bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of tumor cell growth by antibodies induced after vaccination with peptides derived from the extracellular domain of Her‐2/neu
Authors: Jasinska Joanna , Wagner Stefan , Radauer Christian , Sedivy Roland , Brodowicz Thomas , Wiltschke Christoph , Breiteneder Heimo , Pehamberger Hubert , Scheiner Otto , Wiedermann Ursula , Zielinski Christoph C.
Published: January 2004

The anti Her‐2/neu monoclonal antibody Trastuzumab has strong inhibiting effects on tumor growth in vitro and in vivo and is therefore used for immunotherapy in breast cancer patients. Due to necessity of frequent applications, however, cost intensiveness of Trastuzumab treatment and its limited duration of affectivity, an active immunization inducing a perhaps preventive and long‐term immunity to Her‐2/neu remains a desirable goal. We attempted to induce anti Her‐2/neu antibodies by peptide vaccination and to test their efficacy in inhibiting tumor cell growth in vitro. By computer aided analyses, 7 putative B cell epitopes of Her‐2/neu were defined and synthesized. These peptide epitopes were coupled to tetanus toxoid and used for immunization in BALB/c mice. Among these peptides, immunizations with 2 single peptides or a combination of 2 peptides induced anti‐peptide antibody levels, primarily of the IgG1 isotype. These antibodies were also directed against the native Her‐2/neu antigen, as shown in precipitation assays and ELISA with cell lysates of the Her‐2/neu overexpressing breast cancer cell line SK‐BR‐3. Isolated IgG fractions from immune sera incubated with SK‐BR‐3 cells led to a moderate inhibition of the tumor cell growth in vitro, as well as to complement dependent cell lyses comparable to that achieved by incubation with Trastuzumab. Moreover, peptide immunization in rabbits generated anti‐Her 2‐neu IgG that, in contrast to mouse sera, were able to mediate a 31–46% lysis of SK‐BR‐3 cells in ADCC experiments. We conclude from our data that immunization with Her‐2/neu peptides successfully induced humoral immune response with anti‐tumor activity in an animal model. © 2003 Wiley‐Liss, Inc.
The IGF‐1 receptor in cancer biology
Authors: Baserga Renato , Peruzzi Francesca , Reiss Krysztof
Published: January 2004

The type 1 insulin‐like growth factor receptor (IGF‐1R) plays an important role in the establishment and maintenance of the transformed phenotype. It also has a strong antiapoptotic activity and has a significant influence on the control of cell and body size. Downregulation of the IGF‐1R leads to massive apoptosis of cancer cells. These characteristics make it an attractive target for anticancer therapy. © 2003 Wiley‐Liss, Inc.
Comparative evaluation of urokinase‐type plasminogen activator receptor expression in primary breast carcinomas and on metastatic tumor cells
Authors: Hemsen Alice , Riethdorf Lutz , Brünner Nils , Berger Jürgen , Ebel Sebastian , Thomssen Christoph , Jänicke Fritz , Pantel Klaus
Published: January 2004

The urokinase‐type plasminogen activator receptor (uPAR, CD87) plays a central role in the plasminogen activation cascade, which participates in extracellular matrix degradation, cell migration and invasion. Here we performed a comprehensive immmunohistochemical evaluation of uPAR expression in primary tumor cells, tumor‐surrounding fibroblasts, lymph node metastases and micrometastatic cells in bone marrow of patients with breast carcinomas at the time of primary diagnosis. Variable degrees of uPAR staining of tumor cells were observed in 84 of 93 (90%) carcinomas, whereas intratumoral fibroblasts were uPAR‐positive in 70 (75%) carcinomas. The fraction of uPAR‐positive primary tumor cells but not fibroblasts was positively correlated with the presence of tumor cells in bone marrow (p = 0.037), whereas no correlation with lymph node metastasis was found. Immunophenotyping of bone marrow and lymph node specimens revealed expression of uPAR on metastatic tumor cells in 10 of 13 and 22 of 23 cases, respectively. Direct comparison to the autologous primary tumor cells showed different uPAR staining scores in most patients with evidence for both up‐ and downregulation of uPAR on metastatic cells. Our results indicate that uPAR plays an active role in breast cancer metastasis and may therefore be a promising target for new biologic therapies. © 2003 Wiley‐Liss, Inc.
Novel retinoic acid derivative ABPN has potent inhibitory activity on cell growth and apoptosis in cancer cells
Authors: Um Soo‐Jong , Han Hye‐Sook , Kwon Youn‐Ja , Park Si‐Ho , Rho Young‐Soy , Sin Hong‐Sig , Park Jong‐Sup
Published: January 2004

Retinoids are natural and synthetic derivatives of vitamin A that have great promise for cancer therapy and chemoprevention. Of the retinoids developed so far, 4‐(N‐hydroxyphenyl)retinamide (4‐HPR or fenretinide) appears to have the best therapeutic potential in vitro and in vivo and is currently being tested in clinical trials for cancer prevention and therapy. To develop other potentially potent antitumor agents, we synthesized 85 retinoid derivatives. In an initial screening of these synthetic retinoids using the HCT116 colon cancer cell line, we found that 4‐amino‐2‐(butyrylamino)phenyl(2E,4E,6E,8E)‐3,7‐dimethyl‐9‐(2,6,6‐trimethyl‐1‐cyclohexenyl)‐2,4,6,8‐nonatetraenoate (ABPN or CBG41) induced the greatest growth inhibition, with an IC50 value of 0.6 μM. Subsequent studies in other cancer cell lines indicated that ABPN was much more growth‐inhibitory than all‐trans retinoic acid or 4‐HPR. Compared to 4‐HPR, ABPN induced 5.5‐ to 70.0‐fold more growth inhibition in most cancer cells, with the exception of gynecologic cancer cells. In these cells, the antiproliferative effect was only 1.5‐ to 2.8‐fold more than 4‐HPR. We examined the molecular mechanism underlying the difference in growth inhibition between 4‐HPR and ABPN. DAPI staining, DNA fragmentation, FACS and Western blotting analyses suggest that ABPN induced apoptosis by activating caspase‐3 and ‐8, which may result in increased PARP cleavage. Unlike 4‐HPR, ABPN activated all 3 RAR isotypes to an extent similar to AtRA. In addition, ABPN significantly inhibited AP‐1 transcriptional activity and thus greatly suppressed the expression of the matrix metalloproteinase ‐1, ‐2 and ‐3 genes, which are involved in tumor invasion. These results suggest that ABPN may be a promising retinoid derivative offering not only enhanced cytotoxicity, but also increased inhibition of tumor invasiveness. © 2003 Wiley‐Liss, Inc.
Fruits, vegetables and lung cancer: A pooled analysis of cohort studies
Authors: Smith‐Warner Stephanie A. , Spiegelman Donna , Yaun Shiaw‐Shyuan , Albanes Demetrius , Beeson W. Lawrence , van den Brandt Piet A. , Feskanich Diane , Folsom Aaron R. , Fraser Gary E. , Freudenheim Jo L. , Giovannucci Edward , Goldbohm R. Alexandra , Graham Saxon , Kushi Lawrence H. , Miller Anthony B. , Pietinen Pirjo , Rohan Thomas E. , Speizer Frank E. , Willett Walter C. , Hunter David J.
Published: January 2004

Inverse associations between fruit and vegetable consumption and lung cancer risk have been consistently reported. However, identifying the specific fruits and vegetables associated with lung cancer is difficult because the food groups and foods evaluated have varied across studies. We analyzed fruit and vegetable groups using standardized exposure and covariate definitions in 8 prospective studies. We combined study‐specific relative risks (RRs) using a random effects model. In the pooled database, 3,206 incident lung cancer cases occurred among 430,281 women and men followed for up to 6–16 years across studies. Controlling for smoking habits and other lung cancer risk factors, a 16–23% reduction in lung cancer risk was observed for quintiles 2 through 5 vs. the lowest quintile of consumption for total fruits (RR = 0.77; 95% CI = 0.67–0.87 for quintile 5; p‐value, test for trend < 0.001) and for total fruits and vegetables (RR = 0.79; 95% CI = 0.69–0.90; p‐value, test for trend = 0.001). For the same comparison, the association was weaker for total vegetable consumption (RR = 0.88; 95% CI = 0.78–1.00; p‐value, test for trend = 0.12). Associations were similar between never, past, and current smokers. These results suggest that elevated fruit and vegetable consumption is associated with a modest reduction in lung cancer risk, which is mostly attributable to fruit, not vegetable, intake. However, we cannot rule out the possibility that our results are due to residual confounding by smoking. The primary focus for reducing lung cancer incidence should continue to be smoking prevention and cessation. © 2003 Wiley‐Liss, Inc.
Expression of TGF‐β type II receptor antisense RNA impairs TGF‐β signaling in vitro and promotes mammary gland differentiation in vivo
Authors: Lenferink Anne E.G. , Magoon Joanne , Pepin Marie‐Claude , Guimond Alain , O'Connor‐McCourt Maureen D.
Published: January 2004

In order to clarify the role of TGF‐β in mammary development and tumorigenesis, we investigated the efficacy of full‐ or partial‐length TβRII antisense RNA specifically to reduce TβRII levels in both in vitro and in vivo model systems. Here we show that the expression of TβRII antisense RNA in vitro reduced TβRII cell surface expression and inhibited the antiproliferative and transcriptional responses to exogenous TGF‐β. Expression of full‐length TβRII antisense RNA in a transgenic mouse model under control of the mouse mammary tumor virus promotor resulted in precocious lobuloalveolar development of the mammary gland, a phenotype that resembles that of early pregnancy. These data demonstrate that TβRII plays a critical role in maintaining the nondifferentiated character of virgin mammary gland epithelium. © 2003 Wiley‐Liss, Inc.
Near‐infrared Raman spectroscopy for optical diagnosis of lung cancer
Authors: Huang Zhiwei , McWilliams Annette , Lui Harvey , McLean David I. , Lam Stephen , Zeng Haishan
Published: January 2004

Raman spectroscopy is a vibrational spectroscopic technique that can be used to optically probe the molecular changes associated with diseased tissues. The objective of our study was to explore near‐infrared (NIR) Raman spectroscopy for distinguishing tumor from normal bronchial tissue. Bronchial tissue specimens (12 normal, 10 squamous cell carcinoma (SCC) and 6 adenocarcinoma) were obtained from 10 patients with known or suspected malignancies of the lung. A rapid‐acquisition dispersive‐type NIR Raman spectroscopy system was used for tissue Raman studies at 785 nm excitation. High‐quality Raman spectra in the 700–1,800 cm–1 range from human bronchial tissues in vitro could be obtained within 5 sec. Raman spectra differed significantly between normal and malignant tumor tissue, with tumors showing higher percentage signals for nucleic acid, tryptophan and phenylalanine and lower percentage signals for phospholipids, proline and valine, compared to normal tissue. Raman spectral shape differences between normal and tumor tissue were also observed particularly in the spectral ranges of 1,000–1,100, 1,200–1,400 and 1,500–1,700 cm–1, which contain signals related to protein and lipid conformations and nucleic acid's CH stretching modes. The ratio of Raman intensities at 1,445 to 1,655 cm–1 provided good differentiation between normal and malignant bronchial tissue (p < 0.0001). The results of this exploratory study indicate that NIR Raman spectroscopy provides significant potential for the noninvasive diagnosis of lung cancers in vivo based on the optic evaluation of biomolecules. © 2003 Wiley‐Liss, Inc.
Induced antitumor immunity against DMBA‐4 metastatic mammary tumors in rats using laser immunotherapy
Authors: Chen Wei R. , Jeong Sang Won , Lucroy Michael D. , Wolf Roman F. , Howard Eric W. , Liu Hong , Nordquist Robert E.
Published: January 2004

Induced antitumor immunity is a highly effective and long‐term cure for cancer, particularly for metastatic tumors. Laser immunotherapy was developed to induce such an immunologic response. It involves intratumoral administration of a light‐absorbing dye and a specially formulated immunoadjuvant, followed by noninvasive irradiation of a near‐infrared laser. Treatment of DMBA‐4 metastatic mammary tumors in rats with this approach has resulted in local control of primary tumors and eradication of untreated distant metastases. After laser immunotherapy, rats were resistant to tumor rechallenge and developed immunity, which could be adoptively transferred. To better understand the immunity induced in this tumor model, immunization using freeze–thaw DMBA‐4 cell lysates was performed, followed by tumor challenge 21 days later. Tumor cell lysate immunization delayed the emergence of metastases but did not provide immunity against the tumor challenge. Also performed was surgical resection of primary tumors before the observation of metastatic tumors. Removal of primary tumors was unsuccessful at changing the course of tumor progression. Tumors re‐emerged at the primary sites, and metastases developed at multiple remote sites. In contrast, tumor‐bearing rats successfully treated by laser immunotherapy experienced tumor regression and eradication and developed strong resistance to repeated challenges by tumor cells of the same type. Our results show that laser immunotherapy could have potential for the treatment of metastatic tumors by inducing tumor‐specific, long‐lasting immunity. © 2003 Wiley‐Liss, Inc.
Cancer in Greenlandic Inuit 1973–1997: A cohort study
Authors: Friborg Jeppe , Koch Anders , Wohlfarht Jan , Storm Hans‐Henrik , Melbye Mads
Published: January 2004

The increasing westernization of the Arctic countries may influence the very particular cancer profile of these populations. Our objective was to investigate the development in cancer incidence from 1973 to 1997 in a large and well‐defined Inuit population in Greenland. Greenland is part of the Danish Kingdom, and population statistics covering both countries are available from the same registry resource. Data from the Danish Civil Registration System and from the Danish Cancer Registry were used to calculate age‐standardized cancer incidence rates for the periods 1973–1987 and 1988–1997 for persons born in Greenland. Using rates for Denmark, sex‐specific standardized incidence ratios (SIRs) for 1988–1997 were calculated. Furthermore, age‐ and sex‐specific incidence rates in the 2 periods were calculated for selected cancers. Total cancer incidence increased from 248.5 to 277.9 per 100,000 person‐years in men and from 269.4 to 302.2 per 100,000 person‐years in women. The incidence of lung, stomach, breast and colon cancer increased, whereas the incidence of cervical cancer decreased. Compared to the Caucasian population in Denmark, high SIRs were found for cancers of the nasopharynx, salivary gland, esophagus, stomach and cervix and low SIRs for testis, bladder, prostate, breast and hematologic cancers. Overall cancer incidence among Greenlandic Inuit is increasing as a result of increases in several cancers that are common in Western populations. A significant increase in the incidence of stomach cancer in both sexes, which contrasts global trends for this cancer, warrants further investigation. © 2003 Wiley‐Liss, Inc.
Selective and nonselective toxicity of TRAIL/Apo2L combined with chemotherapy in human bone tumour cells vs. normal human cells
Authors: Van Valen Frans , Fulda Simone , Schäfer Karl‐Ludwig , Truckenbrod Borna , Hotfilder Marc , Poremba Christopher , Debatin Klaus‐Michael , Winkelmann Winfried
Published: January 2004

Although TRAIL/Apo2L preferably induces apoptosis in tumour cells without toxicity in normal cells, many tumour cell types display TRAIL/Apo2L resistance. Whether TRAIL/Apo2L in combination with chemotherapy may overcome TRAIL/Apo2L resistance while maintaining tumour selectivity remains to be determined. Here, we report that while ActD, DOX and CDDP sensitised both OS and Ewing's tumour cell lines and normal cells (hOBs, synovial cells, fibroblasts) to TRAIL/Apo2L‐induced apoptosis, the combination of etoposide (VP16) and TRAIL/Apo2L was selectively active on tumour cells without affecting normal cells. Sensitisation of OS cells and hOBs to TRAIL/Apo2L did not correlate with a compatible change in the gene expression profile of the receptors for TRAIL/Apo2L determined by quantitative real‐time RT‐PCR. Also, sensitisation of the TRAIL/Apo2L death pathway did not rely entirely on the chemotherapy‐induced, caspase‐dependent cytotoxicity. Further, chemotherapy did not cause a compatible change in expression levels of proteins such as Bcl‐2, Bcl‐xL, Bax, cIAP2, XIAP and survivin. However, ActD, DOX and CDDP downregulated expression of cFLIP in OS cells as well as expression of p21 in normal hOBs. Interestingly, while VP16 also extinguished cFLIP in OS cells, which were sensitised for TRAIL/Apo2L by VP16, VP16 induced cFLIP and enhanced p21 levels in normal hOBs, which remained refractory to VP16 plus TRAIL/Apo2L. Together, our data reveal that TRAIL/Apo2L combined with certain chemotherapeutic drugs is toxic to bone tumour and normal human cells and suggest that cotreatment with TRAIL/Apo2L and VP16 provides an attractive approach for selective killing of tumour cells while leaving unaffected normal cells. © 2003 Wiley‐Liss, Inc.
The association between stressful life events and breast cancer risk: A meta‐analysis
Authors: Duijts Saskia F.A. , Zeegers Maurice P.A. , Borne Bart Vd
Published: January 2004

Breast cancer is the most prevalent cancer in women in Western societies. Studies examining the relationship between stressful life events and breast cancer risk have produced conflicting results. The purpose of this meta‐analysis was to identify studies on this relationship, between 1966 and December 2002, to summarize and quantify the association and to explain the inconsistency in previous results. Summary odds ratios and standard errors were calculated, using random effect meta‐regression analyses, for the following categories: stressful life events, death of spouse, death of relative or friend, personal health difficulties, nonpersonal health difficulties, change in marital status, change in financial status and change in environmental status. The presence of publication bias has been explored, and sensitivity analyses were performed to identify heterogeneity, using calculation of the percentage of variability due to heterogeneity, meta‐regression analyses and stratification. Only the categories stressful life events (OR = 1.77, 95% CI 1.31–2.40), death of spouse (OR = 1.37, 95% CI 1.10–1.71) and death of relative or friend (OR = 1.35, 95% CI 1.09–1.68) showed a statistically significant effect. Publication bias was identified in both stressful life events (p = 0.00) and death of relative or friend (p = 0.02). Sensitivity analyses resulted in the identification of heterogeneity in all categories, except death of spouse. The results of this meta‐analysis do not support an overall association between stressful life events and breast cancer risk. Only a modest association could be identified between death of spouse and breast cancer risk. © 2003 Wiley‐Liss, Inc.
Estimation of the potential for nitrosation and its inhibition in subjects from high‐ and low‐risk areas for esophageal cancer in southern China
Authors: Lin Kun , Shen Wenying , Shen Zhongying , Cai Shushen , Wu Yongning
Published: January 2004

We studied 2 counties in southern China, which are close to each other but show very different mortality rates from esophageal cancer. We collected 12 hr urine samples and analyzed them for NPRO, other nitrosamino acids, nitrate and ASC. The potential for forming NPRO and the effect on inhibition by ASC were recorded. Urine was collected after (i) no treatment, (ii) a dose of proline and (iii) proline with ASC. Intake and excretion of nitrate were significantly greater in the high‐risk area. After the proline dose, urinary excretion of NPRO was significantly greater in the high‐risk area. The inhibitory effect of ASC after taking it with proline was less in the high‐risk area. Hence, the high‐risk area showed greater potential for forming NPRO, and this formation was less inhibited by ASC. This supports the view that esophageal cancer in this area may be caused by nitrosamines formed in vivo, perhaps from nitrite produced by reduction of ingested nitrate. © 2003 Wiley‐Liss, Inc.
Intensified oxidative and nitrosative stress following combined ALA‐based photodynamic therapy and local hyperthermia in rat tumors
Authors: Frank Juergen , Lambert Christine , Biesalski Hans Konrad , Thews Oliver , Vaupel Peter , Kelleher Debra K.
Published: January 2004

Oxidative stress‐related changes in tumors upon localized hyperthermia (HT), 5‐aminolevulinic acid‐based photodynamic therapy (ALA‐PDT) and their combination (ALA+HT) were examined after the observation that the antitumor effects of ALA‐PDT could be significantly enhanced upon simultaneous application of HT. Rats bearing s.c. DS‐sarcomas (0.6–1.0 ml) on the hind foot dorsum were anesthetized and underwent one of the following treatments: (i) ALA‐PDT (375 mg/kg 5‐ALA i.v.); (ii) localized HT, 43°C for 60 min; (iii) combined ALA‐PDT and HT [=ALA+HT]. Appropriate control experiments were also performed. After treatment, tumors were excised and rapidly frozen for later analysis of nitrosative stress (protein nitration), apoptotic events (TUNEL, caspase activation, DNA and RNA fragmentation), expression of heat shock proteins (hsp70 and HO‐1), glutathione (GSH) levels and glutathione peroxidase (GPx) activity. Protein nitration was found to increase upon treatment, being especially pronounced in the ALA+HT group, and could partially be related to areas surrounding microvessels. The extent of nitrosative stress also correlated well with the appearance of the markers of apoptosis and the inhibition of in vivo tumor growth as seen in a previous study. GSH levels decreased upon treatment, the reduction being most prominent in the ALA‐PDT and ALA+HT groups. GPx activity, however, showed a significant decrease only in the ALA‐PDT group. Whereas hsp70 expression increased upon HT, ALA‐PDT caused a decrease, and these opposing effects were nullified with ALA+HT. The results obtained point to a number of cellular mechanisms—including effects on cellular defense mechanisms and an abrogation of the heat shock defense mechanism—that may interact to achieve the potentiated tumor response rate seen in vivo upon combined treatment. © 2003 Wiley‐Liss, Inc.
DNA methylation of RASSF1A, HIN‐1, RAR‐β, Cyclin D2 and Twist in in situ and invasive lobular breast carcinoma
Authors: Fackler Mary Jo , McVeigh Megan , Evron Ella , Garrett Elizabeth , Mehrotra Jyoti , Polyak Kornelia , Sukumar Saraswati , Argani Pedram
Published: January 2004

Little is known about epigenetic silencing of genes by promoter hypermethylation in lobular breast cancers. The promoter methylation status of 5 cancer‐related genes (RASSF1A, HIN‐1, RAR‐β, Cyclin D2 and Twist) was evaluated in 2 types of lobular cancers, in situ (LCIS) and invasive lobular carcinomas (ILC) (n = 32), and compared to ductal in situ (DCIS) and invasive (IDC) breast cancers (n = 71). By using methylation‐specific PCR (MSP), 100% of ILC and 69% of LCIS cases were found to have 1 or more hypermethylated genes among the panel of 5 genes (compared to 100% IDC and 95% of DCIS). Two or more hypermethylated genes were detected per tumor in 79% of invasive and 61% of in situ lobular carcinomas compared to 81% of IDC and 77% of DCIS. By contrast, DNA from nearly all normal reduction mammoplasty tissues (n = 8) was unmethylated for the 5 genes. The methylation profiles of lobular vs. ductal carcinomas with respect to RASSF1A, Cyclin D2, RARβ, and Hin‐1 genes were similar, suggesting that gene silencing by promoter hypermethylation is likely to be important in both groups of diseases. Distinctly different, Twist was hyper‐ methylated less often in ILC (16%, 3/19 cases) than in IDC (56%, 15/27 cases) (p = 0.01). These results suggest that these 2 types of tumors share many common methylation patterns and some molecular differences. Additional studies might lend further understanding into the etiology and clinical behavior of this tumor type. © 2003 Wiley‐Liss, Inc.
DNA adduct formation by the anticancer drug ellipticine in rats determined by 32P postlabeling
Authors: Stiborová Marie , Breuer Andrea , Aimová Dagmar , Stiborová‐Rupertová Martina , Wiessler Manfred , Frei Eva
Published: January 2004

Ellipticine is a potent antineoplastic agent whose mode of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Recently, we found that ellipticine also forms covalent DNA adducts in vitro and that the formation of the major adduct is dependent on the activation of ellipticine by cytochrome P450 (CYP). Here, we investigated the capacity of ellipticine to form DNA adducts in vivo. Male Wistar rats were treated with ellipticine, and DNA from various organs was analyzed by 32P postlabeling. Ellipticine‐specific DNA adduct patterns, similar to those found in vitro, were detected in most test organs. Only DNA of testes was free of the ellipticine‐DNA adducts. The highest level of DNA adducts was found in liver (19.7 adducts per 107 nucleotides), followed by spleen, lung, kidney, heart and brain. One major and one minor ellipticine‐DNA adducts were found in DNA of all these organs of rats exposed to ellipticine. Besides these, 2 or 3 additional adducts were detected in DNA of liver, kidney, lung and heart. The predominant adduct formed in rat tissues in vivo was identical to the deoxyguanosine adduct generated in DNA by ellipticine in vitro as shown by cochromatography in 2 independent systems. Correlation studies showed that the formation of this major DNA adduct in vivo is mediated by CYP3A1‐ and CYP1A‐dependent reactions. The results presented here are the first report showing the formation of CYP‐mediated covalent DNA adducts by ellipticine in vivo and confirm the formation of covalent DNA adducts as a new mode of ellipticine action. © 2003 Wiley‐Liss, Inc.
Induction of apoptosis and chemosensitization of mesothelioma cells by Bcl‐2 and Bcl‐xL antisense treatment
Authors: Hopkins‐Donaldson S , Cathomas R , Simões‐Wüst AP , Kurtz S , Belyanskya L , Stahel RA , Zangemeister‐Wittke U
Published: January 2004

The original article to which this Erratum refers was published in International Journal of Cancer (2003) 106(2) 160–166
Stage at diagnosis is a key explanation of differences in breast cancer survival across Europe
Authors: Sant M , Allemani C , Capocaccia R , Hakulinen T , Aareleid T , Coebergh JW , Coleman MP , Grosclaude P , Martinez C , Bell J , Youngson J , Berrino F
Published: January 2004

The original article to which this Erratum refers was published in International Journal of Cancer (2003) 106(3) 416–422
Dietary risk factors for testicular carcinoma
Authors: Garner MJ , Birkett NJ , Johnson KC , Shatenstein B , Ghadirian P , Krewski D
Published: January 2004

The original article to which this Erratum refers was published in International Journal of Cancer (2003) 106(6) 934–941
Cancer occurrence in Ardabil: Results of a population‐based Cancer Registry from Iran
Authors: Sadjadi A , Malekzadeh R , Derakhshan MH , Sepehr A , Nouraie M , Sotoudeh M , Yazdanbod A , Shokoohi B , Mashayekhi A , Arshi S , Majidpour A , Babaei M , Mosavi A , Mohagheghi MMA , Alimohammadian M
Published: January 2004

The original article to which this Erratum refers was published in International Journal of Cancer (2003) 107(1) 113–118
The biological effects of N3‐methyladenine
Authors: Fronza Gilberto , Gold Barry
Published: January 2004

The targeting of damage to DNA remains an attractive strategy to kill tumor cells. One of the serious side effects of alkylating agents is that they create both toxic (desired) and mutagenic (undesired) lesions. The result is that patients successfully treated for a primary cancer are at significant risk to develop cancer related to their therapy. To address this issue we have prepared agents that selectively methylate DNA at the N3‐position of adenine. The presence of this lesion in DNA is thought to halt DNA polymerase, and this then initiates a cascade of events including cell death. The toxicity and mutagenicity of the compound, Me‐lex, used to generate N3‐methyladenine is discussed in bacterial, yeast, and mammalian systems. Mechanisms are proposed to explain the biological activities of N3‐methyladenine. © 2003 Wiley‐Liss, Inc.
Modulation of phosphatidylinositol‐3‐kinase/protein kinase B‐ and mitogen‐activated protein kinase‐pathways by tea polyphenols in human prostate cancer cells
Authors: Siddiqui Imtiaz Ahmad , Adhami Vaqar Mustafa , Afaq Farrukh , Ahmad Nihal , Mukhtar Hasan
Published: January 2004

We have earlier shown that oral infusion of a polyphenolic fraction isolated from green tea, at a human achievable dose (equivalent to six cups of green tea per day), significantly inhibits prostate cancer (PCA) development and metastasis in transgenic adenocarcinoma of mouse prostate (TRAMP) model that closely mimics progressive form of human prostatic disease (Gupta et al. [2001]: Proc. Natl. Acad. Sci. U.S.A. 98:10350–10355.). A complete understanding of the mechanism(s) and molecular targets of PCA chemopreventive effects of tea polyphenols may be useful in developing novel approaches for its prevention. In this study, we employed two distinct human PCA cell lines viz. DU145 (androgen‐unresponsive prostate carcinoma cells) and LNCaP (androgen‐responsive prostate carcinoma cells) and, employing immunoblot analysis, we evaluated the effect of epigallocatechin‐3‐gallate (EGCG), the major polyphenol present in green tea and theaflavins (TF), the major polyphenol present in black tea on phosphatidylinositol‐3‐kinase (PI3K)/protein kinase B (PKB) and mitogen‐activated protein kinase (MAPK) pathways. Both EGCG and TF treatment were found to (i) decrease the levels of PI3K and phospho‐Akt and (ii) increase Erk1/2 in both DU145 and LNCaP cells. Our data showing the inhibition of the constitutive levels of PI3K and the phosphorylation of Akt could be important because the treatment approaches should be aimed at the inhibition of the constitutive levels of PI3K and Akt. Our data also suggest that Erk1/2 could be involved in the anti‐cancer effects of EGCG and TF. Taken together, our study, for the first time demonstrated the modulation of the constitutive activation of PI3K/Akt and Erk1/2 pathways by EGCG as well as TF. We suggest that detailed studies in appropriate tumor model system are needed to establish the relevance of the cell culture work to in vivo models. © 2003 Wiley‐Liss, Inc.
Identification of molecular targets for dietary energy restriction prevention of skin carcinogenesis: An idea cultivated by Edward Bresnick
Authors: Birt Diane F. , Przybyszewski Joe , Wang Weiqun , Stewart Jeanne , Liu Y.
Published: January 2004

Dietary energy restriction (DER) has long been known to strikingly inhibit carcinogenesis in many animal models. The animal data has been corroborated by recent and ongoing epidemiological studies demonstrating the importance of energy balance, physical exercise and obesity in human cancer. Dr. Edward Bresnick provided key insights into this important area of research and pivotal direction for the author's research while he served as Director of the Eppley Institute for Research in Cancer, Omaha, NE. These insights moved this research toward demonstrating that DER reduced the expression of key protein kinase C isoforms in mouse skin. More recent studies have uncovered downstream events that are inbibited by DER including blockage of tumor promoter activation of Raf‐1, ERK 1,2 and AP‐1 expression. Parallel studies have demonstrated the DER inhibition of these key cellular signaling events in mouse skin carcinogenesis are dependent upon an intact adrenal gland because adrenalectomized mice fed DER diet did not have reduced tumor burden or inhibited signaling and blocked AP‐1 activation as was observed in DER mice with intact adrenal glands. In addition, the DER inhibition of tumorigenesis and AP‐1 signaling was restored in adrenalectomized mice that were given corticosterone in the drinking water. This showed that in mice in the chemical carcinogenesis protocol glucocorticoid hormone plays a major role in mediating DER prevention of cancer. Studies are ongoing to further assess the mechanism of DER modulation of skin cancer by assessing impacts on transcriptional regulation and expression of genes that are critical in skin carcinogenesis. © 2003 Wiley‐Liss, Inc.
Transcriptional regulation of TNF family receptors and Bcl‐2 family by chemotherapeutic agents in murine CT26 cells
Authors: Choi Kyoung‐Han , Choi Hye Young , Ko Jae‐Kyun , Park Sung‐Shin , Kim Yong‐Nyun , Kim Chul‐Woo
Published: January 2004

Various chemotherapeutic agents have been shown to sensitize cancer cells to members of the tumor necrosis factor (TNF) family. However, it is unclear whether sensitization by chemotherapeutic agents involves the transcriptional regulation of apoptosis‐related genes. In this study, we investigated mRNA regulation of TNF family receptors and Bcl‐2 family members after treating the murine colon cancer cell line, CT26, with various apoptosis inducers. We found that treatment with cycloheximide, a protein synthesis inhibitor, remarkably increased CD40 mRNA levels by semi‐quantitative RT‐PCR. Other protein synthesis inhibitors, such as anisomycin and emetine, also enhanced CD40 mRNA expression, which was significantly blocked by a NF‐κB antagonist and a p38 MAP kinase antagonist. After treatment with cycloheximide, and further cultivation in fresh medium, CD40 protein levels were found to increase by flow cytometry. Additionally, we found that cycloheximide treatment appeared to downregulate the Bcl‐xL mRNA level but not the Bax mRNA level by RNase protection assay. Because the upregulation of CD40 mRNA and the downregulation of Bcl‐xL correlated with CT26 cell death, our results suggest that chemotherapeutic agents, including cycloheximide, may exert their synergistic effects on the TNF family treatment of cancer cells by regulating the mRNA levels of apoptosis‐related genes. © 2003 Wiley‐Liss, Inc.
Hyperplasia, partial hepatectomy, and the carcinogenicity of aflatoxin B1
Authors: Roebuck B.D.
Published: January 2004

Generalized cellular hyperplasia has long been associated as a factor in the causation of liver cancer. Parenchymal cell hyperplasia resulting from hepatotoxins, viruses, parasites, or malnutrition is exceedingly variable as to when it occurs, its extent, and its duration. Partial hepatectomy has been used as an experimental tool precisely because the timing and extent of hyperplasia can be known and controlled. With regards to aflatoxin B1 (AFB1) carcinogenesis, partial hepatectomy has produced variable results. An explanation appears to reside in the hepatotoxic properties of AFB1 that enhance the early stages of carcinogenesis. © 2003 Wiley‐Liss, Inc.
Tailoring cancer chemoprevention regimens to the individual
Authors: Conney Allan H.
Published: January 2004

The present article, which is a tribute to the memory of Dr. Edward Bresnick, emphasizes the importance of environmental and life‐style factors for cancer causation in the human population and points out approaches to cancer prevention. These approaches include vaccinations for the prevention of cancers that are caused by infectious agents as well as the use of cancer chemopreventive agents. The use of tamoxifen and letrozole to prevent breast cancer, finasteride to prevent prostate cancer, sunscreens or topical applications of 5‐fluorouracil to prevent sunlight‐induced skin cancer, and aspirin or calcium to prevent colon cancer are a few examples of cancer chemoprevention in high risk individuals and in the general population. An underdeveloped area of cancer chemoprevention is the use of combinations of agents that work by different mechanisms. It was pointed out that animal studies indicate that many cancer chemopreventive agents inhibit carcinogenesis under one set of experimental conditions but enhance carcinogenesis under another set of experimental conditions. These observations suggest that tailoring the chemopreventive regimen to the individual or to groups of individuals living under different environmental conditions or with different mechanisms of carcinogenesis may be an important aspect of cancer chemoprevention in human populations. How to tailor cancer chemoprevention regimens to the individual is an important challenge for the future. © 2003 Wiley‐Liss, Inc.
Molecular integrals over the gauge‐including atomic orbitals. II. The Breit–Pauli interaction
Authors: Ishida Kazuhiro
Published: January 2004

Each accompanying coordinate expansion (ACE) formula is derived for each of the orbit–orbit interaction, the spin–orbit coupling, the spin–spin coupling, and the contact interaction integrals over the gauge‐including atomic orbitals (GIAOs) by the use of the solid harmonic gradient (SHG) operator. Each ACE formula is the general formula derived at the first time for each of the above molecular integrals over GIAOs. These molecular integrals are arising in the Breit–Pauli two‐electron interaction for a relativistic calculation. We may conclude that we can derive a certain ACE formula for any kind of molecular integral over solid harmonic Gaussian‐type orbitals by using the SHG operator. The present ACE formulas will be useful, for example, for a calculation of a molecule in a uniform magnetic field, for a relativistic calculation, and so on, with the GIAO as a basis function. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1874–1890, 2003
Efficient evaluation of the effective dielectric function of a macromolecule in aqueous solution
Authors: Haberthür Urs , Majeux Nicolas , Werner Philipp , Caflisch Amedeo
Published: January 2004

We propose an analytical approach to calculate the effective dielectric function of proteins in aqueous solution. The screening effect if quantified by a measure of enclosure which is based on the distribution of solute atomic volumes around a pair of charges in a macromolecule. For protein conformations that vary significantly in size and shape, a comparison with finite difference Poisson calculations shows that pair interaction energies, their sums and solvation energies are well reproduced. The approach rivals the speed of simple distance dependent dielectric functions and the accuracy of the generalized Born model. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1936–1949, 2003
Chemical structures from the analysis of domain‐averaged Fermi holes: Multiple metalmetal bonding in transition metal compounds
Authors: Ponec Robert , Yuzhakov Gleb , Carbó‐Dorca Ramon
Published: January 2004

The recently proposed approach based on the analysis of domain‐averaged Fermi holes was applied to the study of the nature of metalmetal bonding in transition metal complexes and clusters. The main emphasis was put on the scrutiny of the systems assumed to contain direct multiple metalmetal bonds. The studied systems involve: (1) systems of the type M2X6 (M = Mo, W, X = CH3) anticipated to contain metalmetal triple bonds; (2) the molecule of W2Cl8(4−) as the representative of the systems with quadruple metalmetal bonding; (3) diatomic molecules Mo2 and V2 considered as the potential candidates for higher than quadruple metalmetal bonding. Although the resulting picture of bonding has been usually shown to agree with the original expectations based on early simple MO models, some examples were also found in which the conclusions of the reported analysis display dramatic sensitivity to the quality of the wave function used for the generation of the Fermi holes. In addition to this we also report some examples where the original theoretical predictions of multiplicity of metalmetal bonds have to be corrected. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1829–1838, 2003
Calculation of the water–cyclohexane transfer free energies of neutral amino acid side‐chain analogs using the OPLS all‐atom force field
Authors: MacCallum Justin L. , Tieleman D. Peter
Published: January 2004

We calculated the free energy of solvation of the neutral analogs of 18 amino acid side‐chains (not including glycine and proline) using the OPLS all‐atom force field in TIP4P water, SPC water, and cyclohexane by molecular dynamics simulation and thermodynamic integration. The average unsigned errors in the free energies of solvation in TIP4P, SPC, and cyclohexane are 4.4, 4.9, and 2.1 kJ/mol respectively. Most of the calculated hydration free energies are not favorable enough compared to experiment. The largest errors are found for tryptophan, histidine, glutamic acid, and glutamine. The average unsigned errors in the free energy of transfer from TIP4P to cyclohexane and from SPC to cyclohexane are 4.0 and 4.1 kJ/mol, respectively. The largest errors, of more than 7.5 kJ/mol, are found for histidine, glutamine, and glutamatic acid. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1930–1935, 2003
Docking macromolecules with flexible segments
Authors: Bastard Karine , Thureau Aurélien , Lavery Richard , Prévost Chantal
Published: January 2004

We address a major obstacle to macromolecular docking algorithms by presenting a new method that takes into account the induced conformational adjustment of flexible loops situated at a protein/macromolecule interface. The method, MC2, is based on a multiple copy representation of the loops, coupled with a Monte Carlo conformational search of the relative position of the macromolecules and their side chain conformations. The selection of optimal loop conformations takes place during Monte Carlo cycling by the iterative adjustment of the weight of each copy. We describe here the parameterization of the method and trials on a protein‐DNA complex of known 3‐D structure, involving the Drosophila prd paired domain protein and its target oligonucleotide Wenqing, X. et al., Cell 1995, 80, 639. We demonstrate that our algorithm can correctly configure and position this protein, despite its relatively complex interactions with both grooves of DNA. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1910–1920, 2003
Gaussian‐type function set without prolapse for the Dirac–Fock–Roothaan equation
Authors: Tatewaki Hiroshi , Watanabe Yoshihiro
Published: January 2004

A Gaussian‐type function (GTF) set without a prolapse (variation collapse) is generated for the Dirac–Fock–Roothaan (DFR) equation. The test atom was mercury. The number of primitive GTFs used is between 7and 62 (abbreviated as 7–62), 6–62, 6–62, 4–36, 4–36, 3–36, and 3–36 for s+, p−, p+, d−, d+, f−, and f+ symmetries. The respective exponent parameters were determined with even‐tempered manner, which requires the minimum and maximum exponents for the respective symmetries. We prepared several sets of these. The total energy (TE) given by the numerical DF (NDF) is −19648.849250 hartree; one of the present sets with largest number of expansion terms gave −19648.849251 hartree. The error (ΔTE) relative to the NDR TE is quite small. We then applied this set to the inert gas atoms Ne (10), Ar (18), Kr (36), Xe (54), Rn (86), and No (102), and also to Es (99) as the representative of the open shell atoms. The absolute values of ΔTE were at most 2.8 × 10−6 hartree, showing the potential of this set as a universal set. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1823–1828, 2003
Critical assessment of side‐chain conformational space sampling procedures designed for quantifying the effect of side‐chain environment
Authors: Gautier R. , Tufféry P.
Published: January 2004

We introduce a family of procedures designed to sample side‐chain conformational space at particular locations in protein structures. These procedures (CRSP) use intensive cycles of random assignment of side‐chain conformations followed by minimization to determine all the conformations that a group of side‐chains can adopt simultaneously. First, we consider a procedure evolving in the dihedral space (dCRSP). Our results suggest that it can accurately map low‐energy conformations adopted by clusters of side‐chains of a protein. dCRSP is relatively insensitive to various important parameters, and it is sufficiently accurate to capture efficiently the constraint induced by the environment on the conformations a particular side‐chain can adopt. Our results show that dCRSP, compared with molecular dynamics (MD), can overcome the problem of the limited set of conformations reached in a reasonable amount of simulations. Next, we introduce procedures (vCRSP) in which valence angles are relaxed, and we assess how efficiently they quantify the conformational entropy of side‐chains in the protein native state. For simple peptides, entropies obtained with vCRSP are fully compatible with those obtained with a Monte Carlo procedure. For side‐chains in a protein environment, however, vCRSP appears of limited use. Finally, we consider a two‐step procedure that combines dCRSP and vCRSP. Our tests suggest that it is able to overcome the limitations of vCRSP. We also note that dCRSP provides a reasonable initial approximation. This family of procedures offers promise in quantifying the contribution of conformational entropy to the energetics of protein structures. © 2003 Wiley Periodicals, Inc. J Comput Chem 15: 1950–1961, 2003
Adaptive integration of molecular dynamics
Authors: Horenko Illia , Weiser Martin
Published: January 2004

This article presents a particle method framework for simulating molecular dynamics. For time integration, the implicit trapezoidal rule is employed, where an explicit predictor enables large time steps. Error estimators for both the temporal and spatial discretization are advocated, and facilitate a fully adaptive propagation. The framework is developed and exemplified in the context of the classical Liouville equation, where Gaussian phase‐space packets are used as particles. Simplified variants are discussed briefly. The concept is illustrated by numerical examples for one‐dimensional dynamics in double well potential. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1921–1929, 2003
Adsorption of organic substances on broken clay surfaces: A quantum chemical study
Authors: Aquino Adélia J.A. , Tunega Daniel , Haberhauer Georg , Gerzabek Martin H. , Lischka Hans
Published: January 2004

Hydrogen‐bonded interactions between local defect structures on broken clay surfaces modeled as molecular clusters and the organic molecules acetic acid, acetate, and N‐methylacetamide (NMA) have been investigated. Density functional theory and polarized basis sets have been used for the computation of optimized interaction complexes and formation energies. The activity of the defect structures has been characterized as physical or chemical in terms of the strength of the hydrogen bonds formed. Chemical defects lead to significantly enhanced interactions with stronger hydrogen bonds and larger elongation of OH bonds in comparison to the physical defects. The type of interaction with the defect structure significantly influences the planarity of the model peptide bond in NMA. Both cases, enhancement of the planarity by increase of the CN double bond character and strong deviations from planarity, are observed. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1853–1863, 2003
Molecular caps for full quantum mechanical computation of peptide–water interaction energy
Authors: Zhang D. W. , Chen X. H. , Zhang J. Z. H.
Published: January 2004

We present a systematic study of numerical accuracy of various forms of molecular caps that are employed in a recently developed molecular fractionation scheme for full quantum mechanical computation of protein–molecule interaction energy. A previously studied pentapeptide (Gly‐Ser‐Ala‐Asp‐Val) or P5 interacting with a water molecule is used as a benchmark system for numerical testing. One‐dimensional potential energy curves are generated for a number of peptide–water interaction pathways. Our study shows that various forms of caps all give consistently accurate energies compared to the corresponding full system calculation with only small deviations. We also tested the accuracy of cutting peptide backbone at different positions and comparisons of results are presented. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1846–1852, 2003