bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5362: Mechanisms involved in hormone promoted growth of preneoplastic mammary lesions
Authors: Arumugam Arunkumar , Lakshmanaswamy Rajkumar 
Published: February 2011

Abstract
Carcinogenesis is a complex process, which involves initiation, promotion and progression. Copenhagen strain of rat is a well known animal model which is resistant to carcinogen-induced mammary carcinogenesis. In our laboratory, we were able to induce a very high incidence of mammary cancers in these rats using combination of carcinogen N-methyl-N-nitrosourea (MNU), followed by estradiol and progesterone treatment. We have demonstrated that the resistance to mammary carcinogenesis in these rats is not due to inhibition of initiation but due to reduced hormone promotional environment and we further extend our research to investigate the molecular mechanisms involved behind this hormone-induced promotion. We used both in vivo and in vitro experimental system to understand the mechanisms involved in mammary cancer promotion and progression. Seven week old female Copenhagen rats were administered a single dose of MNU at a dose of 50 mg/kg body weight intraperitoneally. Four weeks post carcinogen administration, the rats were killed and preneoplastic lesions were excised and used for further in vitro experiments. The preneoplastic lesions were cultured and were treated with estradiol, progesterone or a combination of both hormones. Changes in survival and cell death pathways in the cultured preneoplastic lesions in response to different hormone treatments were analyzed using different molecular techniques. Our result indicates that hormone treatment induces alterations in cell survival and cell death pathways of the preneoplastic lesions demonstrating the significance of hormones in promotion and progression of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5362.
Abstract 5365: Zeranol-containing serum (Z-Sera) harvested from 30-day Z-implanted heifers induce transformation of human normal breast epithelial cells through down-regulation of the protein tyrosine phosphatase γ (PTPγ) tumor suppressor gene
Authors: Lin Young C. , Ye Weiping , Xu Ping-Ping , Threlfall Walter R. , Li Hong , Lin Shu-Hong , Kuo Chieh-Ti 
Published: February 2011

Abstract
The morbidity of breast cancer ranks first in the U.S. it remains the second leading cause of maligancy-related death in women, regardless of advances in novel therapeutic strategies. Many risk factors have been associated with breast cancer initiation, promotion and progression. Recently, Zeranol (Z), one of six growth promoters approved by FDA for use in the beef industry may cause health concerns due to the consumption of beef products containing bio-active Z metabolites. Our laboratory previously demonstrated that Z down-regulates the expression of estrogen-regulated PTPγ in primary cultured human normal breast epithelial cells and transforms the normal human breast epithelial cell line, MCF-10A, to neoplastic breast cancer cells. In the current study, we investigated the biologically active Z metabolites present in Z-Sera harvested from 30-day post Z implanted heifers (72 mg pellet) on MCF-7 cell growth and PTPγ mRNA expression in MCF-10A cells using non radioactive cell proliferation and real time PCR. Our results showed that Z-Sera at 0.5, 2.5 and 12.5% significantly increased the growth of MCF-7 cells by 42, 71, and 108%, respectively. While the sera harvested from the control heifers did not increase MCF-7 cell growth. Treatment with 2.5% Z-sera harvested 30, 60, 90 days post Z-implantation significantly down-regulated the expression of PTP γ mRNA in MCF-7 cells to 18.2, 36.5 and 51%, respectively. Furthermore, neoplastic transformation of MCF-10A cells resulted after exposure of 2.5% Z-Sera in culture medium to MCF-10A for 21-day. The expression of PTPγ mRNA, in transformed MCF-10A cells, was significantly reduced by 83, 96 and 97%, as compared to the controls. We hypothesize that the transformation of MCF-10A cells by bio-active Z metabolites contained in 2.5% Z-sera may be mediated through the down-regulation of estrogen-regulated PTPγ in MCF-10A cells. We have reported that the growth rate of pre-adipocytes isolated from the beef cattle 30-day post Z-implantation was 12 fold faster than the pre-adipocytes isolated from of the control beef cattle. In summary, our in vitro data suggest that potential adverse health risk may result from consuming beef products containing bio-active Z metabolites. (Supported by NIH grant R01 ES 015212).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5365.
Abstract 5378: Targeting CXCL12/CXCR4 signaling axis for pancreatic cancer therapy
Authors: Singh Seema , Talwar Sudha , Srivastava Sanjeev , Braune Sarah , Owen Laurie B. , Singh Ajay P. 
Published: February 2011

Abstract
Pancreatic cancer is a lethal malignancy with an extremely poor prognosis. Furthermore, it is also highly resistant to currently available therapeutic modalities. Hence, it is very important to better understand the drug-resistance mechanisms and to develop novel and effective therapeutic strategies. Chemokine signaling has been shown to play an important role in cancer progression and metastasis. Importantly, a chemokine receptor, CXCR4, has been shown to be expressed in pancreatic cancer tissues, precancerous lesions, and cancer stem cells. CXCR4 signaling induced by binding to its ligand (CXCL12) potentiates pancreatic tumor cell growth, migration and invasion, and distant metastasis in an autocrine and/or paracrine fashion. CXCL12/CXCR4 signaling has also been shown to facilitate the tumor-microenvironment interaction and induce desmoplastic alterations in the stroma, which is a common feature of pancreatic adenocarcinoma. Therefore, targeting CXCR4, alone or in combination with cytotoxic drug, might be an effective strategy for pancreatic cancer therapy. Here, we examined the expression of CXCR4 in a panel of twelve pancreatic cancer cell lines and pancreatic cancer tissues. Our data document that CXCR4 is expressed by all pancreatic cancer cell lines and overexpressed in pancreatic cancer tissues as compared to corresponding normal pancreas. Furthermore, treatment with CXCL12 induced the growth of pancreatic cancer cells, indicating the functionality of the CXCL12/CXCR4 signaling axis and suggesting its potential suitability as a therapeutic target. Interestingly, pancreatic cancer cells treated with CXCL12 showed reduced cytotoxicity to the cytotoxic drug 5-fluoro-uracil (5-FU) as compared to cells treated with drug alone. Treatment with CXCR4 antagonist, AMD3100, arrested the CXCL12-induced pancreatic cancer cell growth, and resulted in a cooperative growth inhibitory effect with 5-FU treatment. Taken together, our findings suggest that targeting of CXCL12/CXCR4 signaling axis can be exploited as a novel and effective approach for pancreatic cancer therapy, alone or in combination with cytotoxic chemotherapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5378.
Abstract 5379: Mechanism of fludarabine and oxaliplatin combined activity depends on the activity of XPF endonuclease
Authors: Zecevic Alma , Ewald Brett , Sampath Deepa , Wierda William , Plunkett William 
Published: February 2011

Abstract
We set out to determine the mechanism by which fludarabine and oxaliplatin exert more than additive cell killing in chronic lymphocytic leukemia (CLL). We postulate that enhanced activity of oxaliplatin and fludarabine combination is based on termination by fludarabine of DNA re-synthesis associated with nucleotide excision repair (NER) following removal of oxaliplatin adducts. The blocked repair would result in single-strand and double-strand DNA breaks which would activate cell DNA damage signaling and apoptosis. More than additive apoptotic killing was observed in 49% (±22) of CLL cells after exposure to oxaliplatin and fludarabine in vitro, although single agents showed minimal increase in cell death (3% ±9 for oxaliplatin, 13% ±14 for fludarabine), as demonstrated by Annexin V and PI staining at 24 hr (expected vs. observed p=0.0003; n=10). Oxaliplatin induced a 2-fold increase in DNA synthesis in CLL cells, which was inhibited by fludarabine, as determined by thymidine incorporation (n=5). Knockdown of XPF, the NER 5′ endonuclease, in CLL patient samples (n=3) eliminated oxaliplatin induced DNA synthesis (3-fold increase in thymidine incorporation with scramble siRNA compared to 1.4-fold increase with XPF siRNA). Wild type CHO (AA8) cells showed more than additive killing after combination treatment similar to the observation with CLL patient samples (predicted survival 50%; observed 21%). In contrast, only additive killing was observed in CHO cells lacking XPF (UV41) with equitoxic doses of oxaliplatin and fludarabine (predicted survival 56%; observed 54%) suggesting that XPF function is essential for the cooperative interaction of the combination. Alkaline assays demonstrated that inhibition of repair by fludarabine was accompanied by DNA strand break formation within 12 hr (n=4) in CLL patients samples. The increase in Olive tail moment ranged from 2- to 5-fold, confirming induction of single-strand breaks. The double-strand break repair proteins ATM, SMC1, H2AX and DNA-PKcs were phosphorylated as early as 2 hr post-treatment with the combination and persisted up to 24 hr (3-fold, 24-fold, 10-fold and 10-fold increase, respectively; n=4). This response suggests that DNA damage generated by fludarabine and oxaliplatin exposure was processed to double-strand DNA breaks in CLL cells. Our work provides evidence that the combination of oxaliplatin and fludarabine results in the formation of toxic DNA damage and that their combined activity depends on a functional NER pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5379.
Abstract 538: Mesenchymal stem cell subset prevents cycling of KG1a leukemic cells by cell-cell interaction
Authors: Donepudi, SreeKanth , Porada Christopher D. , Zanjani Esmail , Almeida-Porada Graça 
Published: February 2011

Abstract
The interactions that occur between leukemic cells and the microenvironment are currently poorly understood. The definition of novel pathways that deliver survival and drug resistance signaling from the milieu to leukemic cells may lead to the discovery of new drugs that are able to target microenvironmental cues perpetuating the leukemic clones. Since the bone marrow (BM) environment is comprised of a complex assortment of different cell types, matrices and soluble and membrane-bound factors, it is crucial to start delineating specific cell-cell interactions and their effects on leukemic cell survival. Mesenchymal stem cells (MSC) are a fundamental component of the BM niche as they support hematopoiesis and are able to differentiate into neighboring cellular types. Therefore, in these studies we investigated the effect of Stro-1+ MSC on the growth and survival of KG1a, a primitive, differentiation-resistant subtype of acute myeloid leukemia. MSC and KG1a cells were co-cultured for 3 days under contact or non-contact conditions, at incremental ratios of 1:1, 1:5, 1:10 and 1:100 respectively, while maintaining a constant initial total number of cells for each dilution (n=3). In transwell non-contact cultures, KG1a cells proliferated at the same rate as KG1a alone with a 3 to 5 fold increase in cell numbers, regardless of the ratio. By contrast, when KG1a were cultured in direct contact with MSC, KG1a growth inhibition was directly proportional to the MSC:KG1a ratio. Specifically, MSC cultured with KG1a cells at ratios of 1:1, 1:5, 1:10, and 1:100 inhibited the growth of KG1a cells by 84%, 76%, 74%, and 45%, respectively while remaining 99-100% viable. Thus, we next performed cell cycle analysis using flow cytometry and found that while the cell cycle distribution of KG1a cultures were: 23% in G0/G1; 19% in G2/M; and 58% in S phase, KG1a co-cultured with MSC had undergone cell cycle arrest in S-phase (98%). Although our results contrast with prior studies showing that MSC inhibited KG1a in G1phase through the production of soluble factors, it is possible that the differences seen are due to the population of MSC used. Within the MSC, Stro-1+ cells constitute a primitive population of cells in intimate relation with the osteoblastic niche, the role of which is to retain stem cells in a quiescent state. Therefore, studies are currently underway to identify molecules responsible cell cycle arrest upon KG1a/MSC interaction.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 538.
Abstract 5383: Cucurbitacin B, a novel in vivo potentiator of gemcitabine with low toxicity in the treatment of pancreatic cancer
Authors: Iwanski Gabriela B. , Thoennissen Nils H. , Lee Dhong Hyung Tony , Doan Ngan B. , Castor Brandon , Le Alison , Toh Melvin , Bokemeyer Carsten , Said Jonathan W. , Koeffler H. Phillip 
Published: February 2011

Abstract
Pancreatic cancer is a highly aggressive malignancy, and improvement in systemic therapy is necessary to treat this frequently encountered metastatic disease. The current targeted agents used in combination with gemcitabine improved objective response rates, but with little or no improvements in survival and also increased toxicities in pancreatic cancer patients. Recently, we showed that the triterpenoid cucurbitacin B inhibited tumor growth in pancreatic cancer cells by inhibition of the JAK/STAT pathway, and synergistically increased antiproliferative effects of gemcitabine in vitro. The anti-tumor and toxicity effects of cucurbitacin B in combination with gemcitabine were tested against human pancreatic cancer cells in a murine xenograft model. The combinatory therapy of cucurbitacin B and gemcitabine at relatively low doses (0.5 mg/kg and 25 mg/kg, respectively) resulted in highly significant tumor growth inhibition of pancreatic cancer xenografts by up to 79% (p&lt;0.001). Remarkably, this therapy was well tolerated by the animals, including histology of inner organs, analysis of serum chemistries, full blood counts, and bone marrow colony numbers. Western blot analysis of the tumor samples of mice who received both agents, cucurbitacin B and gemcitabine, revealed stronger inhibition of Bcl-XL, Bcl-2 and c-myc, and higher activation of the caspase-cascades compared to single agent treated mice. The in vivo combination therapy of cucurbitacin B and gemcitabine has profound antiproliferative effects against human pancreatic cancer cells, without any significant signs of toxicity. This promising combination should be examined in therapeutic trials of pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5383.
Abstract 5391: Rosiglitazone and Gemcitabine combination therapy limits tumor progression and prolongs survival in pancreatic adenocarcinoma
Authors: Bunt Stephanie K. , Hollingsworth Michael A. 
Published: February 2011

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer related mortality with a dismal 2-5% 5-year survival rate because clinically apparent disease is usually detected late in disease progression and lacks effective therapies. The current ‘standard of care’ for pancreatic cancer patients is Gemcitabine, a deoxycytidine analog, which has been shown to increase quality of life and the median survival of patients by a few weeks. Although Gemcitabine therapy limits pancreatic tumor progression, PDA is often insensitive to chemotherapeutic agents, limiting their success and underlining the need for additional therapies which would enhance the efficacy of current treatments.
We investigated combinations of Gemcitabine with drugs that target both the growing tumor and the immunosuppressive inflammatory microenvironment. Inflammation accompanies tumor progression in pancreatic cancer which can support tumor cell survival and growth directly, enhance tumor cell resistance to Gemcitabine and limit anti-tumor immune responses through induction of immunosuppressive mechanisms. Rosiglitazone Maleate, an FDA-approved drug for the treatment of type II diabetes, targets the PPARγ receptor, a major modulator of the inflammatory response. Rosiglitazone has been shown to limit tumor growth through effects on angiogenesis, differentiation and apoptosis. Additionally, some evidence suggests that PPARγ may regulate multi-drug resistance and may therefore limit tumor chemoresistance.
We found that Rosiglitazone enhanced the efficacy of Gemcitabine by reducing tumor proliferation, limiting invasiveness, and enhancing tumor cell apoptosis in vitro. Therapeutic combination of Rosiglitazone and Gemcitabine was evaluated in subcutaneous and orthotopic models of pancreatic cancer, and revealed that the combination significantly reduced tumor progression and metastasis, enhanced tumor cell apoptosis in vivo and significantly extended overall survival compared to Gemcitabine alone. Together these results provide pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic adenocarcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5391.
Abstract 5393: Regression of a human T-cell leukemia lacking the methylthioadenosine phosphorylase (MTAP) gene without toxicity of 6-thioguanine (6TG) by pretreatment with methylthioadenosine (MTA)
Authors: Bertino Joseph R. , Johnson-Farley Nadine , Perez Raymond P. , Lubin Adam , Lubin Martin 
Published: February 2011

Abstract
The MTAP gene, at chromosomal locus 9p21, is frequently co-deleted with p16, especially in T-cell acute lymphocytic leukemias, mesotheliomas, gliomas, lung and pancreatic carcinomas, and sarcomas. In normal cells, MTAP cleaves MTA to adenine and 5-methylthioribose-1-phosphate, which are converted to adenine nucleotides and methionine. We previously showed that mice are protected from 6TG toxicity by preadministration of MTA, generating adenine and blocking conversion of 6TG to its nucleotide. (Lubin M, Lubin A. 2009: Proceedings of the American Association for Cancer Research. Abstract LB-29; Selective Killing of Tumors Deficient in Methylthioadenosine Phosphorylase: A Novel Strategy: PLoS One, ePub May 29, 2009). We now demonstrate that MTA completely protects mice bearing MTAP-negative CEM-CCRF human T-cell leukemia from 6TG toxicity while the tumor remains responsive. Following two small pilot studies, 24 NOD-SCID mice were inoculated subcutaneously with 5 million CEM cells; when tumor size reached 500 cubic mm, mice were randomized to 4 groups of 6 animals. All mice treated with vehicle or MTA alone were sacrificed on day 14 because of tumor size; MTA showed no toxicity. Animals treated with 6TG (75 mg/kg), on days 1, 4, 7, had marked tumor regression but died of toxicity by day 12. However, animals treated with MTA (100 mg/kg) followed one hour later by 6TG (75 mg/kg) had complete tumor regression by day 14, and no weight loss; but tumor recurred in all animals by day 24. While further optimization of dose and schedule is needed, these studies clearly show that marked tumor regression can be obtained without toxicity in tumors lacking MTAP, by competitively inhibiting 6TG conversion to nucleotides. As MTA has been given safely to humans, we are planning clinical trials using this strategy in patients with tumors lacking MTAP.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5393.
Abstract 5398: Drug combination synergy quantification in animals and clinics using computerized combination index method
Authors: Chou Ting-Chao 
Published: February 2011

Abstract
Drug combination has been used for thousand of years, and currently widely used in the treatments of cancer, AIDS, and other diseases. Drug combination studies have been carried out mostly in vitro but rarely in animals and clinics due to cost, efficiency, ethical considerations, etc. However, the “definition of synergy” is universal and can be quantitatively determined as indicated by Chou & Talalay in (i). Adv. Enz. Regul. 22: 27-55, 1984 and by Chou in (ii). Pharmacol. Rev. 58: 621-681, 2006, (iii). Leukemia & Lymphoma 49: 2059-2080, 2008, and (iv). Cancer Res. Perspective Article 2009 (in press). By definition, synergism is more than the additive effect, however, additive effect cannot be determined by the arithmetic sum of effect, nor by the fractional product method, nor by statistics, p value, but rather by the combination index (CI) where CI = 1, &lt; 1, and &gt; 1 indicate additive effect, synergism, and antagonism, respectively. The theory, experimental design, and computerized simulation have been discussed or illustrated in (i-iii), and in (iv) outlined the pitfalls, common errors, and frequently asked questions. The CI method of Chou-Talalay has been cited in over 400 journals and in (i) alone has been cited over 1,916 times with citations over 1,000-fold higher than the journal's impact number. The CI method, based on the median-effect principle of the mass-action law, is quantitative, efficient, simple and economical which allows using small number of data points. This paper will illustrate how synergism of two anticancer drugs can be determined in nude mice bearing mammary carcinoma MX-1, and why two similar anti-HIV clinical trials, where both used surrogate markers and fractionated doses, were published and had different results; one used 366 patients (N. Engl. J. Med. 333: 1662-1669, 1995) but was unable to determine synergism due to the experimental design, and another, which applied the CI method, used only 36 patients (Antivir. Ther. 1: 77-88, 1996), and yet was able to quantitatively determine synergism.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5398.