bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B48: Lack of efficacy of the anti-diabetic drug metformin in the ER+ methylnitrosourea (MNU)-induced and the ER- MMTV-Neu/p53KO models of mammary cancer
Authors: Lubet Ronald A. , Bode Ann M. , Steele Vernon E. , Grubbs Clinton J.
Published: January 2011

Metformin, an anti-diabetic drug, activates AMP-activated protein kinase (AMPK), and has generated a great deal of interest as a potential preventive agent for a variety of cancers, including breast. This interest is based both on epidemiologic studies showing that diabetics treated with metformin have a lower incidence of a variety of cancers, and on mechanistic considerations arguing that activation of AMPK is likely to be relevant to cancer treatment and prevention. We examined the preventive efficacy of metformin in ER+ and ER- rodent mammary cancer models. Treatment of Sprague-Dawley female rats at 50 days of age with a single dose of MNU (75 mg/kg BW) resulted in the development of multiple ER+ mammary cancers beginning approximately 7 weeks after MNU treatment. This model has been highly responsive to a wide variety of agents that affect ER+ tumors in humans (SERMs, aromatase inhibitors, pregnancy, ovariectomy). Metformin was administered by gavage (7x/week) at either 150 or 50 mg/kg BW/day beginning 7 days after MNU dosing, and continuing for the duration of the study. Metformin failed to decrease mammary tumor incidence and, in fact, increased tumor multiplicity in this model by approximately 35%. In addition, we are evaluating the ability of metformin to inhibit mammary cancer in MMTV-Neu/p53KO mice (which spontaneously develop ER- cancers). In this study, metformin was administered in the diet at a dose level of 1500 mg/kg diet. Initial supplementation of the diet with this agent began when the mice were 60 days of age, and will continue for 10 months. This study similarly has shown no preventive efficacy of metformin (av. tumors/mice: controls, 2.1; metformin, 2.5). Thus, these initial studies fail to observe any chemopreventive efficacy of metformin in two commonly employed models of ER+ and ER- mammary cancers in rodents. Supported by NCI contract number HHSN261200433001C.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B48.
Abstract B49: Use of MMTV-Neu/P53 KO transgenic mice to screen for potential chemopreventive agents
Authors: Lubet Ronald A. , Grubbs Clinton J. , Juliana Margaret , Bode Ann , Steele Vernon E. , Iwata Kenneth
Published: January 2011

The MMTV-Neu transgenic model of mammary cancer was developed almost 20 years ago in which mice develop Neu over-expressing ER- mammary cancers. Since human ER- Neu over-expressing mammary cancers often also have mutations in P53, a heterozygous KO of P53 was incorporated into the model. We used this model to examine a wide variety of potential chemopreventive agents. The agents were routinely administered to virgin female MMTV-Neu/P53 KO mice beginning when they were 60 days of age. Initiation at this time is somewhat later than is often employed in other laboratories (i.e., agents are typically started when mice are roughly 5-6 weeks of age). Mice were routinely monitored until 360 days of age. In agreement with Brown and colleagues (e.g., Cancer Res. 62: 6376-6380, 2002), it was found both RXR agonists (Targretin, UAB-30) and EGFR 1 and/or 2 inhibitors (Tarceva, Lapatinib) were highly effective in preventing the development of these cancers. More surprisingly, tamoxifen which is ineffective as a therapeutic agent against ER- breast cancer in women was effective in this model. It was also observed that a wide variety of agents were ineffective; including Atorvastatin, rosiglitazone (a PPAR gamma agonist), SAHA (an HDAC inhibitor), metformin, and a soy isoflavones mixture. In separate studies, mice bearing small palpable mammary tumors were treated for five days with these various agents, and examined for alterations in potential biomarkers; including proliferation. Effective agents (e.g., Iressa, Tarceva, and Targretin) strongly inhibited cancer cell proliferation, whereas ineffective agents failed to significantly inhibit proliferation. Thus, such a short-term assay might be employed to determine potential chemopreventive compounds. Short-term treatment with the EGFR inhibitors also decreased levels of expression of phosphorylated EGFR and downstream proteins; e.g., AKT/ERK. Supported by NCI contract number HHSN26120043301C.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B49.
Abstract B5: Personal and social predictors of sharing genetic test results within the family
Authors: Daly Mary B. , Montgomery Susan , Barsevick Andrea , Egleston Brian , Bingler Ruth , Ruth Karen , Miller Suzanne , Malick John
Published: January 2011

Purpose: As testing for cancer susceptibility gene mutations becomes more prevalent, there is a growing need to understand the challenges faced by probands as they attempt to share genetic test results with family members. This study reports on a communication skills intervention, guided by the Theory of Planned Behavior (TPB), to improve the process of communication.

Methods: Participants seeking BRCA1/2 genetic testing were randomized to a communication skills-building intervention or a wellness control. Primary outcome was the number of first degree adult relatives with whom results were shared and ease of sharing. Questionnaires addressed TPB tenets and psychosocial factors.

Results: 233 participants shared test results with 743 of their 907 eligible relatives (81.9%). There was no significant difference between intervention and control in sharing test results, or in the level of sharing-related distress. When data from both arms were combined, the proband's perception of her relative's opinion about genetic testing and her confidence in effectively sharing results were strong predictors of sharing. Results were more likely to be shared with female relatives and with children.

Conclusion: While this data does not support a communication intervention in improving the sharing of genetic test results, it does identify the importance of the proband's perception of her relative's opinion of genetic testing and her perceived ability to relay this information. It highlights the selective nature of sharing, with male relatives and parents less likely to be recipients.

Impact: Psychosocial factors play a significant role in the communication of genetic test results within families.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B5.
Abstract B50: Antiproliferative activity of the polar extract of Justicia spicigera on LNCaP cells
Authors: Fernández-Pomares Cynthia , Bravo-Ávila Myriam , Muñoz-Muñiz Omar , Juárez-Aguilar Enrique , Domínguez-Ortiz Miguel Ángel , Hernández-Aguilar María Elena
Published: January 2011

Justicia spicigera is a Mexican plant employed in traditional medicine for treatment of anemia, stomach illness and skin diseases. Furthermore, it has been suggested that this plant has anticancer properties on leukemia patients and in other types of cancer. However, the scientific evidence supporting these properties is not sufficient. The aim of this study was to evaluate the effect of Justicia spicigera on proliferation and viability of the androgen-dependent human prostate cancer cell line, LNCaP.A polar extract was obtained by exhaustive maceration with water and ethanol (v/v) of the air parts of the plant. The phytochemical analysis by the color test and thin layer chromatography (TLC) showed the presence of antioxidant compounds like coumarins, flavonoids and anthocyanins, which was corroborated by Nuclear Magnetic Resonance (H1 NMR). At the same time, the extract showed the presence of polyphenolic compounds detected by the Folin-Ciocalteu's reagent. The reducing power and the free radical scavenging capacity, was not too high in comparison with other less polar extracts of this plant, this could be explained by the high rate of glycosylation of the compounds in the sample. In the other hand, the polar extract of Justicia spicigera showed an antiproliferative activity on LNCaP cells since 500 g/ml of extract, measured by the MTT assay and direct cell account. Interestingly, cell morphology was not affected under these conditions. Likewise, the same extract did not show a relevant citotoxic effect (MTT assay) or an affectation on cellular viability (trypan blue assay) of LNCaP cells. Our study showed an antiproliferative effect of the polar extract of Justicia spicigera on LNCaP cells suggesting a potential use as anticancer agent. Further studies should focus on the characterization of compounds responsible of the effects observed on LNCaP cells, as well as in the definition of the mechanisms by which they affect the growth of these cells.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B50.
Abstract B51: Prevention of mouse lung tumors by combinations containing SAHA and atorvastin
Authors: Pereira Michael A. , Casto Bruce C. , Lubet Ronald A. , Steele Veron E.
Published: January 2011

The use of combinations of chemopreventive agents is a promising strategy for increasing efficacy while lowering toxicity to prevent cancer, including lung cancer. To test whether this strategy of using combinations would enhance efficacy, combinations containing SAHA and atorvastatin were evaluated for their ability to prevent mouse lung tumors. Lung tumors were induced in female strain A/J mice (8-9 week-old) by administering i.p. an injection of 16 mg/kg vinyl carbamate once a week for three weeks. Two weeks after the last injection of vinyl carbamate, some of the mice started to receive in their diet, either 500mg/kg SAHA, 18, 60 or 180 mg/kg atorvastatin, combinations containing SAHA and one of the three dose levels of atorvastatin, or the Control Diet. Mice were sacrificed either at 21 or 32 weeks after the first dose of vinyl carbamate. At week 21, SAHA, the low (18 mg/kg diet) and high (180 mg/kg) concentrations of atorvastatin, and the three combinations containing SAHA and atorvastatin decreased the multiplicity of lung tumors/mouse, while at Week 32, lung tumor multiplicity was reduced by only SAHA (31.5 ± 1.6 lung tumors/mouse) and the combinations containing SAHA with either 60 or 180 mg/kg concentration of atorvastatin (21.9 ± 1.7 and 24.7 ± 1.9 lung tumors/mouse, respectively) compared to the yield in the Control Group of 42.7 ± 1.6 lung tumors/mouse. At both sacrifices, the combinations containing SAHA and the middle and high concentrations of atorvastatin demonstrated greater efficacy in decreasing tumor multiplicity than either SAHA or atorvastatin administered alone (p-value ≤ 0.05). At Week 21, both the size of the lung tumors and the multiplicity of adenocarcinomas were decreased by SAHA, 180 mg/kg atorvastatin and all three combinations, while at Week 32 only the combinations containing SAHA with either 60 or 180 mg/kg atorvastatin (0.160 ± 0.094 and 0.041 ± 0.041 lung adenocarcinomas/mouse, respectively) decreased the size of the lung tumors and the multiplicity of adenocarcinomas (1.44 ± 0.25 lung adenocarcinomas/mouse, p-value ≤ 0.05). Although, the ability of the two chemopreventive agents and the combinations to decrease the occurrence of lung tumors, to slow the growth of the tumors, and to slow their progression to carcinomas decreased with time, the efficacy of the combinations was still significant at the Week 32 sacrifice. Hence, the combinations of SAHA and atorvastatin demonstrated greater and more prolonged efficacy in preventing and slowing the progression of mouse lung tumors supporting the concept of using combinations of chemopreventive agents for cancer prevention. Supported in part by N01-CN-35116 from NCI.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B51.
Abstract B54: Prevention of mouse lung tumors by combinations of budesonide and Targretin or SAHA
Authors: Casto Bruce C. , Schmalbrock Petra M.F. , Wassenaar Peter A. , Heverhagen Johannes T. , Pereira Michael A.
Published: January 2011

Individual chemopreventive drugs have been shown to prevent and slow the growth and progression of mouse lung tumors. Combinations of these chemopreventive agents have been proposed as a strategy for increasing efficacy, while lowering drug toxicity. In addition, non-invasive procedures such as MRI have been suggested as a means to determine the ability of drugs to inhibit the growth of tumors and avoid using serial sacrifices. Three drugs representing different mechanisms of action (budesonide, a nonsteroidal anti-inflammatory; Targretin, a selective activator of RXR; and suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor) were used singly and in combination to inhibit development of mouse lung tumors. Lung tumors were induced in female Strain A/J mice by i.p. administration of 100 mg/kg 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNK) once a week for four consecutive weeks. Two weeks after the fourth dose of NNK, the mice started to receive a diet (AIN-76A) containing either1.6 mg/kg budesonide, 160 mg/kg Targretin, 500 mg/kg SAHA, or combinations of budesonide plus either Targretin or SAHA. At Week 21, the multiplicity of lung tumors in control mice (28.13 ± 1.62) was significantly reduced to 10.50 ± 0.74, 15.96 ± 0.90, and 12.42 ± 1.57 by budesonide, Targretin, and SAHA, respectively. The combinations containing budesonide plus Targretin or SAHA demonstrated significantly more inhibition of total tumors than either agent acting alone, resulting in 7.25 ± 0.87 and 5.00 ±1.16 tumors/mouse, respectively. The multiplicity of carcinomas was also significantly reduced by budesonide, Targretin, and SAHA from 5.10 ± 0.83 in control mice to 0.88 ± 0.21, 1.12 ± 0.27, and 0.37 ± 0.15, respectively, whereas the combinations demonstrated a greater efficacy than either agent acting alone, yielding 0.10 ± 0.07, and 0.12 ± 0.12 for the combinations containing Targretin or SAHA, respectively. Mice administered budesonide,

Targretin or the control diet were monitored by MRI at Weeks 21, 26 and 31 after the first dose of NNK and groups sacrificed at Weeks 21 and 31 after MRI for tumor counts. The two drugs (budesonide and Targretin) significantly reduced the size and number of tumors when monitored by MRI. At week 21, it was demonstrated by MRI that Targretin and budesonide significantly reduced the multiplicity of total lung tumors by 32% and 64%, respectively, from controls. In conclusion, relative to their individual effects, combinations containing budesonide and either Targretin or SAHA demonstrated greater efficacy in inhibiting both the occurrence of mouse lung tumors and their progression to carcinomas. Supported in part by NCI grant 5R21CA135335.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B54.
Abstract B58: Discovery of a novel drug KBU2046 that inhibits conversion of human prostate cancer to a metastatic phenotype
Authors: Xu Li , Farmer Rebecca , huang xiaoke , Pavese Janet , Voll Eric , Irene Ogden , Biddle Margaret , Nibbs Antoinette , Valsecchi Matias , Scheidt Karl , Bergan Raymond
Published: January 2011

Epidemiological evidence, preclinical studies and prospective phase II studies in humans indicate that the isoflavone, genistein, will inhibit the conversion of human prostate cells to an invasive, and ultimately, a metastatic phenotype. Though promising, genistein exerts many additional effects that have the potential for future toxicity in humans. We therefore sought to discover a new drug with improved efficacy and most importantly, with high specificity. Starting from an isoflavone chemical scaffold, we employed a fragment-based chemical synthesis diversification approach, and coupled it to three in vitro screens: 1) cell invasion (efficacy), 2) cell growth inhibition (an indicator of general toxicity), and 3) several measures of estrogenic activity. From multiple synthesis/biological assay iterations we developed a refined structure-activity relationship map, thereby leading us to discover KBU2046. KBU2046 represents a new and chemically distinct class of bioactive compounds. It has greater anti-invasion efficacy than genistein, and more importantly, no cell toxicity or estrogenic activity. Extensive toxicity studies in mice were negative. At low nanomolar blood concentrations, KBU2046 will prevent orthotopically implanted human prostate cancer cells from forming metastasis in a dose-responsive fashion. In summary, we have successfully discovered and developed a compound that prevents progression to a metastatic phenotype for human prostate cancer. We are in the process of bringing KBU2046 into the clinic, with the goal of preventing death from the second most common cause of cancer related death in men.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B58.
Abstract B59: The effect of resveratrol on azoxymethane (AOM)-induced colon carcinogenesis in mice with aberrant crypt foci (ACF)
Authors: Sakai Eiji , Endo Hiroki , Uchiyama Takashi , Hosono Kunihiro , Michiko Sugiyama , Takahashi Hirokazu , Nakajima Atsushi
Published: January 2011

Introduction: Resveratrol (trans-3,4,5-trihydroxy-trans-stilbene) is a naturally occurring phytoalexin with antioxidant and antiinflammatory properties. Moreover, recent studies suggest that resveratrol possesses anticancer effects on the major stages (initiation, promotion and progression) of malignant transformation. The present study was designed to investigate the effect of resveratrol on azoxymethane (AOM)-induced colon carcinogenesis in mice with aberrant crypt foci (ACF).

Methods and Results: 8-week-old male C57/BL6 mice were randomly assorted into experimental five groups and administered several doses resveratrol (0.1, 1, 10, 50mg/kg/day). All mice were injected twice (1 week apart) of 10 mg/kg AOM, and sacrificed 6weeks after the first injection of AOM. Colon and rectum were stained with methylene blue for the determination of ACF. The number of ACF was significantly decreased in groups of mice treated with resveratrol in dose-dependent manner.

Discussion: Colorectal cancer (CRC) poses a major clinical challenge in the developed world where the disease is common. However chemoprevention is defined as the use of natural, synthetic or chemical agents to reverse, suppress or prevent carcinogenic progress. No drug is confirmed for CRC chemoprevention. Present study demonstrated resveratrol may have chemopreventive effect for CRC. Resveratrol considered to be a food supplement and a relatively safe natural medication, so seems to be tolerated to long-term administration for CRC chemoprevention.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B59.
Abstract B62: Zinc supplementation reduces forestomach tumor burden in N-nitrosomethylbenzylamine-treated mice
Authors: Sun Jin , Liu James , Pan Xueliang , Quimby Donald , Zanesi Nicola , Druck Teresa , Pfeifer Gerd , Croce Carlo M. , Fong Louise , Huebner Kay
Published: January 2011

Zinc deficiency is associated with high incidences of esophageal and other human cancers. In addition, zinc status in plasma and white blood cells is a better indicator of tumor burden and stage of the disease in head and neck cancer patients than overall nutritional status. Research in rodents found that zinc insufficiency leads to a highly proliferative hyperplastic condition in the upper gastrointestinal tract. Zn replenishment reduces the incidence of lingual, esophageal, and forestomach tumors in Zn-deficient rats and mice. While previous animal studies focused on the effect of Zn deficiency on cancer prevention and development, in this study we investigated the effect of Zn supplementation on carcinogenesis in Zn-sufficient mice of wild type and three tumor suppressor-deficient mouse strains, Fhit−/−, Fhit−/−Nit1−/−, and Fhit−/−Rassf1a−/−. About fifty mice from each strain received 6-8 doses of N-nitrosomethylbenzylamine (NMBA). Half the mice then received Zn supplemented water while another half received regular water. Sixteen weeks after last NMBA administration, mice were sacrificed and tumors were found only in forestomach. Mice without Zn supplementation had developed more tumors than Zn-supplemented mice: wild type C57BL/6 mice developed an average of 7.0 vs 5.0 tumors for Zn supplemented (p<0.05); Zn-supplemented Fhit−/− mice averaged 5.7 vs 8.0 for control mice (p< 0.01); Zn-supplemented Fhit−/−Nit1−/− mice averaged 5.4 vs 9.2 for control mice (p< 0.01); and Zn-supplemented Fhit−/−Rassf1a−/−mice averaged 5.9 vs 9.1 for control mice (p< 0.01). Zn supplementation reduced tumor burdens by 28% (wild type) to 42% (Fhit−/−Nit1−/−). Histological analysis of forestomach tissues also showed significant decreases in severity of preneoplastic and neoplastic lesions in Zn-supplemented cohorts of each mouse strain. Thus, Zn supplementation significantly reduced tumor burdens in mice with multiple tumor suppressor deficiencies. When Zn supplementation was begun at 7 weeks after the final carcinogen dose, the reduction in tumor burden was the same as observed when supplementation began immediately after carcinogen dosing, suggesting that Zn supplementation may affect tumor progression rather than tumor initiation. Our study suggests that Zn could have an important role in tumor prevention and perhaps treatment of specific human cancers and should be more thoroughly studied in preclinical models.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B62.
Abstract B64: Zinc supplementation has antitumor effects in 4-nitroquinoline 1-oxide-induced rat oral carcinogenesis
Authors: Fong Louise Y.Y. , Jiang Yubao , Rawahneh Maysoon L. , Croce Carlo M. , Farber John L. , Huebner Kay
Published: January 2011

Zinc (Zn)-deficiency promotes esophageal/tongue tumorigenesis in rats by causing cell proliferation and changes in gene expression and Zn-replenishment inhibits tumorigenesis by attenuating cell proliferation and abnormal gene expression. Whether Zn has antitumor activities in a Zn-sufficient animal, however, is unknown. Here we examined the effects of Zn supplementation on tongue carcinogenesis in Zn-sufficient male Sprague-Dawley rats formerly exposed for 8 weeks to the carcinogen 4-nitroquinoline 1-oxide (NQO) at 10 and 20-30 ppm dose levels. Immediately after the cessation of NQO exposure, Zn gluconate (0, 20 ppm) was administered in the drinking water and continued for 10-13 weeks. At both NQO levels, Zn-supplemented rats had fewer tongue lesions than respective controls (10 ppm NQO: 5.2 ± 0.4 vs 8.6 ± 0.7, P<0.001; 20-30 ppm NQO: 10.6 ± 1.1 vs. 18.4 ± 1.2, P<0.01). Additionally, Zn-supplementation reduced the incidence of early tongue squamous cell carcinomas (SCC) from 40% [10/25] to 11.5% [3/26] (P=0.027) and that of invasive SCC from 93.8% [15/16] to 47.1% [8/17] (P=0.007) in rats exposed to 10 and 20-30 ppm NQO, respectively. The cell proliferative activity, as measured by quantitative proliferating cell nuclear antigen (PCNA)-immunohistochemistry, was significantly lower in the nontumorous tongue epithelia from Zn-supplemented rats than untreated controls (P<0.001). Compared with invasive tongue SCC from controls, Zn treatment led to less proliferative tongue SCCs with reduced immunostaining of cyclin D1, COX-2, NF-kB p65, and p53 proteins but increased apoptotic index. Thus, our finding that Zn inhibits tongue cancer progression in Zn-sufficient as in Zn-deficient animals should lead to prevention and therapeutic possibilities for oral cancer. Supported by National Institute of Health Grants R01CA118560 (LYYF) and R01 CA115965 (CMC).

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B64.
Abstract B67: In vitro and in vivo inhibitory effects of cranberry proanthocyanidins against esophageal adenocarcinoma
Authors: Zeyzus-Johns Bree , Exum Amy , Howell Amy B. , Kresty Laura A.
Published: January 2011

This study investigated the cancer inhibitory potential of a proanthocyanidin rich cranberry extract utilizing a panel of authenticated human esophageal adenocarcinoma cell lines (EAC), a nude mouse xenograft model, and the rat esophagogastrodoudenal anastomosis (EGDA) model of EAC. PACs effects on cell morphology, global gene expression, phase of cell cycle, and cell death induction via apoptosis, autophagy, and necrosis were evaluated. Methods included RapidDiff and MDC staining, Annexin/PI and BrdU staining with flow cytometric evaluation, transmission electron microscopy (TEM), protein evaluation utilizing standard Western blot techniques, and validation of global gene expression changes by real-time PCR. PAC treatment [50-100µg/ml] of EAC cancer cell lines resulted in significant increases in apoptosis, autophagy and necrosis. Differential cell death induction was noted based upon the cell lines resistance to a bile/acid cocktail mimicking acid exposure in humans as well as the status of the apoptotic and autophagic machinery of the select cell line. PACs cell death inducing capacity correlated with altered MAPKinase signaling as evidenced by activation of P-p38 and P-JNK and inhibition of P-ERK1/2. PAC treatment induced other proapoptotic markers including cleaved PARP, BAK1, BAX, and cytochrome C, but in a cell line dependent manner. Mild increases in Beclin-1 were noted following PAC treatment, as were significant increases in LC3II, a marker of autophagasome formation which occurs during autophagy induction. Results were confirmed by TEM and MDC staining. PAC induced cell cycle arrest at the G2/M transition, increased the percent of cells in G1, caused an S-phase delay and increased P21 levels in all three cell lines. PAC administration significantly inhibited the growth of OE19 xenografts via modulation of cell cycle and MAPK signaling pathways. Oral gavage of PAC [250µg/mouse] six times a week to nude mice resulted in a 67% decrease in OE19 tumor volume, increased cytochrome C protein levels and decreased levels of P-ERK1/2, cyclin A, PCNA, and CD31 in PAC treated tumors compared to vehicle treated tumors. Lastly, a four week pilot study was performed to evaluate the safety of daily administration of PAC in the rodent EGDA model. PAC appeared well tolerated given the average daily dose of 450µg/rat/day as evidenced by normal body weight and food consumption, serology profiles and histopathology of the major organs. Further long-term studies are planned to more fully access the chemopreventive potential of PAC against esophageal adenocarcinoma and premalignancy utilizing the clinically relevant rat EGDA surgical model.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B67.
Abstract B69: Potential cancer chemopreventive compounds from Oplopanax horridus, a native North American plant
Authors: Wang Chong-Zhi , Calway Tyler D. , Yuan Chun-Su
Published: January 2011

Distributed throughout the west of North America, the plant Oplopanax horridus, or devil's club, belongs to the genus Oplopanax, which consists of three species (O. elatus, O. japonicus and O. horridus). Although many studies on the other two species have been performed, phytochemical and pharmacological investigations on O. horridus have been limited, especially cancer chemopreventive studies. After comparing differences of antiproliferative potentials among different plant parts of O. horridus, the root bark was selected to perform further phytochemical isolation to prepare active anticancer fractionations and compounds. The hydrophobic fractions showed potent antiproliferative effects on human HCT-116 and SW-480 colorectal cancer cells. Subsequent isolation of the hydrophobic fractions gave six polyynes and one polyene; in which two novel compounds, Oplopantriol A and Oplopantriol B, were obtained and their absolute structures were elucidated by detailed spectroscopic analyses, including 1D and 2D NMR techniques and chemical methods. The content of these seven compounds in the O. horridus root bark was determined using an on-line SPE-HPLC method. Pharmacological studies showed that two polyynes, including a novel compound (Oplopantriol A), possessed strong cancer cell inhibitory activities (P < 0.001). The IC50 of these two polyynes were observed at 1-5 µM on the colorectal cancer cells. Treatment with active fraction and compounds noticeably induced apoptosis, and distinctly induced the G2/M phase arrest of the cell cycle in a time- and concentration-dependent manner. The trend of increasing cyclin A and cyclin B1 were similar to the increase of G2/M phase cells in all treated groups. These results suggested that active O. horridus fraction and selected polyynes had potential antiproliferative activities on human colorectal cancer cells. The observed cancer chemopreventive effects could be related to the induction of apoptosis and regulation of cell cycle transition. (This work was supported in part by the NIH/NCCAM grants AT003255, AT004418 and AT005362).

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B69.
Abstract B70: Physical activity and BMI in a population-based case-control study of endometrial cancer risk
Authors: Arem Hannah , Irwin Melinda L. , Zhou Yang , Lu Lingeng , Risch Harvey , Yu Herbert
Published: January 2011

Introduction: Endometrial (uterine corpus) cancer is the fourth most common incident cancer among women in the United States. Recent systematic reviews have published summary data suggesting an inverse association between physical activity and risk of endometrial cancer. However, studies show conflicting results, many do not report on reliability or validity of physical activity questionnaires, and few studies have examined the combination of physical activity and BMI on endometrial cancer risk. Thus, we evaluated the independent association between physical activity, BMI and endometrial cancer risk, as well as the combination of physical activity and BMI on risk.

Methods: We identified 668 incident cases of endometrial cancer through the population-based Rapid Case Ascertainment Shared Resource at the Yale Cancer Center and age-matched 665 controls using random digit dialing. Research staff interview-administered structured questionnaires, collecting information on demographic features, environmental exposures and lifestyle factors. We performed unconditional logistic regression to examine the relationship between moderate- to vigorous-intensity sports/recreational physical activity (MV PA) and endometrial cancer risk.

Results: We found, compared to women reporting 0 Metabolic Equivalent (MET) hours per week of MV PA, those who reported 7.5 MET hr/wk or more of MV PA had a 34% lower endometrial cancer risk (Odds Ratio (OR) = 0.66, 95% CI: 0.50-0.87) after adjusting for other risk factors including BMI. We created a composite measure of physical activity (inactive ≤ 7.5 MET hr/wk, active > 7.5 MET hr/wk) and BMI (normal weight < 25 kg/m,2 overweight ≥ 25 kg/m2), and found that women who were normal weight and active had a 73% lower endometrial cancer risk (OR = 0.27, 95% CI: 0.19-0.38) compared to the reference group of overweight and inactive. Women who were normal weight but inactive had a 55% lower endometrial cancer risk (OR = 0.45, 95% CI: 0.31-0.65) and women who were overweight but active had a 38% lower risk of endometrial cancer (OR= 0.62, 95% CI: 0.47-0.83).

Conclusion: Our data support an inverse, independent association between physical activity and endometrial cancer risk after adjusting for BMI and other risk factors. However, the combination of physical activity and BMI appears to further impact risk of endometrial cancer. Programs to increase physical activity levels to the current recommendation of 150 minutes per week may lower the incidence of endometrial cancer.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B70.
Abstract B72: Clinical and morphological traits of patients with triple-negative breast cancer
Authors: Petrova Valentina Dmitriyevna , Sinkina Tatiyana Vladimirovna , Selezneva Inna Anatolievna , Dimitriady Julia Nicolaevna , Boyarskikh Uljana Aleksandrovna , Ermolenko Natalya Aleksandrovna , Filipenko Maxim Leonidovich , Lazarev Alexander Fedorovich
Published: January 2011

Background: Breast cancer (BC) is the most prevalent cause of mortality from cancer in women aged 40-69 years in Russian Federation. There are results of clinical researches about triple negative BC [ER(-); PR(-); HER2/neu (-)].

Materials and Methods: The register consisted of 1428 Caucasian women with BC aged 20-79 years (756 — familial and 672 — sporadic BC), control group composed 1581 Caucasian women aged 19-84 years without of cancer. The questioning including data of pheno- and genotype. BRCA or other mutations were performed to all patients. The researching morphological traits of tumor were histological type, estrogen receptor (ER), progesterone receptor (PR) and HER2/neu.

Results: Triple negative BC was found out by 21 BRCA positive patients, 32 BRCA negative patients and 27 patients with sporadic BC. Some of reproductive and clinical factors differed in two groups: triple negative and non-triple negative BC. Among triple negative BC patients, women with sporadic BC were older and had clinical stage higher. Specific gravity of rare tumors was higher by patients with BRCA mutations.

Conclusion: The women with BC can be divided into two groups: having triple negative phenotype and all the rest. Considering these factors let us prognosticate progress notes and form an individual plan of special treatment.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B72.
Abstract B73: Body mass index modifies the association between SMAD7 polymorphism rs4939827 and colorectal cancer risk
Authors: Coghill Anna E. , Passarelli Michael N. , Makar Karen W. , Zheng Yingye , Potter John D. , Wernli Karen J. , Hutter Carolyn M. , Newcomb Polly A.
Published: January 2011

Introduction: SMAD7 inhibits the activity of transforming growth factor beta (TGF-β), an anti-inflammatory molecule that acts as a tumor suppressor and might be important for colorectal cancer incidence. We investigated the association between the risk of colorectal cancer and two common polymorphisms in SMAD7 (rs4939827, rs4464148) previously identified in GWAS as potentially associated with colorectal cancer. We further investigated these relationships across strata of environmental factors related to inflammation, including non-steroidal anti-inflammatory drug (NSAID) use and body mass index (BMI).

Methods: Incident cases of invasive colorectal cancer diagnosed from 1997-2002 in Caucasian, post-menopausal women residing in 13 counties in western Washington State were identified from SEER reports. Community-based controls were randomly selected from population lists, matched on 5-year age intervals to the cases. Women completed a baseline interview and provided a blood or buccal sample, which was genotyped for rs4939827 and rs4464148. Logistic regression was used to generate odds ratios (OR) and 95% confidence intervals (CI) for the association between SMAD7 polymorphisms and colorectal cancer risk. Interaction terms for body mass index (BMI) and non-steroidal anti-inflammatory drug (NSAID) use were included in logistic regression models to investigate potential effect modification.

Results: We did not observe evidence for any association between rs4464148 and colorectal cancer risk. However, the minor allele for rs4939827 (C allele) was associated with a significantly decreased risk of colorectal cancer overall (CT: OR: 0.81; 95% CI 0.62-1.06; CC OR: 0.73; 95% CI 0.53-1.01), p-trend=0.05. We observed significant heterogeneity for the association between rs4939827 and colorectal cancer (p-interaction=0.02) according to body mass index. Reductions in colorectal cancer risk associated with rs4939827 were limited to only non-obese women. No differences in the association of either SMAD7 polymorphism with colorectal cancer according to NSAID use were observed.

Conclusion: Our results support a role for genetic variation in SMAD7 in altering colorectal cancer risk among women. SMAD7 likely alters the risk of colorectal carcinogenesis through its regulatory role in the TGF-β pathway, which is involved in both cellular proliferation and inflammation. Our findings also suggest that exogenous and modifiable risk factors that affect inflammation, such as body mass index, may have the potential to alter the association between endogenous factors such as SMAD7 and colorectal cancer.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B73.
Abstract B84: Prospective study of self-reported diabetes and risk of upper gastrointestinal cancers
Authors: Lin Shih-Wen , Freedman Neal , Hollenbeck Albert , Abnet Christian
Published: January 2011

While gastric non-cardia adenocarcinoma (GNCA) incidence rates in the United States have decreased, the rates of gastric cardia adenocarcinoma (GCA) and esophageal adenocarcinomas (EADC) have increased. Obesity increases the risks of GCA and EADC, and the associations may be partially mediated by insulin resistance. A few case-control studies have shown an association between diabetes and an increased risk of EADC. We examined the association between self-reported diabetes and GCA, GNCA, EADC, and esophageal squamous cell carcinoma (ESCC) in a prospective cohort of approximately 500,000 people in the United States, ages 50-69 at baseline, using Cox proportional hazards regression to estimate the hazard ratios (HR) and 95% confidence intervals (CIs), controlling for multiple potential confounders. In contrast with previous case-control studies, the results of our prospective analysis showed no association with risk of EADC, HR (95% CI) = 0.98 (0.73-1.31). Furthermore, self-reported diabetes showed no association with ESCC, HR (95% CI) = 1.02 (0.60-1.74), or GNCA, HR (95% CI) = 0.98 (0.70-1.37). However, diabetes was significantly associated with an increased risk of GCA, HR (95% CI) = 1.89 (1.43-2.50). The association between diabetes and risk of GCA remained after adjustment for body mass index (BMI), HR (95% CI) = 1.70 (1.28-2.26). Analyses stratified on World Health Organization BMI categories yielded similar estimates. Our results suggest that the metabolic and hormonal changes related to diabetes may play an important role in the etiology of GCA independently from BMI.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B84.
Abstract B86: Changes in social inequalities in male smoking-attributable mortality in two European countries
Authors: Singhal Sonica , Jha Prabhat , Zatonski Witold , Menvielle Gwenn , Boreham Jill , Peto Richard
Published: January 2011

Background: Past studies have assessed trends in smoking prevalence among different social strata in developed countries. However, we know of no study that quantifies changes in social inequalities in smoking-attributable mortality rates over time. The aim of this study was to assess changes in social inequalities for smoking-attributable male mortality rates by educational level between two time periods in France and Poland.

Methods: The contribution of smoking to adult male mortality in each population was estimated indirectly from disease-specific death rates in that population (using absolute lung cancer rates to indicate proportions due to smoking of mortality from certain other diseases). We applied these methods to male death rates at ages 35-69 years from three different social strata in France and Poland, based on a total of 202,779 deaths. The social strata were low, middle, and high based on completed years of education (less than 12 years, 12 years, and more than 12 years, respectively). For France, the comparison periods were 1990-94 and 1995-99; for Poland, 1995 was compared to 2002.

Results: Smoking-attributable mortality rates were 3 to 6 times higher in the lowest education group as compared to the highest education group in both countries. In France, smoking-attributable mortality rates within each education group remained similar between 1990-94 and 1995-99. Between 1995 and 2002, Poland showed a reduction in smoking-attributable mortality rates by 15%, 4%, and 52% in the low, middle, and high education group, respectively.

Conclusion: Although men in the lowest education group in France were around four times more likely to die from smoking as compared to those in the highest education group, there was little change between the periods studied for this country. While smoking-attributable mortality rates in the highest education group of Polish males decreased much more compared to the lower education groups; declines were seen in all education groups. Mortality rates from more recent years, when tobacco control efforts have accelerated in both countries, will be of interest to confirm these trends.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B86.
Abstract B87: Cigarette smoking, lifetime exposure to passive smoking, and the risk of non-Hodgkin lymphoma in the California Teachers Study
Authors: Lu Yani , Wang Sophia S. , Reynolds Peggy , Sullivan-Halley Jane , Chang Ellen T. , Clarke Christina A. , Ma Huiyan , Bernstein Leslie
Published: January 2011

Background: Overall, epidemiological studies conducted to date do not support a causal relationship between smoking and non-Hodgkin lymphoma (NHL) risk. However, previous studies did not account for passive smoking in the referent group of never smokers, which may have masked subtle effects. We therefore examined the effects of cigarette smoking and passive smoking on NHL risk in the prospective California Teachers Study (CTS) cohort.

Methods: The CTS collected lifetime smoking and household passive smoking exposures in 1995 and lifetime passive smoking exposures in three settings (household, workplace, and social) in 1997-1998. Multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CI) were estimated by fitting Cox proportional hazards models for NHL risk with follow-up through 2007.

Results: Compared to never smokers, ever smokers had a 1.11-fold elevated NHL risk (95% CI=0.94-1.30) which increased to 1.22 (95% CI=0.95-1.57) when women with household passive smoking were excluded from the reference category. Statistically significant dose-response trends were observed for lifetime cumulative smoking exposures (intensity and pack-years) when women with household passive smoking were excluded from the reference category (both p-trend=0.02). Among never smokers, NHL risk increased with increasing lifetime passive smoking exposure [RR=1.51 (95% CI=1.03-2.22) for more than 40 vs. less than or equal to 5 years, p-trend=0.03]. Both smoking and passive smoking were associated with increased risk of follicular lymphoma, but not other NHL subtypes.

Conclusion: Our study provides evidence that smoking and passive smoking may play a role in NHL etiology, particularly for follicular lymphoma. Studies evaluating the effect of smoking should consider the effects of passive smoking.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B87.
Abstract B88: Smoking and survival after breast cancer diagnosis: Role of molecular subtype, body mass index, and menopausal status
Authors: Braithwaite Dejana , Tammemagi Martin , Moore Dan H. , Hiatt Robert A. , Nair Seena , Caan Bette
Published: January 2011

Background: Cigarette smoke has been found to affect the metastatic potential of tumor cells and stimulate angiogenesis but its effect on survival among women diagnosed with breast cancer remains poorly understood.

Methods: In a cohort of 2265 multiethnic women diagnosed with breast cancer between 1997 and 2000 and followed for the median of 9 years, we examined whether smoking affected death from breast cancer, non-breast cancer-related causes and all causes. Proportional-hazards models were used to determine whether smoking was associated with time to death while taking into account baseline age, education, body mass index, tumor characteristics and adjuvant treatment. All statistical tests were two-sided.

Results: There were 164 deaths from breast cancer and 120 deaths from non-breast cancer causes during the median follow up of 9 years. Compared with never smokers, women who were current or past smokers had a 39% higher rate of dying from breast cancer [hazard ratio (HR)=1.39, 95% confidence interval (CI) 1.05-1.84] and a two-fold higher rate of dying from competing (non-breast cancer) causes (HR=2.16, 95%CI 1.57-3.00). Subgroup analyses revealed that the adverse effect of smoking on breast cancer survival was highest among women with HER2 negative tumors (HR=1.61, 95%CI 1.12-2.32), body mass index of <25kg/m2 (HR=1.83, 95%CI 1.10-3.04) and postmenopausal status (HR=1.47, 95%CI 1.08-1.99).

Conclusions: In this prospective cohort study, smoking was associated with an important increased in the risk of death from all causes, competing and breast cancer-specific causes independently of clinical, sociodemographic and other lifestyle-related factors. Molecular breast cancer subtype, body mass index and menopausal status modified the effect of smoking on breast cancer-specific survival.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B88.
Abstract B9: Is delayed diagnosis of lung cancer preventable?
Authors: Hassan Wafaa
Published: January 2011

Background: Major efforts have been made worldwide to speed the process of referral for patients with suspected lung cancer. Delay in diagnosis of cancer is recognized as an important factor in the overall outcome of treatment.

Aim: The purpose of this study was to test if the symptom history of patients with operable disease differs from that of patients with inoperable disease.

Methods: 39 men and women recently diagnosed with lung cancer at Assiut University Hospital during the period from August 2009-June 2010 were included in this study. The main outcome measures were the symptoms leading up to a diagnosis of lung cancer in operable and inoperable cases.

Results: Patients recalled having new symptoms for many months, typically over the year before their diagnosis, irrespective of their disease stage once diagnosed.

In the time interval between appearance of the first symptom and operation, a significantly shorter median delay was found for patients with operable and inoperable lung cancer (P=0.028). Concerning the interval from first contact with the healthcare system to operation a significantly shorter median delay was found for the group of patients in operable compared to the inoperable patients (P=0.019).

Conclusion: Our findings, although preliminary, suggest that the widely held view that lung cancer is silent until far advanced may be inaccurate. Encouragement to present early with signs of lung cancer should be considered alongside other efforts to speed up diagnosis and treatment. A few months delay before final treatment of a non-small-cell lung cancer seems to have an impact on the perioperative stage of the cancer, and thereby on the patients prognosis. A screening of asymptomatic risk-group patients will result in recognition of early lung cancer.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B9.