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1.  Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma 
We have developed magnetite cationic liposomes (MCLs) and applied them to local hyperthermia as a mediator. MCLs have a positive charge and generate heat under an alternating magnetic field (AMF) by hysteresis loss. In this study, the effect of hyperthermia using MCLs was examined in an in vivo study of hamster osteosarcoma.
MCLs were injected into the osteosarcoma and then subjected to an AMF.
The tumor was heated at over 42°C, but other normal tissues were not heated as much. Complete regression was observed in 100% of the treated group hamsters, whereas no regression was observed in the control group hamsters. At day 12, the average tumor volume of the treated hamsters was about 1/1000 of that of the control hamsters. In the treated hamsters, no regrowth of osteosarcomas was observed over a period of 3 months after the complete regression.
These results suggest that this treatment is effective for osteosarcoma.
PMCID: PMC400754  PMID: 15040804
2.  Obesity promotes 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in female zucker rats 
Breast Cancer Research  2005;7(5):R627-R633.
High body mass index has been associated with increased risk for various cancers, including breast cancer. Here we describe studies using 7,12-dimethylbenz(a)anthracene (DMBA) to investigate the role of obesity in DMBA-induced mammary tumor susceptibility in the female Zucker rat (fa/fa), which is the most widely used rat model of genetic obesity.
Fifty-day-old female obese (n = 25) and lean (n = 28) Zucker rats were orally gavaged with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly for detection of mammary tumors. Rats were killed 139 days after DMBA treatment.
The first mammary tumor was detected in the obese group at 49 days after DMBA treatment, as compared with 86 days in the lean group (P < 0.001). The median tumor-free time was significantly lower in the obese group (P < 0.001). Using the days after DMBA treatment at which 25% of the rats had developed mammary tumors as the marker of tumor latency, the obese group had a significantly shorter latency period (66 days) than did the lean group (118 days). At the end of the study, obese rats had developed a significantly (P < 0.001) greater mammary tumor incidence (68% versus 32%) compared with the lean group. The tumor histology of the mammary tumors revealed that obesity was associated with a significant (P < 0.05) increase in the number of rats with at least one invasive ductal and lobular carcinoma compared with lean rats.
Our results indicate that obesity increases the susceptibility of female Zucker rats to DMBA-induced mammary tumors, further supporting the hypothesis that obesity and some of its mediators play a significant role in carcinogenesis.
PMCID: PMC1242129  PMID: 16168107
3.  Effects of high-isoflavone soy diet vs. casein protein diet and obesity on DMBA-induced mammary tumor development 
Oncology Letters  2010;2(1):29-36.
Obesity and elevated serum insulin growth factor-1 (IGF-1) level are major risk factors in the development of breast cancer. We investigated the long-term effects of high-isoflavone soy intake and obesity on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor development and on serum IGF-1 and binding protein (IGFBP-3) levels. Lean and obese female Zucker rats fed casein or high-isoflavone soy protein were orally gavaged at age 50 days with DMBA and sacrificed after 147 days. The majority of lean casein-fed rats (69%) developed mammary tumors compared to 50% in lean soy-fed rats (P=0.176). In the obese groups, 76% of soy-fed rats developed mammary tumors compared to 15% of obese casein-fed rats (P<0.001). At age 43 days, IGFBP-3 was increased in the lean soy-fed rats compared to the lean casein-fed rats (P<0.05). At age 99 days, soy- and obese casein-fed rats exhibited increased serum IGF-1 compared to the lean rats and this increase was maintained for the rest of the experiment (P<0.05). Obese rats fed casein exhibited increased IGFBP-3 levels (P<0.001). However, obese rats fed soy exhibited a significant decrease in IGFBP-3 levels compared to the lean soy-fed rats (P<0.001) and a significant decrease in IGFBP-3 levels compared to the obese casein-fed rats (P<0.001). At age 197 days, IGFBP-3 levels were increased in obese casein-and soy-fed rats (P<0.001). The results suggest that female Zucker rats fed casein diets are protected against DMBA-induced mammary tumors, which is not the case for those on high-isoflavone soy diet, and changes in the concentration of serum IGFBP-3 may contribute to the incidence of DMBA-induced mammary tumors.
PMCID: PMC3412466  PMID: 22870124
obesity; soy diet; breast cancer; insulin growth factor-1
4.  Chemopreventive effect of a novel oleanane triterpenoid in a chemically induced rodent model of breast cancer 
Breast cancer represents one of the most frequently diagnosed cancers and predominant causes of death in women worldwide. The value of preventive therapy to limit the devastating impact of breast cancer is well established. Various plant triterpenoids and their synthetic analogs have shown significant promise as potent chemopreventive agents in breast cancer. The current study was initiated to investigate mechanism-based chemopreventive potential of a novel synthetic oleanane triterpenoid (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis, an experimental rodent tumor model that closely resembles human mammary cancer. Rats were orally administered with AMR-Me (0.8, 1.2 and 1.6 mg/kg) three times per week for 18 weeks. Following two weeks of AMR-Me treatment, mammary carcinogenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks following DMBA exposure), AMR-Me exhibited a striking inhibition of DMBA-induced mammary tumor incidence, total tumor burden, average tumor weight and reversed histopathological alterations without toxicity. AMR-Me dose-dependently suppressed abnormal cell proliferation, induced apoptosis, up-regulated pro-apoptotic protein Bax and down-regulated anti-apoptotic protein Bcl-2 in mammary tumors. AMR-Me up-regulated the transcriptional levels of Bax, Bad, caspase-3, caspase-7 and poly(ADP-ribose) polymerase and down-regulated Bcl-2. These results clearly demonstrate for the first time that novel triterpenoid AMR-Me exerts chemopreventive efficacy in the classical DMBA model of breast cancer by suppressing abnormal cell proliferation and inducing apoptosis mediated through mitochondrial pro-apoptotic mechanisms. AMR-Me could be developed as a chemopreventive drug to reduce the risk of human breast cancer that remains a devastating disease.
PMCID: PMC3702660  PMID: 23404339
Chemoprevention; breast cancer; DMBA; oleanane triterpenoid; cell proliferation; apoptosis
5.  Size dependent heat generation of magnetite nanoparticles under AC magnetic field for cancer therapy 
We have developed magnetic cationic liposomes (MCLs) that contained magnetic nanoparticles as heating mediator for applying them to local hyperthermia. The heating performance of the MCLs is significantly affected by the property of the incorporated magnetite nanoparticles. We estimated heating capacity of magnetite nanoparticles by measuring its specific absorption rate (SAR) against irradiation of the alternating magnetic field (AMF).
Magnetite nanoparticles which have various specific-surface-area (SSA) are dispersed in the sample tubes, subjected to various AMF and studied SAR.
Heat generation of magnetite particles under variable AMF conditions was summarized by the SSA. There were two maximum SAR values locally between 12 m2/g to 190 m2/g of the SSA in all ranges of applied AMF frequency and those values increased followed by the intensity of AMF power. One of the maximum values was observed at approximately 90 m2/g of the SSA particles and the other was observed at approximately 120 m2/g of the SSA particles. A boundary value of the SAR for heat generation was observed around 110 m2/g of SSA particles and the effects of the AMF power were different on both hand. Smaller SSA particles showed strong correlation of the SAR value to the intensity of the AMF power though larger SSA particles showed weaker correlation.
Those results suggest that two maximum SAR value stand for the heating mechanism of magnetite nanoparticles represented by hysteresis loss and relaxation loss.
PMCID: PMC2579422  PMID: 18928573
6.  Comparison of microwave and magnetic nanoparticle hyperthermia radiosensitization in murine breast tumors 
Proceedings of SPIE  2011;7901:10.1117/12.876515.
Hyperthermia has been shown to be an effective radiosensitizer. Its utility as a clinical modality has been limited by a minimally selective tumor sensitivity and the inability to be delivered in a tumor-specific manner. Recent in vivo studies (rodent and human) have shown that cancer cell-specific cytotoxicity can be effectively and safely delivered via iron oxide magnetic nanoparticles (mNP) and an appropriately matched noninvasive alternating magnetic field (AMF). To explore the tumor radiosensitization potential of mNP hyperthermia we used a syngeneic mouse breast cancer model, dextran-coated 110 nm hydrodynamic diameter mNP and a 169 kHz / 450 Oe (35.8 kA/m) AMF. Intradermally implanted (flank) tumors (150 ± 40 mm3) were treated by injection of 0.04 ml mNP (7.5 mg Fe) / cm3 into the tumor and an AMF (35.8 kA/m and 169 kHz) exposure necessary to achieve a CEM (cumulative equivalent minute) thermal dose of 60 (CEM 60). Tumors were treated with mNP hyperthermia (CEM 60), radiation alone (15 Gy, single dose) and in combination. Compared to the radiation and heat alone treatments, the combined treatment resulted in a greater than two-fold increase in tumor regrowth tripling time (tumor treatment efficacy). None of the treatments resulted in significant normal tissue toxicity or morbidity. Studies were also conducted to compare the radiosensitization effect of mNP hyperthermia with that of microwave-induced hyperthermia. The effects of incubation of nanoparticles within tumors (to allow nanoparticles to be endocytosed) before application of AMF and radiation were determined. This preliminary information suggests cancer cell specific hyperthermia (i.e. antibody-directed or anatomically-directed mNP) is capable of providing significantly greater radiosensitization / therapeutic ratio enhancement than other forms of hyperthermia delivery.
PMCID: PMC3877316  PMID: 24392200
Hyperthermia; radiation; nanoparticle; microwave; AMF; radiosensitization; intracellular hyperthermia
7.  Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis 
British Journal of Cancer  1999;80(11):1682-1688.
Prepubertal exposure to a pharmacological dose (500 mg kg−1) of the phyto-oestrogen genistein can reduce the incidence and multiplicity of carcinogen-induced mammary tumours in rats. However, such an exposure also disrupts the function of the hypothalamic–pituitary–gonadal axis, making it unsuitable for breast cancer prevention. We studied whether prepubertal exposure to genistein at a total body dose broadly comparable to the level typical of Oriental countries, approximately 1 mg kg−1 body weight, affects mammary tumorigenesis. We also studied whether prepubertal exposure to zearalenone, a major source for phyto-oestrogens in the USA, influences breast cancer risk. Prepubertal rats were treated between postnatal days 7 and 20, with 20 μg (~ 1 mg kg−1 body weight) of either genistein or zearalenone. Zearalenone exposure significantly reduced both the incidence and multiplicity of mammary tumours induced by 7,12-dimethylbenz(a)anthracene (DMBA). Genistein exposure significantly reduced tumour multiplicity, but not tumour incidence, when compared with vehicle-treated animals. Furthermore, 60% of the tumours in the genistein group were not malignant, while all the tumours analysed for histopathology in the vehicle and zearalenone groups were adenocarcinomas. A higher number of differentiated alveolar buds, and lower number of terminal ducts, were present in the DMBA-treated mammary glands of the phyto-oestrogen exposed rats. The concentration of oestrogen receptor (ER) binding sites after the DMBA treatment was low in the mammary glands of all groups but a significantly higher proportion of the glands in the zearalenone exposed rats were ER-positive (i.e. ER levels ≥ 5 fmol mg−1 protein) than the glands of the vehicle controls. Our data suggest that a prepubertal exposure to a low dose of either zearalenone or genistein may protect the mammary gland from carcinogen-induced malignant transformation, possibly by increasing differentiation of the mammary epithelial tree. © 1999 Cancer Research Campaign
PMCID: PMC2363126  PMID: 10468283
genistein; zearalenone; prepuberty; mammary tumorigenesis
8.  Iron Oxide Hyperthermia And Radiation Cancer Treatment 
It is established that heat can enhance the effect of radiation cancer treatment. Due to the ability to localize thermal energy using nanoparticle hyperthermia, as opposed to other, less targeted, hyperthermia modalities, it appears such enhancement could be accomplished without complications normally associated with systemic or regional hyperthermia. This study employs non-curative (suboptimal), doses of heat and radiation, in an effort to determine the therapeutic enhancement potential for IONP hyperthermia and radiation.
MTG-B murine breast adenocarcinoma cell are inoculated into the right flanks of female CH3/HEJ mice and grown to volumes of 150mm3 +/− 40 mm3. A single dose of 15 Gy (6 MeV) radiation was uniformly delivered to the tumor. A pre-defined thermal dose is delivered by direct injection of iron oxide nanoparticles into the tumor. By adjusting the field strength of the 160 KHz alternating magnetic field (AMF) an intra-tumoral temperature between 41.5 and 43 degrees Celsius was maintained for 10min. The alternating magnetic field was delivered by a water-cooled 36mm diameter square copper tube induction coil operating at 160 kHz with variable magnet field strengths up to 450 Oe. The primary endpoint of the study is the number of days required for the tumor to achieve a volume 3 fold greater than the volume at the time of treatment (tumor regrowth delay).
Preliminary results suggest the addition of a modest IONP hyperthermia to 15 Gy radiation achieved an approximate 50% increase in tumor regrowth delay as compared to a 15 Gy radiation treatment alone. The therapeutic effects of IONP heat and radiation combined were considered additive, however in mice that demonstrated complete response (no tumor present after 30 days), the effect was considered superadditive or synergistic. Although this data is very encouraging from a multimodality cancer therapy standpoint, additional temporal and dose related information is clearly necessary to optimize the therapy.
PMCID: PMC4208073  PMID: 25346582
Iron oxide; nanoparticle; AMF; adenocarcinoma; transmission electron microscopy; TEM; murine; MTG-B; HT-29
9.  Iron oxide nanoparticle hyperthermia and chemotherapy cancer treatment 
The benefit of combining hyperthermia and chemotherapy to treat cancer is well established. However, combined therapy has not yet achieved standard of care status. The reasons are numerous and varied, however the lack of significantly greater tumor cell sensitivity to heat (as compared to normal cells) and the inability to deliver heat to the tumor in a precise manner have been major factors. Iron oxide nanoparticle (IONP) hyperthermia, alone and combined with other modalities, offers a new direction in hyperthermia cancer therapy via improved tumor targeting and an improved therapeutic ratio. Our preliminary studies have demonstrated tumor cell cytotoxicity (in vitro and in vivo) with IONP heat and cisplatinum (CDDP) doses lower than those necessary when using conventional heating techniques or cisplatinum alone. Ongoing studies suggest such treatment could be further improved through the use of targeted nanoparticles.
In vivo: IONPs (5mg of iron per gram of tumor) were administered into MTG-B flank tumors in female C3H-HEJ mice directly after cisplatinum chemotherapy (0.1ml/kg of body mass) was intraperitoneally injected. An 160 KHz, 350–450 Oe AMF (alternating magnetic field) was used to induce particle heating.
In vitro: Mouse mammary adenocarcinoma cells (MTG-B) cells were grown and exposed to IONP hyperthermia and cisplatinum. IONPs not associated with cells were removed by washing prior to heat induction by an AMF field. Acute cell survival, via trypan blue assay, was used to quantify the level of cytotoxicity.
In vitro studies, using IONP + cisplatinum, have demonstrated promising cytotoxicity enhancement. Ongoing studies are being pursued to further define the mechanism of action, temporal associations and pathophysiology of combined IONP hyperthermia and chemotherapy treatment. Preliminary in vivo IONP /cisplatinum studies have shown a tumor growth delay/volume reduction greater than either modality alone at comparable doses. Further enhancement of this treatment success appears to depend on a better understanding of IONP dose and tumor cell association, chemotherapy dose and administration technique, the spatial and temporal treatment relationship of the two modalities and optimal AMF - IONP coupling.
PMCID: PMC4208066  PMID: 25346581
Iron oxide; nanoparticle; AMF; chemotherapy; cisplatinum; murine; MTG-B; HT-29
10.  Preventive and curative effect of melatonin on mammary carcinogenesis induced by dimethylbenz[a]anthracene in the female Sprague–Dawley rat 
Breast Cancer Research  2005;7(4):R470-R476.
It has been well documented that the pineal hormone, melatonin, which plays a major role in the control of reproduction in mammals, also plays a role in the incidence and growth of breast and mammary cancer. The curative effect of melatonin on the growth of dimethylbenz [a]anthracene-induced (DMBA-induced) mammary adenocarcinoma (ADK) has been previously well documented in the female Sprague–Dawley rat. However, the preventive effect of melatonin in limiting the frequency of cancer initiation has not been well documented.
The aim of this study was to compare the potency of melatonin to limit the frequency of mammary cancer initiation with its potency to inhibit tumor progression once initiation, at 55 days of age, was achieved. The present study compared the effect of preventive treatment with melatonin (10 mg/kg daily) administered for only 15 days before the administration of DMBA with the effect of long-term (6-month) curative treatment with the same dose of melatonin starting the day after DMBA administration. The rats were followed up for a year after the administration of the DMBA.
The results clearly showed almost identical preventive and curative effects of melatonin on the growth of DMBA-induced mammary ADK. Many hypotheses have been proposed to explain the inhibitory effects of melatonin. However, the mechanisms responsible for its strong preventive effect are still a matter of debate. At least, it can be envisaged that the artificial amplification of the intensity of the circadian rhythm of melatonin could markedly reduce the DNA damage provoked by DMBA and therefore the frequency of cancer initiation.
In view of the present results, obtained in the female Sprague–Dawley rat, it can be envisaged that the long-term inhibition of mammary ADK promotion by a brief, preventive treatment with melatonin could also reduce the risk of breast cancer induced in women by unidentified environmental factors.
PMCID: PMC1175060  PMID: 15987452
11.  Simultaneous disruption of estrogen receptor and Wnt/β-catenin signaling is involved in methyl amooranin-mediated chemoprevention of mammary gland carcinogenesis in rats 
Molecular and cellular biochemistry  2013;384(0):10.1007/s11010-013-1803-7.
Methyl-amoorain (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me), a novel synthetic oleanane triterpenoid, exerts a striking chemopreventive effect against 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumorigenesis through antiproliferative and proapoptotic actions. Nevertheless, the underlying mechanisms of action remain to be established. As estrogen receptor (ER) and canonical Wnt/β-catenin signaling are involved in the development and progression of breast cancer, the current study was designed to investigate the effects of AMR-Me treatment on the expressions of ER-α, ER-β, β-catenin and cyclin D1 in rat mammary tumors induced by DMBA. Mammary tumor samples were harvested from an 18-week chemopreventive study in which AMR-Me (0.8–1.6 mg/kg) was shown to inhibit mammary carcinogenesis in a dose–response manner. The expressions of ER-α, ER-β, β-catenin, and cyclin D1 were determined by immunohistochemistry and reverse transcription-polymerase chain reaction. AMR-Me downregulated the expression of intratumor ER-α and ER-β and lowered the ratio of ER-α to ER-β. AMR-Me also reduced the expression, cytoplasmic accumulation, and nuclear translocation of β-catenin, the essential transcriptional cofactor for Wnt signaling. Furthermore, AMR-Me modulated the expression of cell growth regulatory gene cyclin D1, which is a downstream target for both ER and Wnt signaling. AMR-Me at 1.6 mg/kg for 18 weeks did not exhibit any hepatotoxicity or renotoxicity. The results of the present study coupled with our previous findings indicate that simultaneous disruption of ER and Wnt/β-catenin signaling possibly contributes to antiproliferative and apoptosis-inducing effects implicated in AMR-Me-mediated chemoprevention of DMBA-induced breast tumorigenesis in rats. Our results also suggest a possible crosstalk between two key regulatory pathways, namely ER and Wnt/β-catenin signaling, involved in mammary carcinogenesis and the value of simultaneously targeting these pathways to achieve breast cancer chemoprevention.
PMCID: PMC3874467  PMID: 24078029
Mammary carcinogenesis; DMBA; Oleanane triterpenoid; Estrogen receptors; Cyclin D1; β-Catenin
12.  Protective effect of chorionic gonadotropin on DMBA-induced mammary carcinogenesis. 
British Journal of Cancer  1990;62(2):243-247.
The effect of the placental hormone chorionic gonadotropin (hCG) on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumours was studied in young virgin Sprague-Dawley rats. This hormone when administered at a dose of 100 IU day-1 does not induce toxic effects, measured as alterations in body weight or weight of endocrine organs, and has a reversible effect on oestrous cycle. The lack of toxicity and the fact that hCG treatment terminated prior to administration of the chemical carcinogen DMBA protects the mammary gland from malignant transformation, led us to test the effect of hCG treatment on DMBA-initiated mammary tumours. Fifty day-old virgin Sprague-Dawley rats received intragastrically 8 mg DMBA per 100 g body weight and were divided into two groups: group I animals were treated with DMBA only and group II received DMBA at age 50 and in addition, a daily intraperitoneal injection of 100 IU hCG for days 21-81 post carcinogen administration. Tumorigenic response was evaluated by biweekly palpation of all animals and by complete autopsy 24 weeks after DMBA treatment. Group I animals developed an incidence of 100% of both tumours and adenocarcinomas. Group II animals developed a significantly lower incidence of tumours and adenocarcinomas, 51.5% and 45.5% respectively. In both groups lesions developed more frequently in thoracic than in abdominal mammary glands. It is postulated that hCG treatment, probably through stimulation of ovarian oestrogen and progesterone synthesis, induces differentiation of mammary epithelium that although affected by the carcinogen can still be rescued from malignant transformation.
PMCID: PMC1971833  PMID: 2117463
13.  Prepubertal exposure to cow’s milk reduces susceptibility to carcinogen-induced mammary tumorigenesis in rats 
Cow’s milk contains high levels of estrogens, progesterone and insulin-like growth factor 1 (IGF-1), all of which are associated with breast cancer. We investigated whether prepubertal milk exposure affects mammary gland development and carcinogenesis in rats. Sprague Dawley rats were given either whole milk or tap water to drink from postnatal day (PND) 14 to PND 35, and thereafter normal tap water. Mammary tumorigenesis was induced by administering 7,12-dimethylbenz[a]anthracene (DMBA) on PND 50. Milk exposure increased circulating E2 levels on PND 25 by 10-fold (p<0.001) and accelerated vaginal opening, which marks puberty onset, by 2.5 days (p<0.001). However, rats exposed to milk before puberty exhibited reduced carcinogen-induced mammary carcinogenesis; i.e., their tumor latency was longer (p<0.03) and incidence was lower (p<0.05) than in the controls. On PND 25 and 50, mammary glands of the milk exposed rats had significantly less terminal end buds (TEBs) than the tap water exposed controls (p<0.019). ER-α protein levels were elevated in the TEBs and lobules of milk rats, compared to rats given tap water (p<0.019), but no changes in cyclin D1 expression, cell proliferation or apoptosis were seen. IGF-1 mRNA levels were reduced on PND 50 in the mammary glands of rats exposed to milk at puberty. Our results suggest that drinking milk before puberty reduces later risk of developing mammary cancer in rats. This might be mediated by a reduction in the number of TEBs and lower expression of IGF-1 mRNA in the mammary glands of milk-exposed animals.
PMCID: PMC3384739  PMID: 20232392
Cow’s milk; breast cancer; prepubertal exposure; animal model
14.  IL-6 Regulates Mcl-1L Expression through the JAK/PI3K/Akt/CREB Signaling Pathway in Hepatocytes: Implication of an Anti-Apoptotic Role during Liver Regeneration 
PLoS ONE  2013;8(6):e66268.
To investigate the role and the regulation of the long variant of myeloid cell leukemia-1 protein (Mcl-1L) during liver regeneration.
Liver regeneration is an important phenomenon after liver injury. The rat partial hepatectomy (PH) model was used to characterize liver regeneration and Mcl-1L expression after PH.
Male Wistar rats were subjected to 70% PH. The expression of mcl-1L mRNA was determined by quantitative RT-PCR, and protein levels were analyzed by Western blot analysis and immunohistochemistry during liver regeneration. Functional evaluations of Mcl-1L were tested using chemical inhibition (flavopiridol), genetic inhibition (siRNA) of Mcl-1L production, and by assaying for annexin V levels and DNA ladder formation. Serum IL-6 levels were determined by enzyme immunoassays; signal transduction of IL-6-regulated Mcl-1L expression was verified by chemical inhibitors and decoy double-stranded oligodeoxynucleotides.
High levels of Mcl-1L were observed in remnant tissue at 4 h after PH. Administration of flavopiridol decreased Mcl-1L accumulation and also inhibited liver regeneration. IL-6 administration promoted the accumulation of Mcl-1L in rat hepatocytes, an effect that was impaired by siRNA treatments that reduced Mcl-1L production. Chemical inhibition and decoy oligonucleotide competition demonstrated that IL-6-induced Mcl-1L production required signaling mediated by JAK kinase, phosphoinositide 3-kinase (PI3K), and cAMP response-element-binding (CREB) proteins.
Mcl-1L is an anti-apoptotic protein induced during liver regeneration after PH in rats. The expression of Mcl-1L is induced by IL-6 through the JAK/PI3K/Akt/CREB signaling pathway. Chemotherapy drugs that depend on Mcl-1L- or IL-6-related signaling should be considered carefully before use in patients undergoing hepatectomy for malignant tumor resection.
PMCID: PMC3692501  PMID: 23825534
15.  High Therapeutic Efficiency of Magnetic Hyperthermia in Xenograft Models Achieved with Moderate Temperature Dosages in the Tumor Area 
Pharmaceutical Research  2014;31(12):3274-3288.
Tumor cells can be effectively inactivated by heating mediated by magnetic nanoparticles. However, optimized nanomaterials to supply thermal stress inside the tumor remain to be identified. The present study investigates the therapeutic effects of magnetic hyperthermia induced by superparamagnetic iron oxide nanoparticles on breast (MDA-MB-231) and pancreatic cancer (BxPC-3) xenografts in mice in vivo.
Superparamagnetic iron oxide nanoparticles, synthesized either via an aqueous (MF66; average core size 12 nm) or an organic route (OD15; average core size 15 nm) are analyzed in terms of their specific absorption rate (SAR), cell uptake and their effectivity in in vivo hyperthermia treatment.
Exceptionally high SAR values ranging from 658 ± 53 W*gFe−1 for OD15 up to 900 ± 22 W*gFe−1 for MF66 were determined in an alternating magnetic field (AMF, H = 15.4 kA*m−1 (19 mT), f = 435 kHz). Conversion of SAR values into system-independent intrinsic loss power (ILP, 6.4 ± 0.5 nH*m2*kg−1 (OD15) and 8.7 ± 0.2 nH*m2*kg−1 (MF66)) confirmed the markedly high heating potential compared to recently published data. Magnetic hyperthermia after intratumoral nanoparticle injection results in dramatically reduced tumor volume in both cancer models, although the applied temperature dosages measured as CEM43T90 (cumulative equivalent minutes at 43°C) are only between 1 and 24 min. Histological analysis of magnetic hyperthermia treated tumor tissue exhibit alterations in cell viability (apoptosis and necrosis) and show a decreased cell proliferation.
Concluding, the studied magnetic nanoparticles lead to extensive cell death in human tumor xenografts and are considered suitable platforms for future hyperthermic studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11095-014-1417-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4224751  PMID: 24890197
CEM43T90; in vivo; iron oxide nanoparticles; magnetic hyperthermia; temperature dose
16.  Loss of PPARγ expression in mammary secretory epithelial cells creates a pro-breast tumorigenic environment 
Breast cancer is the leading cause of new cancer diagnoses among women. Using peroxisome proliferator-activated receptor (PPAR)γ(+/−) mice, we showed normal expression of PPARγ was critical to stop 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast tumorigenesis. PPARγ is expressed in many breast cell types including mammary secretory epithelial (MSE) cells. MSEs proliferate as required during pregnancy, and undergo apoptosis or reversible transdifferentiation during involution once lactation is complete. Thus, MSE-specific loss of PPARγ was hypothesized to enhance DMBA-mediated breast tumorigenesis. To test this, MSE cell-specific PPARγ knockout (PPARγ-MSE KO) and control (PPARγ-WT) mice were generated, mated and allowed to nurse for three days. One week after involution, dams were treated with DMBA to initiate breast tumors, and randomized on week 7 to continue receiving a normal chow diet (DMBA Only: PPARγ-WT, n = 15; PPARγ-MSE KO, n = 25) or one supplemented with a PPARγ activating drug (DMBA + ROSI: PPARγ-WT, n = 17; PPARγ-MSE KO, n = 24), and monitored for changes in breast tumor outcomes. PPARγ-MSE KOs had significantly lower overall survival and decreased mammary tumor latency as compared to PPARγ-WT controls. PPARγ activation significantly reduced DMBA-mediated malignant mammary tumor volumes irrespective of genotype. MSE-specific PPARγ loss resulted in decreased mammary gland expression of PTEN and Bax, increased superoxide anion production, and elevated serum eotaxin and RANTES, creating a protumorigenic environment. Moreover, PPARγ activation in MSEs delayed mammary tumor growth in part by down-regulating Cox-1, Cox-2 and cyclin D1. Collectively, these studies highlight a protective role of MSE-specific PPARγ during breast tumorigenesis, and support a novel chemotherapeutic role of PPARγ activation in breast cancer.
PMCID: PMC4233966  PMID: 23934545
breast cancer; PPARγ; mammary secretory epithelial cells; knockout mouse model; chemical carcinogenesis; chemotherapy
17.  Study on cow ghee versus soybean oil on 7,12-dimethylbenz(a)-anthracene induced mammary carcinogenesis & expression of cyclooxygenase-2 & peroxisome proliferators activated receptor- γ in rats 
Background & objectives
Breast cancer is a leading cause of cancer death in women; dietary fat is the one of the factors that influences its incidence. In the present study we investigated the effect of feeding cow ghee versus soybean oil on 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary cancer in rat and expression of cyclooxygenase-2 and peroxisome proliferators activated receptor- γ (PPAR-γ) in mammary gland.
Two groups of 21 day old female rats (30 each) were fed for 44 wk diet containing cow ghee or soybean oil (10%). The animals were given DMBA (30mg/kg body weight) through oral intubation after 5 wk feeding. Another two groups (8 each) fed similarly but not given DMBA served as control for the gene expression study.
In DMBA treated groups, the animal fed soybean oil had higher tumour incidence (65.4%), tumour weight (6.18 g) and tumour volume (6285 mm3) compared to those fed cow ghee (26.6%, 1.67 g, 1925 mm3, respectively). Tumour latency period was 23 wk on soybean oil compared to 27 wk on cow ghee. Histological analysis of tumours showed that the progression of carcinogenesis was more rapid on soybean oil than on cow ghee. The expression of cyclooxygenase-2 was observed only in DMBA treated rats and it was significantly less on cow ghee than on soybean oil. The expression of PPAR-γ was significantly more on cow ghee than on soybean oil.
Interpretation & conclusions
Our results show that dietary cow ghee opposed to soybean oil attenuates mammary carcinogenesis induced by DMBA; and the effect is mediated by decreased expression of cyclooxygenase-2 and increased expression of PPAR-γ in the former group.
PMCID: PMC3121280  PMID: 21623034
Cow ghee; cyclooxygenase 2; DMBA; mammary carcinogenesis; PPAR-γ; soybean oil
18.  Local hyperthermia for esophageal cancer in a rabbit tumor model: Magnetic stent hyperthermia versus magnetic fluid hyperthermia 
Oncology Letters  2013;6(6):1550-1558.
Magnetic-mediated hyperthermia (MMH) is a promising local thermotherapy approach for cancer treatment. The present study investigated the feasibility and effectiveness of MMH in esophageal cancer using a rabbit tumor model. The therapeutic effect of two hyperthermia approaches, magnetic stent hyperthermia (MSH), in which heat is induced by the clinical stent that is placed inside the esophagus, and magnetic fluid hyperthermia (MFH), where magnetic nanoparticles are applied as the agent, was systematically evaluated. A rabbit esophageal tumor model was established by injecting VX2 carcinoma cells into the esophageal submucosa. The esophageal stent was deployed perorally into the tumor segment of the esophagus. For the MFH, magnetic nanoparticles (MNPs) were administered to the rabbits by intratumoral injection. The rabbits were exposed under a benchtop applicator using an alternative magnetic field (AMF) with 300 kHz frequency for the hyperthermia treatment. The results demonstrated that esophageal stents and MNPs had ideal inductive heating properties upon exposure under an AMF of 300 kHz. MSH, using a thermal dose of 46°C with a 10-min treatment time, demonstrated antitumor effects on the rabbit esophageal cancer. However, the rabbit esophageal wall is not heat-resistant. Therefore, a higher temperature or longer treatment time may lead to necrosis of the rabbit esophagus. MFH has a significant antitumor effect by confining the heat within the tumor site without damaging the adjacent normal tissues. The present study indicates that the two hyperthermia procedures have therapeutic effects on esophageal cancer, and that MFH may be more specific than MSH in terms of temperature control during the treatment.
PMCID: PMC3833863  PMID: 24260045
magnetic mediated hyperthermia; esophageal cancer; magnetic nanoparticles; esophageal stent; alternative magnetic field
19.  Hepatocyte-specific deletion of the anti-apoptotic protein Mcl-1 triggers proliferation and hepatocarcinogenesis in mice 
Hepatology (Baltimore, Md.)  2010;51(4):1226-1236.
Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes towards apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and non-responsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1Δhep) spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in >50% of Mcl-1Δhep mice already by the age of 8 months, whereas 12 month-old wild-type and heterozygous Mcl-1flox/wt mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1Δhep mice was paralleled by markedly increased levels of survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers.
The present study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases.
The survival of multicellular organisms depends on the maintenance of tissue homeostasis. Under physiological conditions apoptosis contributes to liver homeostasis by removing damaged hepatocytes. Proliferation, growth and programmed hepatocyte cell death are highly coordinated and tightly controlled events in the normal liver (1).
On the one hand, increased apoptosis sensitivity contributes to liver injury. On the other hand, defective apoptosis was demonstrated to lead to excessive hepatocellular survival and has emerged as a major mechanism by which pre-malignant hepatocytes obtain a competitive advantage over normal liver cells (2). Various molecular alterations have been characterized causing an imbalance in the regulation of apoptosis. Among these are alterations in p53 signalling, expression of death receptors, growth factors and mitochondrial integrity (3). Decreased activity of pro-apoptotic signalling as well as increased activity of anti-apoptotic events are associated with HCC development and progression (4).
Among the main cellular changes that trigger apoptosis of hepatocytes is the permeabilization of the outer mitochondrial membrane followed by the release of pro-apoptotic factors (5). The Bcl-2 protein family plays a pivotal role for mitochondrial integrity and the selective interactions between pro- and anti-apoptotic family members regulate mitochondrial activation (6). Bcl-2 family members are similar within the Bcl-2 homology regions (BH1-BH4) and can be divided in pro- and anti-apoptotic Bcl-2 proteins.
Pro-apoptotic Bcl-2 proteins comprise (1) multi-domain members, which lack the BH4 domain (e.g. Bax, Bak), and (2) BH3-only proteins, which lack BH1, 2 and 4 domains (e.g. Bid, Noxa, Puma). BH3-only proteins initiate the mitochondrial signalling cascade by sensing cellular damage (7). After activation, BH3-only proteins are released to neutralise anti-apoptotic Bcl-2 proteins. Subsequently, Bax and Bak trigger mitochondrial membrane leakage and the release of mitochondrial proteins, including cytochrome c, Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI) and apoptosis-inducing factor (AIF). Smac/DIABLO proteins inactivate the IAP (inhibitors of apoptosis proteins) family, which consists of IAP1/2, BRUCE, NAIP, ILP2, ML-IAP, survivin and XIAP. XIAP is a direct caspase inhibitor. Other IAPs including survivin have several functions apart from caspase inhibition, eg, triggering of ubiquitination processes (8). Anti-apoptotic Bcl-2 family members (eg, Bcl-2, Bcl-xL and Mcl-1), interact with Bax and Bak to inhibit the activation of mitochondria (7).
Both Bcl-xL and Mcl-1 have been identified as major anti-apoptotic Bcl-2 proteins in the liver (9-11). Liver homeostasis is severely disturbed in Mcl-1Δhep mice (10, 11). Spontaneous hepatocyte apoptosis was observed in livers of Mcl-1Δhep mice in profound liver cell damage and increased susceptibility of hepatocytes towards pro-apoptotic stimuli (10). In addition, Mcl-1 has been shown to be highly expressed in a subset of human HCC, contributing to apoptosis resistance of cancer cells (12, 13). Thus, abrogation of the pro-survival function of Mcl-1 (1) either by diminishing its levels or (2) by inactivating its function, have shown promising results with regards to treatment of HCC (12, 13).
In this study, we show that liver-specific depletion of Mcl-1 increases hepatocyte apoptosis, induces hepatocellular proliferation and causes HCC in the absence of overt inflammation.
PMCID: PMC2936921  PMID: 20099303
liver; hepatocellular carcinoma; apoptosis; Bcl-2 proteins; survivin
20.  Mouse Mammary Tumor Virus Proviral Sequences Congenital to C3H/Sm Mice Are Differentially Hypomethylated in Chemically Induced, Virus-Induced, and Spontaneous Mammary Tumors 
Journal of Virology  1982;43(3):876-884.
C3H/Sm mice have lost the exogenous milk-borne mouse mammary tumor virus (MMTV) characteristic of the C3H strain and have a very low (1.5%) incidence of spontaneous mammary tumors, yet they are highly susceptible to mammary carcinogenesis by either chemical carcinogens or infection with the milk-borne virus. We have analyzed the MMTV proviral DNA content of normal tissues and of spontaneous, virus-induced, and chemically induced mammary tumors by restriction endonuclease digestion and Southern blot analysis. Although the results clearly showed additional MMTV sequences in the virus-induced tumor which are not present in normal liver DNA, none of the spontaneous or chemically induced tumors could be shown to contain either newly acquired exogenous or amplified endogenous MMTV sequences. Interestingly, mammary tumors arising in C3H/Sm mice treated simultaneously with infectious MMTV (C3H) and dimethylbenz[a]anthracene (DMBA) possessed new exogenous MMTV DNA even though no quantitative change in tumor production was observed when these mice were compared with C3H/Sm mice treated with DMBA alone (Smith et al., Int. J. Cancer 26:373-379, 1980). Our data indicate that the endogenous MMTV proviral units are extensively methylated in normal tissues, such as livers and normal nonlactating mammary glands. In the absence of MMTV (C3H), we found that in the rare, spontaneously occurring C3H/Sm mammary tumors, certain endogenous MMTV sequences were specifically hypomethylated. Hypomethylation of endogenous MMTV sequences was also noted in the chemically induced mammary tumors, even though radioimmune competition assays for MMTV gp52 and p28 are negative (Smith et al., Int. J. Cancer 27:81-86, 1981). Our results support the conclusion that amplification of endogenous MMTV sequences is not intrinsic to C3H/Sm mouse mammary tumors arising spontaneously or after induction by chemicals. On the other hand, integration of exogenous MMTV DNA into the genome was a constant feature of mammary tumors developing in MMTV (C3H)-infected C3H/Sm mice, even when DMBA was used as the carcinogen. Hypomethylation of some endogenous MMTV sequences is characteristic of C3H/Sm mammary tumors, whether spontaneous or induced by chemicals, which suggests that these sequences are located in actively transcribing regions of the tumor cell genome.
PMCID: PMC256198  PMID: 6292467
21.  The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions 
Mechanisms underlying low-penetrance, common, non-protein coding variants in breast cancer risk loci are largely undefined. We showed previously that the non-protein coding mammary carcinoma susceptibility locus Mcs5a/MCS5A modulates breast cancer risk in rats and women. The Mcs5a allele from the Wistar-Kyoto (WKy) rat strain consists of two genetically interacting elements that have to be present on the same chromosome to confer mammary carcinoma resistance. We also found that the two interacting elements of the resistant allele are required for the downregulation of transcript levels of the Fbxo10 gene specifically in T-cells. Here we describe mechanisms through which Mcs5a may reduce mammary carcinoma susceptibility.
We performed mammary carcinoma multiplicity studies with three mammary carcinoma-inducing treatments, namely 7,12-dimethylbenz(a)anthracene (DMBA) and N-nitroso-N-methylurea (NMU) carcinogenesis, and mammary ductal infusion of retrovirus expressing the activated HER2/neu oncogene. We used mammary gland and bone marrow transplantation assays to assess the target tissue of Mcs5a activity. We used immunophenotyping assays on well-defined congenic rat lines carrying susceptible and resistant Mcs5a alleles to identify changes in T-cell homeostasis and function associated with resistance.
We show that Mcs5a acts beyond the initial step of mammary epithelial cell transformation, during early cancer progression. We show that Mcs5a controls susceptibility in a non-mammary cell-autonomous manner through the immune system. The resistant Mcs5a allele was found to be associated with an overabundance of gd T-cell receptor (TCR)+ T-cells as well as a CD62L (L-selectin)-high population of all T-cell classes. In contrast to in mammary carcinoma, gdTCR+ T-cells are the predominant T-cell type in the mammary gland and were found to be overabundant in the mammary epithelium of Mcs5a resistant congenic rats. Most of them simultaneously expressed the CD4, CD8, and CD161α markers. In cultured T-cells of Mcs5a resistant congenic rats we found increased mitogen-induced proliferation and production of Th1 cytokines IFNg, IL-2, and Tumor Necrosis Factor (TNF), but not Th2 cytokines IL-4 and IL-6, or Th17 cytokine IL-17 when compared with susceptible control rats.
These data support a hypothesis that Mcs5a displays a non-mammary cell-autonomous mechanism of action to modulate breast cancer risk through the immune system. The resistant Mcs5a allele is associated with alterations in T-cell homeostasis and functions, and overabundance of γδTCR+ T-cells in carcinogen-exposed mammary epithelium.
PMCID: PMC3236344  PMID: 21846333
22.  Study of the cytotoxicity of asiaticoside on rats and tumour cells 
BMC Cancer  2014;14:220.
Cancer chemoprevention is considered one of the most promising areas in current cancer research, and asiaticoside, which is derived from the plant Centella asiatica, has a relative lack of systemic toxicity. The purpose of this study was to investigate whether asiaticoside is effective against 7,12-dimethylbenz(a)anthracene (DMBA)-induced carcinogenicity in vitro (MCF-7 and other cells) and in vivo (DMBA-induced rat cancer).
An MTT assay was performed involving the treatment of MCF-7 cells for 48 h with H2O2 alone and H2O2 + different asiaticoside concentrations. Flow cytometry was performed, and the level of caspase 3, tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) were quantified. Adult female Sprague–Dawley (SD) rats were divided into five groups designated I (control), II (DMBA-induced cancer), III (pre- and post-treatment with asiaticoside (200 μg/animal) in DMBA-induced cancer), IV (post-treatment with asiaticoside in DMBA-induced cancer), and V (treated with asiaticoside alone, drug control). Twelve weeks post-DMBA, rats developed mammary tumours. Rats either were sacrificed or imaged with MIBI. Histological examination of tumour tissues was performed. Tumour MIBI uptake ratios were determined. The data are expressed as the means ± standard deviation. Appropriate t-test and ANOVA statistical methods were used to compare data.
The IC50 of asiaticoside for MCF-7 cells was determined to be 40 μM. Asiaticoside has potential for hydrogen peroxide cytotoxicity, and the caspase-3 activity increased with increasing asiaticoside dose in MCF-7 cells treated for 48 h. The expression of the cytokines TNF-α and IL-1β was significantly decreased and correlated with MIBI uptake ratios in vitro and in vivo after asiaticoside administration.
This study demonstrates that asiaticoside is effective in vitro and in vivo in inducing apoptosis and enhancing anti-tumour activity.
PMCID: PMC3986932  PMID: 24667059
Asiaticoside; DMBA; Tumour; Proliferation; Apoptosis; Rats
23.  Genistein and Daidzein, in Combination, Protect Cellular Integrity during 7,12-Dimethylbenz[a]anthracene (DMBA) Induced Mammary Carcinogenesis in Sprague-Dawley Rats 
The status of glycoconjugates (protein bound hexose, hexosamine, sialic acid and fucose) in plasma or serum serve as potential biomarkers for assessing tumor progression and therapeutic interventions. Aim of the present study was to investigate the protective effect of two major soy isoflavones, genistein and daidzein, in combination on the status of glycoconjugates in plasma, erythrocyte membrane and mammary tissues during 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinogenesis in female Sprague-Dawley rats. A single subcutaneous injection of DMBA (25 mg rat−1) in the mammary gland developed mammary carcinoma in female Sprague-Dawley rats. Elevated levels of plasma and mammary tissue glycoconjugates accompanied by reduction in erythrocyte membrane glycoconjugates were observed in rats bearing mammary tumors. Oral administration of genistein + daidzein (20 mg + 20 mg kg−1 bw/day) to DMBA treated rats significantly (p< 0.05) brought back the status of glycoconjugates to near normal range. The present study thus demonstrated that genistein and daidzein in combination protected the structural integrity of the cell surface and membranes during DMBA-induced mammary carcinogenesis.
PMCID: PMC3252688  PMID: 22238489
Mammary carcinoma; Glycoconjugates; Membrane integrity; Genistein; Daidzein; DMBA
24.  Comparison of iron oxide nanoparticle and microwave hyperthermia alone or combined with cisplatinum in murine breast tumors 
Proceedings of SPIE  2011;7901:10.1117/12.876535.
Surgery, radiation and chemotherapy are currently the most commonly used cancer therapies. Hyperthermia has been shown to work effectively with radiation and chemotherapy cancer treatments. The major obstacle faced by previous hyperthermia techniques has been the inability to deliver heat to the tumor in a precise manner. The ability to deliver cytotoxic hyperthermia to tumors (from within individual cells) via iron oxide magnetic nanoparticles (mNP) is a promising new technology that has the ability to greatly improve the therapeutic ratio of hyperthermia as an individual modality and as an adjuvant therapy in combination with other modalities. Although the parameters have yet to be conclusively defined, preliminary data suggests mNP hyperthermia can achieve greater cytotoxicity (in vitro) than conventional water bath hyperthermia methods. At this time, our theory is that intracellular nanoparticle heating is more effective in achieving the combined effect than extracellular heating techniques.1 However, understanding the importance of mNP association and uptake is critical in understanding the potential novelty of the heating modality. Our preliminary data suggests that the mNP heating technique, which did not provide time for particle uptake by the cells, resulted in similar efficacy to microwave hyperthermia. mNP hyperthermia/cisplatinum results have shown a tumor growth delay greater than either modality alone at comparable doses
One hour before nanoparticle hyperthermia, CDDP chemotherapy (5mg/kg of body mass) was delivered intraperitoneally (IP). Iron oxide nanoparticles, 7.5mg of iron per gram of tumor, were injected into MTGB flank tumors in female C3H mice immediately before activation. A 170 KHz, 400-450 Oe alternating magnetic field (AMF) was used to induce particle heating. A comparison of nanoparticle induced hyperthermia to non-nanoparticle induced hyperthermia was also made using a 915 MHz microwave generator. Treatment duration was determined by the use of the cumulative equivalent minutes (CEM) algorithm. A CEM 60 was selected as the thermal dose for all experimental groups.
1) Preliminary mNP hyperthermia/cisplatinum results have shown a tumor growth delay greater than either modality alone at comparable doses.
2) mNP hyperthermia delivered 10 minutes post mNP injection and microwave hyperthermia, with the same thermal dose, demonstrate similar treatment efficacy.
PMCID: PMC3877302  PMID: 24386533
Iron oxide; nanoparticle; hyperthermia; microwave; AMF; chemotherapy; cisplatinum; MTGB
25.  Charles River Sprague Dawley Rats Lack Early Age-Dependent Susceptibility to DMBA-Induced Mammary Carcinogenesis 
Developmental stages of mammary glands influence their susceptibility to initiating events related to carcinogenesis. The “window of susceptibility” to mammary carcinogenesis is classically defined as the time in early puberty when the mammary gland morphology is most sensitive to initiation events. Administration of the polyaromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene (DMBA), in a single oral dose yields maximal mammary tumor formation when administered in this “window”. We examined the DMBA treated mammary glands, precursor lesions, and morphology of the uninvolved mammary epithelium for the first 100 days of life for Charles River Sprague Dawley CDR IGS. Our goal was to determine the DMBA dose at which 50% of the rats (IC50) developed carcinoma in situ (CIS) within three months of dosing. Here we demonstrate, rather than the classical U-shaped dose curve in which there is maximum sensitivity for DMBA at 50 days, there is an increasing degree of sensitivity with age in the CDR IGS rat. Additionally, we report that vehicle-treated animals developed mammary CIS without any known initiator, and 100 day virgin animals demonstrated lactational changes, independent of DMBA exposure or dose. Lastly, we demonstrate this strain of virgin female rats has elevated pituitary prolactin immunoreactivity independent of the level of mammary differentiation. We conclude this strain of Charles River Sprague Dawley rats has prolactin-induced pituitary stimulation, and therefore, the window of susceptibility for mammary tumorigenesis is absent.
PMCID: PMC2017109  PMID: 17940635
DMBA; mammary carcinogenesis; Charles River Sprague Dawley rats

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