Rat Breast Tumor Research Articles

Science to Practice: Will Randomized Prospective Clinical Trials Be Necessary for RF Ablation of Large Liver Tumors with Liposomal Doxorubicin?

HomeRadiologyVol. 255, No. 1 Next SCIENCE TO PRACTICEScience to Practice: Will Randomized Prospective Clinical Trials Be Necessary for RF Ablation of Large Liver Tumors with Liposomal Doxorubicin?Evan C. UngerEvan C. UngerEvan C. UngerPublished Online:Mar 10 2010https://doi.org/10.1148/radiol.092424MoreSectionsFull textPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In AbstractThe study by Solazzo et al, defining the mechanisms of cell stress and repair, provides a scientific backstop to help support the clinical use of liposomal doxorubicin at radiofrequency ablation.References1 Solazzo S, Ahmed M, Schor-Bardach Ret al.. Liposomal doxorubicin increases radiofrequency ablation–induced tumor destruction by increasing cellular oxidative and nitrative stress and accelerating apoptotic pathways. Radiology 2010;255(1):62–74. Link, Google Scholar2 Curley SA. Radiofrequency ablation of malignant liver tumors. Oncologist 2001;6(1):14–23. Crossref, Medline, Google Scholar3 Chen MH, Yang W, Yan Ket al.. Large liver tumors: protocol for radiofrequency ablation and its clinical application in 110 patients—mathematic model, overlapping mode, and electrode placement process. Radiology 2004;232(1):260–271. Link, Google Scholar4 Goldberg SN, Girnan GD, Lukyanov ANet al.. Percutaneous tumor ablation: increased necrosis with combined radiofrequency ablation and intravenous liposomal doxorubicin in a rat breast tumor model. Radiology 2002;222(3):797–804. Link, Google Scholar5 Goldberg SN, Kamel IR, Kruskal JBet al.. Radiofrequency ablation of hepatic tumors: increased tumor destruction with adjuvant liposomal doxorubicin therapy. AJR Am J Roentgenol 2002;179(1):93–101. Crossref, Medline, Google Scholar6 Doxil. Centocor Ortho Biotech Products. http://www.doxil.com/assets/DOXIL_PI_Booklet.pdf. Accessed September 2009. Google Scholar7 Rivera E. Liposomal anthracyclines in metastatic breast cancer: clinical update. Oncologist 2003;8(suppl 2):3–9. Crossref, Medline, Google ScholarArticle HistoryPublished online: Mar 10 2010Published in print: Apr 2010 FiguresReferencesRelatedDetailsRecommended Articles Therapeutic Effects of CT-guided Radiofrequency Ablation with Concurrent Platinum-Doublet Chemotherapy in a Rabbit VX2 Lung Tumor ModelRadiology2016Volume: 283Issue: 2pp. 391-398Targeting STAT3 to Suppress Systemic Pro-Oncogenic Effects from Hepatic Radiofrequency AblationRadiology2017Volume: 286Issue: 2pp. 524-536Hepatic Thermal Ablation: Effect of Device and Heating Parameters on Local Tissue Reactions and Distant Tumor GrowthRadiology2016Volume: 281Issue: 3pp. 782-792Radiofrequency Ablation Followed by Surgical Excision versus Lumpectomy for Early Stage Breast Cancer: A Randomized Phase II Clinical TrialRadiology2018Volume: 289Issue: 2pp. 317-324Science to Practice: Molecular-targeted Drug Delivery in Combination with Radiofrequency Ablation of Liver Cancer: A Magic Bullet?Radiology2017Volume: 285Issue: 2pp. 333-335See More RSNA Education Exhibits Novel Image-Guided Micro-Invasive Percutaneous Treatments of Breast Lesions: Where Do We Stand?Digital Posters2019The Fast and the Furious: Rapid Progression of HCC After Locoregional Therapy — A Tri-Institutional Collaboration on Imaging PatternsDigital Posters2018Imaging Follow-Up After Radiofrequency Ablation (RFA) in Patients with Early Stage Non-Small Cell Lung Cancer (NSCLC): An Experience-Based Pictorial ReviewDigital Posters2018 RSNA Case Collection Solitary breast plasmacytomaRSNA Case Collection2021AIDS-associated Kaposi sarcomaRSNA Case Collection2020Medication Related Osteonecrosis of the Jaw RSNA Case Collection2021 Vol. 255, No. 1 Metrics Altmetric Score PDF download

Specific overexpression of cyclin E·CDK2 in early preinvasive and primary breast tumors in female ACI rats induced by estrogen.

Overexpressed Aurora A, amplified centrosomes, and aneuploidy are salient features of estrogen-induced mammary preinvasive lesions and tumors in female August--Copenhagen Irish (ACI) rats. Intimately involved in these events are cyclins and their associated cyclin-dependent kinase (CDK) partners. Cyclin E1·CDK2 overexpression plays an important dual role in late G1/S phase of the cell cycle in cancer cells. It increases DNA replication providing growth advantage to cancer cells and facilitates aberrant centrosome duplication, generating chromosomal instability and aneuploidy leading to tumor development. Presented herein, a 24.0- and 45.0-fold elevation in cyclin E1 and CDK2 was found in 17β-estradiol (E(2))-induced ACI rat mammary tumors (MTs), respectively. Cyclin E·CDK2 positive staining was confined to the large round cells found within focal dysplasias, ductal carcinomas in situ, and invasive MTs. Co-immunoprecipitation and in vitro kinase activity of these tumors revealed that these cell cycle entities are functional. When mammary tissue derived from untreated normal, E(2)-induced hyperplasia and primary tumors were normalized to cyclin E1 levels, low molecular weight (LMW) cyclin E1 forms (33- and 45-kDa) were detected in all of these tissue groups. Moreover, increasing concentrations of protease inhibitor in tissue lysates resulted in a marked reduction of LMW forms, indicating that the presence of cyclin E1 LMW forms can be markedly reduced. Significant increases in cyclin E1 mRNA (2.1-fold) were detected in primary ACI rat E(2)-induced breast tumors, and quantitative real-time polymerase chain reaction revealed a 20% amplification of the cyclin E1 gene (CCNE1). Collectively, these results support the involvement of cyclin E1·CDK2 in centrosome overduplication during each stage of E(2)-induced mammary tumorigenesis.

Immunomodulatory Effects of Radiofrequency Ablation in a Breast Cancer Model

Radiofrequency ablation (RFA), a minimally invasive surgical procedure has an increasing application in the surgical treatment of tumors. Data indicate that RFA might stimulate anti-cancer immunity possibly through the induction of necrosis and heat shock proteins (HSP) expression. This study tests a hypothesis that RFA leads to bidirectional immunoregulation. Experimental rat breast tumors were treated with RFA, surgical excision or sham operation. RFA resulted in the highest NK cells infiltration, increased HSP70 expression and activation of caspase-3 enzyme in the tumor margins. A significant reduction of the circulatory regulatory T (Treg) cells was found in both RFA- and excision-treated rats, although less pronounced in the RFA-group. The splenocyte proliferation to tumor cell lysate was stronger in the RFA-treated rats in comparison with untreated tumor-bearing rats. The potential role of self-HSP for immunomodulation was examined using in vitro proliferation assay to tetanus toxoid using human peripheral leukocytes. The response to the tetanus toxoid was significantly suppressed by HSP90 plus auto-antibodies versus HSP90 or auto-antibodies alone. In conclusion, RFA reduced the circulatory Tregs although not as efficient as tumor excision. HSPs plus natural antibodies suppress the anti-tumor response probably by stimulating Tregs. Therefore, RFA may play a role in anti-cancer therapy if combined with Tregs suppression.

Abstract A221: Results of preclinical and clinical phase I/II open-label dose-ranging trial with HE3235, a synthetic adrenal hormone, in castrate-resistant prostate cancer

Abstract Background: HE3235 (17α-ethynyl-5α-androstane-3α, 17β-diol) is an androstenediol analog, which shows activity in preclinical CRPC and breast cancer models. HE3235 decreased AR expression in LNCaP cells in vitro, in the CRPC LuCaP 35V xenograft, and suppressed ER-a expression in MNU-induced breast tumors in rats. HE3235 also decreased intra-tumoral androgen synthesis (both T and DHT) in the LuCaP 35V tumors. In toxicology studies, it decreased steroidogenesis (DHEA and T in male dogs and sex steroids in female rats). HE3235 did not inhibit CYP17 in H295R adrenal tumor cells, but inhibited the conversion of d-cholesterol to d-pregnenolone. We are therefore conducting a Phase I/II clinical study in CRPC patients to determine safety, tolerance, pharmacokinetics, maximum tolerated dose and activity of this compound. Methods: Men with CRPC and an ECOG PS of <2 who progressed either radiographically or biochemically through at least one taxane-containing chemotherapy regimen are eligible. HE3235 is given orally, twice daily in cohorts of 3–6 pts. Cohorts were defined by doses of 10 mg, 20 mg, 30 mg, 50 mg or higher until MTD is observed. Cohorts may be expanded based on dose limiting toxicity, activity or pharmacokinetics demonstrating adequate blood concentrations of drug to deliver a therapeutic effect. Subjects were treated on 28-day cycles until toxicity or disease progression. Scans were obtained every 2 cycles. The Prostate Cancer Consortium Clinical Trials consortium sites were supported by a grant form the Department of Defense. Results: 22 subjects have been treated to date at doses of 10 mg/day (n=7), 20 mg/day (n=9) and 30 mg/day (n=6). Dose escalation continues to determine the MTD. Pharmacokinetics was dose proportional with a drug half-life of 11–14 hours. HE3235 was well tolerated. Nine of 22 subjects experienced a drop in PSA during treatment with 6 of 22 equal to or greater than 20%. No patient had a 50% decline in PSA. Eight of 17 (47%) subjects who were evaluable for response had stable disease. Median time to progression was 56 days (IQR 55, 224) for 10 mg/day, 112 days (IQR 56, 168) for 20 mg/days, 112 days (IQR 56, >122) for 30 mg/day and 112 days (IQR 56, 168) for all 22 subjects. Conclusion: HE3235 is a novel, small orally delivered compound with preclinical activity for CRPC. It is well tolerated through a dose of 30 mg, and has a T1/2 linear to dose in cohorts tested to date. The trial continues to accrue, and a cohort of patients with chemotherapy-naïve CRPC will be enrolled into the ongoing Phase I/II Study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A221.

Dendra2 Photoswitching through the Mammary Imaging Window

In the last decade, intravital microscopy of breast tumors in mice and rats at single-cell resolution1-4 has resulted in important insights into mechanisms of metastatic behavior such as migration, invasion and intravasation of tumor cells5, 6, angiogenesis3 and immune cells response7-9. We have recently reported a technique to image orthotopic mammary carcinomas over multiple intravital imaging sessions in living mice10. For this, we have developed a Mammary Imaging Window (MIW) and optimized imaging parameters for Dendra211 photoswitching and imaging in vivo. Here, we describe the protocol for the manufacturing of MIW, insertion of the MIW on top of a tumor and imaging of the Dendra2- labeled tumor cells using a custom built imaging box. This protocol can be used to image the metastatic behavior of tumor cells in distinct microenvironments in tumors and allows for long term imaging of blood vessels, tumor cells and host cells.

Dendra2 Photoswitching through the Mammary Imaging Window

In the last decade, intravital microscopy of breast tumors in mice and rats at single-cell resolution1-4 has resulted in important insights into mechanisms of metastatic behavior such as migration, invasion and intravasation of tumor cells5, 6, angiogenesis3 and immune cells response7-9. We have recently reported a technique to image orthotopic mammary carcinomas over multiple intravital imaging sessions in living mice10. For this, we have developed a Mammary Imaging Window (MIW) and optimized imaging parameters for Dendra211 photoswitching and imaging in vivo. Here, we describe the protocol for the manufacturing of MIW, insertion of the MIW on top of a tumor and imaging of the Dendra2- labeled tumor cells using a custom built imaging box. This protocol can be used to image the metastatic behavior of tumor cells in distinct microenvironments in tumors and allows for long term imaging of blood vessels, tumor cells and host cells.

4-Aminobiphenyl Downregulation of NAT2 Acetylator Genotype-Dependent N- and O-acetylation of Aromatic and Heterocyclic Amine Carcinogens in Primary Mammary Epithelial Cell Cultures from Rapid and Slow Acetylator Rats

Aromatic and heterocyclic amine carcinogens present in the diet and in cigarette smoke induce breast tumors in rats. N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) enzymes have important roles in their metabolic activation and deactivation. Human epidemiological studies suggest that genetic polymorphisms in NAT1 and/or NAT2 modify breast cancer risk in women exposed to these carcinogens. p-Aminobenzoic acid (selective for rat NAT2) and sulfamethazine (SMZ; selective for rat NAT1) N-acetyltransferase catalytic activities were both expressed in primary cultures of rat mammary epithelial cells. PABA, 2-aminofluorene, and 4-aminobiphenyl N-acetyltransferase and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine and N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline O-acetyltransferase activities were two- to threefold higher in mammary epithelial cell cultures from rapid than slow acetylator rats. In contrast, SMZ (a rat NAT1-selective substrate) N-acetyltransferase activity did not differ between rapid and slow acetylators. Rat mammary cells cultured in the medium supplemented 24 h with 10muM ABP showed downregulation in the N-and O-acetylation of all substrates tested except for the NAT1-selective substrate SMZ. This downregulation was comparable in rapid and slow NAT2 acetylators. These studies clearly show NAT2 acetylator genotype-dependent N- and O-acetylation of aromatic and heterocyclic amine carcinogens in rat mammary epithelial cell cultures to be subject to downregulation by the arylamine carcinogen ABP.

Multifunctional nanocarriers for mammographic quantification of tumor dosing and prognosis of breast cancer therapy

Nanoscale therapeutic interventions are increasingly important elements in the portfolio of cancer therapeutics. The efficacy of nanotherapeutics is dictated, in part, by the access they have to tumors via the leaky tumor vasculature. Yet, the extent of tumor vessel leakiness in individual tumors varies widely resulting in a correspondingly wide tumor dosing and resulting range of responses to therapy. Here we report the design of a multifunctional nanocarrier that simultaneously encapsulates a chemotherapeutic and a contrast agent which enables a personalized nanotherapeutic approach for breast cancer therapy by permitting tracking of the nanocarrier distribution by mammography, a widely used imaging modality. Following systemic administration in a rat breast tumor model, imaging demonstrated a wide range of intratumoral deposition of the nanocarriers, indicating variable tumor vessel leakiness. Notably, specific tumors that exhibited high uptake of the nanocarrier as visualized by imaging were precisely the animals that responded best to the treatment as quantified by low tumor growth and prolonged survival.

Investigation of biphasic tumor oxygen dynamics induced by hyperoxic gas intervention: the dynamic phantom approach

We have developed dynamic tumor vascular phantoms and utilized them to investigate the biphasic behavior of increases in light absorption, which is directly associated with oxygenated hemoglobin concentration that was observed in vivo from rat breast tumor experiments during carbogen/oxygen inhalation. The experimental setup for the phantom study included a continuous-wave, multichannel, near-infrared spectroscopy (NIRS) system and syringe pumps to drive the simulated blood through the dynamic vascular phantoms. The results from such phantom experiments clearly show that the two time constants observed in tumor oxygenation dynamics in vivo can result from two different perfusion rates or two different blood flow velocities. We provide experimental support for our previous hypothesis: the biphasic tumor hemodynamic feature stems from a well-perfused and poorly perfused region that could be detected with the two time constants of the NIRS signals. With a multichannel approach, noninvasive NIRS measurements may have useful and prognostic values to quantify the therapeutic effects of cancer treatments.

Evaluation of Tumor Angiogenesis with a Second-Generation US Contrast Medium in a Rat Breast Tumor Model

ObjectiveTumor angiogenesis is an important factor for tumor growth, treatment response and prognosis. Noninvasive imaging methods for the evaluation of tumor angiogenesis have been studied, but a method for the quantification of tumor angiogenesis has not been established. This study was designed to evaluate tumor angiogenesis in a rat breast tumor model by the use of a contrast-enhanced ultrasound (US) examination with a second-generation US contrast agent.Materials and MethodsThe alkylating agent 19N-ethyl-N-nitrosourea (ENU) was injected into the intraperitoneal cavity of 30-day-old female Sprague-Dawley rats. Three to four months later, breast tumors were detected along the mammary lines of the rats. A total of 17 breast tumors larger than 1 cm in nine rats were evaluated by gray-scale US, color Doppler US and contrast-enhanced US using SonoVue. The results were recorded as digital video images; time-intensity curves and hemodynamic parameters were analyzed. Pathological breast tumor specimens were obtained just after the US examinations. The tumor specimens were stained with hematoxylin and eosin (H & E) and the expression of CD31, an endothelial cell marker, was determined by immunohistochemical staining. We also evaluated the pathological diagnosis of the tumors and the microvessel density (MVD). Spearman's correlation and the Kruskal-Wallis test were used for the analysis.ResultsThe pathological diagnoses were 11 invasive ductal carcinomas and six benign intraductal epithelial proliferations. The MVD did not correlate with the pathological diagnosis. However, blood volume (BV) showed a statistically significant correlation with MVD (Spearman's correlation, p < 0.05).ConclusionContrast-enhanced US using a second-generation US contrast material was useful for the evaluation of tumor angiogenesis of breast tumors in the rat.

Medical hyperspectral imaging to facilitate residual tumor identification during surgery

Introduction: Adequate evaluation of breast tumor resection at surgery continues to be an important issue in surgical care, as over 30% of postoperative tumors recur locally unless radiation is used to destroy remaining tumor cells in the field. Medical Hyperspectral Imaging (MHSI) delivers near-real time images of biomarkers in tissue, providing an assessment of pathophysiology and the potential to distinguish different tissues based on spectral characteristics.Method: We have used an experimental DMBA-induced rat breast tumor model to examine the intraoperative utility of MHSI, in distinguishing tumor from normal breast and other tissues. Rats bearing tumors underwent surgical exposure and MHSI imaging, followed by partial resection of the tumors, then MHSI imaging of the resection bed, and finally total resection of tumors and of grossly normal-appearing glands. Resected tissue underwent gross examination, MHSI imaging, and histopathological evaluation.Results: An algorithm based on spectral characteristics of tissue types was developed to distinguish between tumor and normal tissues. Tissues including tumor, blood vessels, muscle, and connective tissue were clearly identified and differentiated by MHSI. Fragments of residual tumor 0.5 - 1 mm in size intentionally left in the operative bed were readily identified. MHSI demonstrated a sensitivity of 89% and a specificity of 94% for detection of residual tumor, comparable to that of histopathological examination of the tumor bed (85% and 92%, respectively).Conclusion: We conclude that MHSI may be useful in identifying small residual tumor in a tumor resection bed and for indicating areas requiring more extensive resection and more effective biopsy locations to the surgeon. 3

Inhibition of AP‐1 activation in DMBA‐induced rat breast tumors by dietary soy protein

Inhibition of AP‐1 activation in DMBA‐induced rat breast tumors by dietary soy protein

BRCA1 Suppresses Osteopontin-mediated Breast Cancer

BRCA1 is a well described breast cancer susceptibility gene thought to be involved primarily in DNA repair. However, mutation within the BRCA1 transcriptional domain is also implicated in neoplastic transformation of mammary epithelium, but responsible mechanisms are unclear. Here we show in a rat mammary model system that wild type (WT) BRCA1 specifically represses the expression of osteopontin (OPN), a multifunctional estrogen-responsive gene implicated in oncogenic transformation, particularly that of the breast. WT.BRCA1 selectively binds OPN-activating transcription factors estrogen receptor alpha, AP-1, and PEA3, inhibits OPN promoter transactivation, and suppresses OPN mRNA and protein both from an endogenous gene and a relevant model inducible gene. WT.BRCA1 also inhibits OPN-mediated neoplastic transformation characterized by morphology change, anchorage-independent growth, adhesion to fibronectin, and invasion through Matrigel. A mutant BRCA1 allele (Mut.BRCA1) associated with familial breast cancer lacks OPN suppressor effects, binds to WT.BRCA1, and impedes WT.BRCA1 suppression of OPN. Stable transfection of rat breast tumor cell lines with Mut.BRCA1 dramatically up-regulates OPN protein and induces anchorage independent growth. In human primary breast cancer, BRCA1 mutation is significantly associated with OPN overexpression. Taken together, these data suggest that BRCA1 mutation may confer increased tissue-specific cancer risk, in part by disruption of BRCA1 suppression of OPN gene transcription.

Quantitative dynamic contrast‐enhanced MRI in tumor‐bearing rats and mice with inversion recovery TrueFISP and two contrast agents at 4.7 T

To characterize tumor vascularization by dynamic-contrast enhanced (DCE) MRI using low and medium molecular weight paramagnetic contrast agents (CA) and inversion recovery (IR) true fast imaging with steady state precession (TrueFISP) in tumor-bearing rats and mice. T(1) mapping was performed using IR True FISP in phantoms and in vivo at 4.7 T and validated with a segmented IR gradient-echo (IR GE) method. CA concentration in DCE-MRI studies in vivo was calculated from time-series T(1) maps using the CAs GdDOTA and P792 (low and medium molecular weight, respectively). Standard vascular input functions (VIFs) were measured in the jugular veins and were used for modeling of the CA kinetics with a two-compartment model. In rat breast tumors, vascular permeability (transfer constant K(trans)), fractional plasma volume v(p), and fractional leakage space v(e) were quantified and parametric maps were generated. The IR TrueFISP T(1) was slightly underestimated in phantoms and overestimated in vivo (10%) with respect to IR GE. VIFs showed only small interindividual variation. Mean K(trans) values were 0.062 +/- 0.017 min(-1) for GdDOTA and 0.015 +/- 0.005 min(-1) for P792 (N = 12). Mean v(e) and v(p) values were 0.15 +/- 0.04 (0.09 +/- 0.03) and 0.04 +/- 0.01 (0.03 +/- 0.01) for GdDOTA (P792). DCE-MRI with IR TrueFISP provided absolute values for K(trans), v(p), and v(e). Direct comparison between GdDOTA and P792 revealed significant differences in the VIF, model-fit-quality, permeability, leakage space, and plasma volume. The larger molecular weight CA P792 appears to be better for measuring tumor vascular parameters.

Beneficial effects of soy protein in the initiation and progression against dimethylbenz [a] anthracene-induced breast tumors in female rats

This study was to demonstrate by histological grading whether soy protein protects against dimethylbenz[a]anthracene (DMBA) -induced breast tumors in female rats. At 25 days of age, rats were fed diets containing either casein or soy protein. After 25 days on diets, a single dose of DMBA in sesame oil (80 mg/kg) was administered by gavage. All tumors were detected by palpation. The number of tumors per rat was less in soy group than that in casein group at any time point up to 122 days after DMBA administration. Incidence of tumors was less in soy protein group than that in casein group. Casein group had 20% grade I, 60% grade II, and 20% grade III adenocarcinoma. However, the soy group had 100% grade I adenocarcinoma and no aggressive grade II or grade III tumor. There was a delay in the development of tumor in the soy protein group in comparison to the casein group. Again, unlike casein, the soy group had cessation of angiogenesis at several sites of tumor, and reduced levels of angiogenic markers, VEGF and bFGF. Immunohistochemical analysis of the breast tissues did not show any CD-31 positive stain in soy protein group, whereas some CD-31 positive stain was revealed in casein group, which further suggests that soy protein controls angiogenesis. Furthermore, proliferative index as assessed by Ki-67 staining was less in soy protein group than that in casein group. These findings suggest that the soy protein may protect against the development of a more aggressive breast carcinoma.

2310: Evaluation of tumor perfusion with a second-generation US contrast medium in rat breast tumor model

Objectives: In spite of many studies, method for imaging quantification of tumor perfusion is not established yet. This study is to evaluate the tumor perfusion in rat breast tumor model with contrast-enhanced ultrasound examination using a new second generation ultrasound contrast SonoVue.

Beneficial Effects of Soy Protein in the Development of DMBA‐Induced Breast Tumors in Rats

Beneficial Effects of Soy Protein in the Development of DMBA‐Induced Breast Tumors in Rats

PhIP Carcinogenicity in Breast Cancer: Computational and Experimental Evidence for Competitive Interactions with Human Estrogen Receptor

Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here, we describe our work with the human estrogen receptor alpha (ERalpha), the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, and IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We demonstrate both by computational docking and NMR analysis that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. In vitro assays show that PhIP, in contrast to the other heterocyclic amines, increases cell proliferation in MCF-7 human breast cancer cells and activates the ERalpha receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ERalpha activation. We propose that the mechanism for the tissue-specific carcinogenicity seen in the rat breast tumors and the presumptive human breast cancer associated with the consumption of well-done meat maybe mediated by this receptor activation.

Effect of Photothermal Therapy on Breast Tumor Vascular Contents: Noninvasive Monitoring by Near‐infrared Spectroscopy¶

ABSTRACTThe goal of this study was to investigate the effect of photothermal laser irradiation on rat breast tumor (DMBA‐4) vascular contents. An 805‐nm diode laser was used in our experiment with a power density ranging from 0.32 to 1.27 W/cm2. The dynamic changes of oxygenated hemoglobin and total hemoglobin concentrations, Δ[HbO2] and Δ[Hb]total, in rat tumors during photothermal irradiation were noninvasively monitored by a near‐infrared spectroscopy system. A multichannel thermal detection system was also used simultaneously to record temperatures at different locations within the tumors. Our experimental results showed that: (1) photoirradiation did have the ability to induce hyperthermic effects inside the rat breast tumors in a single exponential trend; (2) the significant changes (P &lt; 0.005) of Δ[HbO2] and Δ[Hb]total in response to a low dosage of laser irradiation (0.32 W/cm2) have a single exponential increasing trend, similar to that seen in the tumor interior temperature; and (3) the increase in magnitude of Δ[Hb]total is nearly two times greater than that of Δ[Hb]total, suggesting that photoirradiation may enhance tumor vascular oxygenation. The last observation may be important to reveal the hidden mechanism of photoirradiation on tumors, leading to improvement of tumor treatment efficiency.

Investigation of bi-phasic tumor oxygen dynamics induced by hyperoxic gas intervention: A numerical study

This study intends to explore the underlying principle of the biphasic behavior of increases in oxygenated hemoglobin concentration that was observed in vivo from rat breast tumors during carbogen/oxygen inhalation. We have utilized the Finite Element Method (FEM) to simulate the effects of different blood flow rates, in several geometries, on the near infrared measurements. The results show clearly that co-existence of two blood flow velocities can result in a bi-phasic change in optical density, regardless of the orientation of vessels. This study supports our previous hypothesis that the bi-phasic tumor hemodynamic feature during carbogen inhalation results from a well-perfused and a poorly perfused region in the tumor vasculature.