract Colorectal cancer is a contributing factor for significant mortalities in the United States, with 50,000 deaths per year and around 140,000 new cases expected to be diagnosed in this year. Epidemiological studies have pointed out that obese people have a higher risk for colon cancer. It is well known that overweight or obesity is induced by excess energy intake from dietary fat. Additionally, consumption of well-done red meat and saturated fats, rich in food-borne environmental toxicants such as polycyclic aromatic hydrocarbons (PAHs) has also been implicated as one of the causative factors for sporadic colon cancer. Thus, on one hand, diet-induced obesity and on the other hand exposures to environmental carcinogens contribute to the development of colon cancer. Therefore, the objective of this study was to investigate whether the colon polyp burden was accelerated by diet-induced obesity when exposed to environmental carcinogens.To test this concept, we have employed an adult male transgenic rat model, the Polyposis In the Rat Colon (PIRC) kindred type. This rat is a mutagen-induced nonsense allele of the rat Apc gene on an inbred F344/NTac (F344) genetic background. This rat model is advantageous because of its longer life span and lack of the tumor suppressor gene Apc. We have explored whether tumor burden in PIRC male rat (PIRC-M Heterozygous F344/NTac-Apcam1137) was influenced by the ingestion of different types of fat containing benzo(a)pyrene [B(a)P], a prototypical PAH compound. Treatment consisted of 25 and 50 μg B(a)P/kg body wt., dissolved in tricaprylin, administered to 7-week-old male PIRC rat daily via oral gavage for 60 days. One group of rats received the AIN-76A control diet and the other group, the Western diet throughout the duration of this study. At the end of exposure, rats were sacrificed; colons were retrieved and preserved in 10% formalin for observation of gross pathological changes. An increased prevalence of adenomas in colon of rats that were maintained on Western diet compared to AIN-76A diet and controls (P < 0.05) was noticed. Interestingly, we have also observed adenomas with high grade dysplasia in B(a)P + Western diet group and these incidences were of frequent occurrence at 50 μg/kg compared to 25 μg/kg B(a)P dose group. On the other hand, the B(a)P alone, and AIN-76A diet groups did not show significant differences in the numbers of adenomas and invasive tumors in colon. Also, B(a)P treatment-related changes were seen in body weight and food consumption of rats administered with B(a)P, with the changes more pronounced in the body weight gain of Western diet group compared to the AIN-76A diet group and controls (p < 0.005). In summary, our studies established that Western diet potentiates the development of colon tumors caused by B(a)P in the PIRC rat. Citation Format: Kelly L. Harris, Mohammad S. Niaz, Awadh A. Binhazim, Mary K. Washington, Samuel E. Adunyah, Aramandla Ramesh. Obesity enhances benzo(a)pyrene-induced colon tumorigenesis in a PIRC rat model of colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1278. doi:10.1158/1538-7445.AM2013-1278

Abstract 185: Secoisolariciresinol diglucoside (SDG, flaxseed lignan) improves biomarkers of early mammary gland cancer progression in a rat model of breast and ovarian cancer.

Abstract Breast cancer prevention efforts increasingly are focused on potentially beneficial dietary modifications due to their ease of implementation, wide acceptance and excellent subject compliance. SDG is a bioactive component of flaxseed suggested to have beneficial SERM-like effects in females at high risk for the development of breast cancer. In parallel with a human phase II prevention trial, female Sprague Dawley rats (n=10-12/group) received 0, 1, 10 or 20 mg/kg/day SDG in the feed. Simultaneously, rats were induced to concurrent mammary and ovarian cancer progression in a previously validated model using sustained release 17β-estradiol and local ovarian DMBA treatment starting at 6 weeks of age. Serum was collected at 3 weeks to measure steady state SDG metabolite concentrations. Mammary gland and ovarian tissues were collected at 3 months post-treatment and examined for changes in epithelial cell proliferation (Ki-67, cell counts), histopathology and dysplasia scores as well as a panel of cancer risk and progression biomarker genes. Carcinogen treatment markedly elevated dysplasia scores while SDG decreased dysplasia in a dose-dependent fashion, with an approximately 50% improvement the highest dose. Mammary epithelial cell numbers were increased by carcinogen and this effect was mitigated similarly at all doses of SDG and reflected in reduced Ki-67 expression. Overall, SDG decreased mammary epithelial proliferation and dysplasia resulting from carcinogen treatment. This preclinical benefit occurred at serum concentrations similar to our human pilot study, in which dietary SDG reduced KI-67 expression in mammary epithelial cells, and decreased the proportion of women with RPFNA atypia. Supported in part by funds from Komen for the Cure grant KG101039. Citation Format: Devora Delman, Bruce F. Kimler, Carol J. Fabian, Brian K. Petroff. Secoisolariciresinol diglucoside (SDG, flaxseed lignan) improves biomarkers of early mammary gland cancer progression in a rat model of breast and ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 185. doi:10.1158/1538-7445.AM2013-185

Abstract 4873: Genistein and soy isoflavone isolate decreased tumor incidence and multiplicity in a Sprague-Dawley ER-positive breast cancer model.

Abstract This study evaluated the chemopreventive efficacy of the pure soy isoflavone genistein and of a soy isoflavone mixture (PTI G-4660) containing roughly 90% genistein in an ER-positive breast cancer model in rats. Female Sprague Dawley rats were injected i.v. with N-nitroso-N -methylurea (MNU) at 50 days of age. In a model examining the effects on cancer initiation, promotion, and progression, rats were fed either a standard Teklad diet or a diet supplemented with genistein (200 or 2000 mg/kg diet) beginning at 43 d of age. Supplemented or standard diets were administered continuously thereafter until the end of the study. In a separate study testing the effects on progression, rats were administered standard Teklad diet or diet supplemented with PTI G-4660 (2000 mg/kg diet) beginning at 55 d of age. All rats were weighed weekly, palpated for mammary tumors twice per week, and checked daily for signs of toxicity. The studies were terminated 126 d after MNU treatment and tumors were weighed. After 126 days, genistein at 200 and 2000 mg/kg diet decreased tumor incidence in a dose-dependent fashion by 15 and 20% (p<0.05), respectively, and significantly decreased tumor multiplicity by 49.6 and 60.3% (p<0.05), respectively. PTI non-significantly decreased tumor incidence by 14% and tumor multiplicity by 24%. In addition, gene expression profiling of livers from rats treated with standard Teklad diet or genistein revealed pathways modified by genistein which may be useful as biomarkers. Citation Format: Holly L. Nicastro, Ronald A. Lubet, Barbara K. Dunn, Clinton J. Grubbs. Genistein and soy isoflavone isolate decreased tumor incidence and multiplicity in a Sprague-Dawley ER-positive breast cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4873. doi:10.1158/1538-7445.AM2013-4873

8:48 AM Abstract No. 191 - ■ Dr. Constantin Cope Medical Student Research Award High-field MRI accurately quantifies tumor uptake of therapeutic iron-oxide nanoparticles in the McA-RH7777 rat model of liver cancer

Purpose The rationale for this study was to develop and validate methods to non-invasively quantify drug delivery to tumors. The ideal animal model of hepatocellular carcinoma (HCC) would have histological similarity to human HCC yet permit intraarterial (IA) delivery of therapies. The hypervascular McA-RH7777 tumor in the diminutive Buffalo rat resembles HCC histologically, while the N1S1 tumor in the larger Sprague-Dawley rat is hypovascular. We tested the hypotheses that: a) hypervascular McA tumors can be grown in Sprague-Dawley rats; and b) 7T magnetic resonance imaging (MRI) can quantify intra-tumoral uptake of doxorubicin-loaded superparamagnetic iron oxide nanoparticles (DOX-SPIOs) in this model. Materials and Methods We implanted McA cells into multiple sites in the livers of 18 Sprague-Dawley rats. In successfully inoculated animals, we delivered DOX-SPIOs to tumors via the intravenous (IV) (n=9) or IA (n=11) route. Three identical sets of nanoparticle phantoms were used to validate image analysis methods. We obtained pre- and post-treatment T2*-weighted images using 7T MRI, and obtained ΔR2* from mean signal intensities of tumors in these images. We measured tumor iron concentration ([Fe]), an indicator of DOX-SPIO uptake, using mass spectroscopy. The primary outcome variable was the Pearson coefficient (r) to assess linear correlation between ΔR2* and [Fe]. Results Tumors grew successfully in 13/18 animals (72%). Mean maximum tumor diameter (Dmax) was 0.83 ± 0.25 cm (range: 0.31-1.42 cm). Phantom studies revealed a strong positive correlation between ΔR2* and [Fe], with r=0.99 (p Conclusion McA tumors can successfully be grown in Sprague-Dawley rats. MRI quantification of intra-tumoral uptake strongly correlated with iron concentrations in pathological specimens, suggesting that MRI may be used to quantify uptake of iron-oxide nanotherapeutics. In the future, these imaging methods could potentially be used by interventional oncologists as a tool to quantify drug delivery in patients.

Changes in protein expression and distribution of spinal CCR2 in a rat model of bone cancer pain

Accumulating evidence suggests that chemokine CC motif receptor 2 (CCR2) plays an important role in neuropathic pain. It has been shown that spinal CCR2 is upregulated in several neuropathic pain models and expressed by neuronal and glial cells in the spinal cord. In this study, we investigated the expression changes and cellular localization of spinal CCR2 in a rat model of bone cancer induced by Walker 256 cell inoculation. The present results indicated that mechanical allodynia progressively increased in bone cancer pain (BCP) rats. Western blot and immunohistochemical analysis demonstrated that the expression of CCR2 in the spinal cord was significantly increased on day 6, 12, and 18 in BCP rats, with a peak on day 6. Furthermore, double immunofluorescence labeling indicated that CCR2 was expressed by both microglia and neurons in the spinal cord. These results suggest that CCR2 may be involved in the development of BCP, and that targeting CCR2 may be a new strategy for the treatment of BCP.

Protective effect of melatonin against Adriamycin-induced cardiotoxicity

The aim of this in vivo study was to explore the protective properties of melatonin against Adriamycin-induced myocardial toxicity. A rat model of breast cancer was established and the rats were randomly divided into the blank group (Blank), the solvent group [Diss; dehydrated alcohol: physiological saline (1:9)], the Adriamycin group (ADM), the melatonin group (MLT) and the melatonin + Adriamycin group (M+A). The concentrations of lipid peroxide (LPO), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in myocardial tissues were detected, the changes in myocardial tissues were observed using light microscopy and electron microscopy, and the 1-month survival rates of each group of rats were compared. Breast cancer was established in 116 rats. In the ADM group, the concentration of LPO was higher and the concentrations of SOD and GSH-Px were significantly lower than those in the blank group. In the M+A group, compared with the ADM group, the concentration of LPO was lower (P<0.05) and the concentrations of SOD and GSH-Px were higher (P<0.05). It was observed using light and electron microscopy that the myocardial injuries to the M+A group were significantly alleviated in comparison with those in the ADM group; the 1-month survival rate in the M+A group was higher than that in the ADM group. Melatonin may have a protective role in the myocardium by reducing Adriamycin-induced myocardial oxidative damage.

A new rat model of prostate cancer.

The current status of immunotherapy of cancer dictates that tumour cells should express appropriate antigenic peptides on the cell surface associated with MHC class I antigen. Therapies designed to activate immunity against cell surface expressed target peptides are required to induce antigen specific cytotoxic T-lymphocytes (CTL) capable of mediating tumour rejection and that such immune responses should produce immunological memory. The necessity for both MHC class I (CTL response) and class II (T-helper response) - restricted responses has been well documented and the nature of tumour antigens expressed on a wide variety of human cancers widely reported.

Stage-dependent anti-allodynic effects of intrathecal Toll-like receptor 4 antagonists in a rat model of cancer induced bone pain

It has been reported that Toll-like receptor 4 (TLR4), which plays an important role in glial activation in neuropathic pain, is significantly increased in cancer pain. The present study was designed to assess the role of TLR4 in cancer-induced bone pain (CIBP) by intrathecal administration of TLR4 signaling pathway blocker naloxone or lipopolysaccharide Rhodobacter sphaeroides (LPS-RS). The rats developed significant mechanical allodynia from day 8 after intratibial Walker 256 inoculation. Intrathecal injection of naloxone or LPS-RS at day 8 significantly attenuated mechanical allodynia as shown by increased paw withdrawal thresholds. In contrast, the same pharmacological treatment showed no or slight pain relieving effect at day 16. Our findings demonstrate that the spinal TLR4 signaling pathway contributes to the mechanism underlying CIBP in a stage-dependent manner in rats, and it may be an efficacious target at early stage for the treatment in the future.

Optimization extraction of Ganoderma lucidum polysaccharides and its immunity and antioxidant activities

Extraction of Ganoderma lucidum polysaccharides (GLP) was optimized by response surface method (RSM). By running the optimization program with design expert within the experimental range investigated, the following optimum values were obtained: extraction time 230min; extraction temperature 95°C, and extraction number 5. The predicted polysaccharides production was 1.45%. Results showed that GLP significantly reduced the levels of serum IL-6 and TNF-α levels and increased the levels of serum IL-2, IL-4 and IL-10 in GLP-treated rats compared to gastric cancer model rats. In addition, administration of Ganoderma lucidum polysaccharides to GLP-treated group of rats improved the levels of serum and gastric tissue SOD, CAT and GSH-Px toward the control values in a dose-dependent manner. These findings show that GLP can enhance immunity and antioxidant activities in gastric cancer rats.

Detrimental effects of fluvastatin on plasma lipid metabolism in rat breast carcinoma model

From clinical practice, obvious positive effects of statins on plasma lipid metabolism are well known. On the other hand, there are several experimental rodent studies, where these beneficial effects were not confirmed. The effects of fluvastatin on selected serum lipid parameters in a rat model of experimental breast cancer were determined. The drug was dietary administered at two concentrations of 20 and 200 mg/kg. At the end of the study (experiment duration - 18 weeks) the blood from each animal was collected and serum lipid parameters were evaluated. Fluvastatin in both treated groups significantly increased parameters of serum lipids (mostly in a dose dependent manner). Fluvastatin in both treated groups of animals significantly increased serum levels of triacylglycerols, total cholesterol, and LDL-, HDL-, VLDL-cholesterol when compared to the control group. Our results pointed out to the apparent harmful effects of fluvastatin on plasma lipid metabolism in rat mammary carcinogenesis. Based on our previous results, it seems that rats commonly used in cancer model studies are generally unresponsive to the hypocholesterolemic effects of statins.

Omega-3 Fatty Acids Inhibit Tumor Growth in a Rat Model of Bladder Cancer

Omega-3 (ω-3) fatty acids have been tested on prevention and treatment of several cancer types, but the efficacy on “in vivo” bladder cancer has not been analyzed yet. This study aimed at evaluating the chemopreventive efficacy of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) mixture in an animal model of bladder cancer. Forty-four male Wistar rats were divided into 4 groups during a 20-week protocol: control; carcinogen—N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN); ω-3 (DHA + EPA); and ω-3 + BBN. BBN and ω-3 were given during the initial 8 weeks. At week 20 blood and bladder were collected and checked for the presence of urothelium lesions and tumors, markers of inflammation, proliferation, and redox status. Incidence of bladder carcinoma was, control (0%), ω-3 (0%), BBN (65%), and ω-3 + BBN (62.5%). The ω-3 + BBN group had no infiltrative tumors or carcinoma in situ, and tumor volume was significantly reduced compared to the BBN (0.9 ± 0.1 mm3 versus 112.5 ± 6.4 mm3). Also, it showed a reduced MDA/TAS ratio and BBN-induced serum CRP, TGF-β1, and CD31 were prevented. In conclusion, omega-3 fatty acids inhibit the development of premalignant and malignant lesions in a rat model of bladder cancer, which might be due to anti-inflammatory, antioxidant, anti-proliferative, and anti-angiogenic properties.

Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

We investigated the correlation between plasma ratio of dihydrouracil/uracil (UH2/Ura), a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU) treatment efficacy in rats with colorectal cancer (CRC). 5-FU pharmacokinetic and pharmacodynamic studies were performed using DPD circadian variation in rats with 1,2-dimethylhydrazine-induced CRC. By plotting tumor volume after 5-FU treatment against pre-therapeutic plasma UH2/Ura, we inferred a linear relationship (r(2)=0.988). 5-FU concentration fluctuations induced by DPD activity variation affected tumor volume. In CRC patients receiving proper dosing regimens, plasma UH2/Ura could be an indirect biomarker for predicting 5-FU treatment efficacy, tumor growth, and 5-FU doses.

Estrogen Inhibits Colon Polyp Formation by Reducing Angiogenesis in a Carcinogen-Induced Rat Model

Objective. To study the effects of estrogen on colon polyp formation, proliferation, and angiogenesis on a rat model of colon cancer induced by dimethylhydrazine (DMH). Methods. Thirty-six female ovariectomized (OVX) rats were randomly divided into 3 groups: (I) control group (administrated with vehicles weekly), (II) DMH group (administrated with DMH weekly), and (III) DMH + E2 group (administrated with DMH and 17β-estradiol weekly). The incidence, volumes, and multiplicity of colon polyps in each group were evaluated. The microvessel density (MVD), the expressions of Proliferating Cell Nuclear Antigen (PCNA), and the expressions of HIF-1α and VEGF in polyps were detected in each group. Results. Estrogen reduced the multiplicity, volumes, and the PCNA expressions of DMH-induced colon polyps. The MVD in DMH + E2 group was significantly lower than that in DMH group. Estrogen treatment decreased the HIF-1α and VEGF expressions at both mRNA and protein level. Conclusion. Estrogen replacement was protective for ovariectomized rats from DMH-induced carcinogenesis, and one of the mechanisms for this was due to estrogen's inhibitive effects on blood vessel formation by downregulating VEGF and HIF-1α expressions.

MTOR Inhibitor RAD001 Promotes Metastasis in a Rat Model of Pancreatic Neuroendocrine Cancer

Inhibition of mTOR is commonly considered a valid target in cancer treatment, but this assertion does not address effects on the immune microenvironment that may be detrimental to cancer treatment. Here we show how administration of the mTOR inhibitor RAD001 (everolimus) results in the occurrence of distant metastasis in a rat model of pancreatic cancer. RAD001 was administered twice weekly for 4.5 weeks as a single treatment or combined with [(177)Lu-DOTA,Tyr3]octreotate ((177)Lu-DOTATATE), where the latter targets the somatostatin receptor-2. The hypothesized synergistic therapeutic effect of RAD001 combined with (177)Lu-DOTATATE was, however, not observed in our experiments. The combination was shown to be less effective than (177)Lu-DOTATATE alone. Unexpectedly, tumor metastasis was observed in 77% of the subjects treated with RAD001, either alone or as part of the combination treatment. This was a striking effect, because metastasis did not occur in control or (177)Lu-DOTATATE-treated animals, including those where the primary tumor was surgically removed. These findings may be important clinically among noncompliant patients or patients that discontinue RAD001 therapy because of adverse effects.

Mapping of Three Genetic Determinants of Susceptibility to Estrogen-Induced Mammary Cancer within the Emca8 Locus on Rat Chromosome 5

The ACI rat model of 17β-estradiol (E2)-induced mammary cancer has gained wide use in the study of breast cancer etiology, prevention, and genetics. Emca8, a QTL that determines susceptibility to E2-induced mammary cancer, was previously mapped to rat chromosome 5 (RNO5) in an intercross between resistant Brown Norway (BN) and susceptible ACI rats. In this study, a panel of congenic rat strains, each of which carries BN alleles across a defined segment of RNO5 on the ACI genetic background, was generated and used to map more precisely the Emca8 determinants of mammary cancer susceptibility. Three distinct genetic determinants were localized within Emca8, and two of these were mapped to intervals of less than 15 megabases. Emca8.1 harbors Cdkn2a, Cdkn2b, and other genes and is orthologous to the 9p21 breast cancer locus identified in genome-wide and candidate gene association studies. Emca8.2 harbors Cdkn2c and other genes and is orthologous to the 1p32 locus in humans that is frequently deleted in breast cancers. Both Emca8.1 and Emca8.2 harbor copy number variants that are orthologous to copy number variant regions in humans. Gene expression profiles were defined for mammary tissues from E2-treated ACI and ACI.BN-Emca8 rats to define the impact of Emca8 on gene expression and identify differentially expressed genes residing within Emca8.1 and Emca8.2. This study further illustrates the relevance of the ACI rat model of E2-induced mammary cancer for identifying novel genetic determinants of breast cancer susceptibility and defining the mechanisms through which estrogens contribute to breast cancer development. Cancer Prev Res; 6(1); 59-69. ©2012 AACR.

Bifidobacterium infantis-mediated HSV-TK/GCV suicide gene therapy induces both extrinsic and intrinsic apoptosis in a rat model of bladder cancer

Bladder cancer is the most common cancer in the urological tract. Here, we investigated the molecular pathways involved in the apoptosis of rodent bladder cancer, which was treated with Bifidobacterium infantis (BI)-mediated herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) suicide gene therapy. We engineered the BI-TK system, which consists of BI with the recombinant plasmid PGEX-1λT carrying HSV-TK (that is, TK) gene. Tumor-bearing rats were randomly divided into three groups and tail vein injected with normal saline (group A), BI/PGEX-1λT (group B) or BI-TK (group C), followed by intraperitoneal injection of GCV. The BI-TK/GCV system (group C) was shown to inhibit tumor growth and caused the apoptosis of tumor cells as assessed by in situ terminal transferase dUTP nick-end labeling assay. While varied extents of apoptosis were detected in tumor cells from all groups, tumor cells treated with BI-TK/GCV system (group C) exhibited the highest level of apoptosis (P < 0.05), consistent with our previous studies. Furthermore, we found that the expression levels of Fas, FasL, Cyt-C and caspase-9 in tumor tissues derived from group C were significantly higher than the other two groups (P < 0.001). Therefore, our results have demonstrated that the BI-TK/GCV therapy system exhibits a sustainable antitumor growth activity in the rodent model of bladder cancer. Mechanistically, both extrinsic and intrinsic apoptosis pathways are involved in the BI-TK/GCV antitumor functionality.

Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats

To investigate the hepatic dihydropyrimidine dehydrogenase (DPD) activity in colorectal cancer (CRC), which is critically important to create a patient-specific dosing regimen, we performed 5-FU pharmacokinetic studies in 1,2-dimethylhydrazine-induced CRC model rats (CRC rats). After rats received 5-FU intravenous (IV) bolus injections, the area under the plasma concentration-time curve (AUC) and elimination half-life (t 1/2) in CRC rats (10.02±0.37μg h mL(-1), 0.30±0.02h, respectively) were significantly lower than that in control rats (13.46±1.20μg h mL(-1), 0.52±0.05h, respectively), whereas total plasma clearance (CLtot) in CRC rats (2.01±0.07L h(-1) kg(-1)) was significantly increased compared with that in control rats (1.54±0.14L h(-1) kg(-1)). Conversely, the avoidance ratio of the hepatic first-pass effect was approximately 20% lower than that in control rats. Of interest is that hepatic DPD activity levels and the dihydrouracil-uracil ratio (UH2/Ura ratio) in plasma, which may act as a potential biomarker to evaluate hepatic DPD activity levels, were significantly increased in CRC rats. These results suggest that the decrease of hepatic availability in CRC rats is brought about by the increase in intrinsic clearance induced by the increase in DPD activity, resulting in a decrease in AUC and t 1/2 and an increase in CLtot after 5-FU IV bolus injection. Along with a proper dosing regimen for patients with CRC, a hepatic DPD activity monitoring system, such as the determination of UH2/Ura ratio in plasma, is desirable.

Nanoparticle Mediated Thermoablation in Tumors of the Spinal Column in a Rat Model of Metastatic Breast Cancer

Nanoparticle Mediated Thermoablation in Tumors of the Spinal Column in a Rat Model of Metastatic Breast Cancer