bluuebunny/crossref_metadata_2025 huggingface dataset:
Human papillomavirus and cervical neoplasia: A case‐control study in Taiwan
Authors: Liaw Kai‐Li , Hsing Ann W. , Chen Chem‐Jen , Schiffmfman Mark H. , Zhang Tracy Y. , Hsieh Chang‐Yao , Greer Catherine E. , You San‐Lin , Huang Thomas W. , Wu Tzyy‐Choou , O'leary Timothy J. , Seidman Jeffrey D. , Blot William J. , Meinert Curtis L. , Manos M. Michele
Published: February 2007

As part of a large‐scale, community‐based cervical neoplastic screening project in rural Taiwan, a case‐control study was undertaken to evaluate the etiologic role of human papillomavirus (HPV) infection in this mainly monogamous (2% reported having multiple sexual partners) female population. A total of 88 biopsy‐confirmed cases and 261 cytologically normal controls were selected for the study. The case group included 40 cases of cervical intraepithelial neoplasia (CIN) 1, 9 of CIN 2, 36 of CIN 3 and 3 cases of invasive cancer. Cervical swabs collected at screening from study subjects were tested for HPV DNA by an LI consensus primer polymerase chain reaction (PCR)‐based technique. HPV DNA was found in 92% of high‐grade cases (CIN 2‐3 and invasive cancer); 54% of low‐grade cases (CIN I); and 9% of controls. HPV was significantly associated with both high‐grade and low‐grade cervical neoplasia. As reported in Western countries, HPV 16 was the predominant type among HPV‐positive high‐grade cases. However, HPVs 52 and/or 58 combined were the most common types among HPV‐positive low‐grade cases and controls. Among women without any high‐risk HPV infection (types 16, 18, 31 or 45), those with multiple‐type HPV infection had a higher risk for high‐grade cervical neoplasia than those with single‐type infection. Overall, 91% of high‐grade cases and 50% of low‐grade cases could be attributed to HPV infection. Our results show that, even in this monogamous population, HPV is the major risk factor for high‐grade cervical neoplasia. © 1995 Wiley‐Liss, Inc.
Sequence‐dependent antitumor activity of paclitaxel (taxol) and cisplatin in vivo
Authors: Milross Christopher G. , Peters Lester J. , Hunter Nancy R. , Mason Kathy A. , Milas Luka
Published: February 2007

The established antitumor efficacy of paclitaxel and cisplatin as single agents and their distinctly different mechanisms of action have prompted laboratory and clinical research into their use in combination. Our in vivo study was performed to investigate the importance of sequence of administration and inter‐agent interval. C3Hf/Kam mice bearing OCa‐1 tumors received paclitaxel and cisplatin. The antitumor efficacy of the combination, measured as re‐growth delay and expressed as the enhancement factor (EF), was determined for inter‐agent intervals of I, 9, 24, 48 and 72 hr. Morphometric analysis was used to determine the contribution of induced apoptosis. Our findings showed an additive effect when cisplatin preceded paclitaxel by 1 and 24 hr, producing EF of 1.1 and 1.0, respectively, and a greater than additive effect for 9 and 48 hr, producing EF of 1.3 and 1.8, respectively. This sequence, however, was associated with significant morbidity and mortality. When paclitaxel preceded cisplatin the effect was greater than additive with the EF for I, 9 and 24 hr, being 1.2, 1.5 and 1.5, respectively, and increasing to a maximum of 1.9 at 48 hr. Thus, for this combination, the therapeutic ratio was improved when paclitaxel preceded cisplatin and was greatest when a 48 hr interval was allowed between drugs. We were unable to attribute the efficacy of the drug combination to increased induction of apoptosis and suggest other possible mechanisms. © 1995 Wiley‐Liss, Inc.
Cloning of the gene encoding TROP‐2, a cell‐surface glycoprotein expressed by human carcinomas
Authors: Fornaro Mara , Arciprete Roberta Dell' , Stella Manuela , Bucci Cecilia , Nutini Michele , Capri Maria Grazia , Alberti Saverio
Published: February 2007

We have cloned by expression the cDNA encoding Trop‐2, a cell‐surface glycoprotein expressed by most human carcinomas. Formal proof of the identity of the clone is the hybridization to DNA and RNA from genomic TROP2 transfectants. TROP2 is a single‐copy gene in human cells, hybridizes to a single 1.8‐kb mRNA from expressing sources and encodes a 35,709 Da type‐1 transmembrane protein with a single transmembrane domain. TROP2 is essentially identical to GA733‐1. Thus, we have proven that GA733‐1, for which a protein product had not been identified, is a functional gene. TROP2 is also homologous to TROPI/KSA/GA733‐2, confirming the serological similarities between the 2 molecules. The homology between the Trop‐1 and Trop‐2 peptides is clustered in 2 extracytoplasmic domains and in the transmembrane/cytoplasmic region. Twelve cysteines and a potential cytoplasmic tyrosine phosphorylation site are also conserved. Trop‐1 and Trop‐2 are homologous to serum IGF‐11‐binding proteins and appear as signal transducers. Thus, they likely represent novel cell‐surface receptors and may play a role in regulating the growth of carcinoma cells. On the other hand, we have found no evidence for a role of Trop‐2 and Trop‐1 as homophilic adhesion molecules. © 1995 Wiley‐Liss, Inc.
Butyrate regulates gene expression of the plasminogen activating system in colon cancer cells
Authors: Antalis Toni M. , Reeder Jennifer A.
Published: February 2007

Butyrate is a potent differentiating agent present in high concentrations in colonic lumen as a result of metabolic breakdown of dietaiy fibre and, as such, may directly influence colonic cancer progression. We have investigated the effects of butyrate on an enzyme system important in colonic tumour progression, the plasminogen‐activating system, in a poorly differentiated colon cancer cell. Butyrate was found to induce a rapid and transient increase in plasminogen activator inhibitor type 1 (PA1‐1) mRNA while concomitantly suppressing the constitutive production of both urokinase‐type plasminogen activator (uPA) and uPA receptor (uPAR) mRNA transcripts. We have investigated the mechanisms involved in mediating these effects by run‐on transcription and RNA stability analyses. Our data show that PA1‐1 mRNA induction occurs through both regulation of the stability of the alternately spliced 3.3 kb PA1‐1 mRNA transcript and induction of the 2.4 kb PA1‐1 mRNA transcript. Studies using modulators of signal transduction pathways demonstrate that induction of PA1‐1 mRNA synthesis is independent of protein kinase C but dependent on the activation of protein kinase A. Suppression of uPA mRNA by butyrate was found to occur by down‐regulation of gene transcription through a process independent of de novo protein synthesis. The transcription rate of the uPAR gene was not modulated by butyrate, but rapid turnover of the uPAR gene by butyrate was dependent on ongoing protein synthesis. Our results demonstrate that butyrate can effect rapid changes in the expression of genes of the plasminogen‐activating system through several different mechanisms in a gene‐specific manner. © 1995 Wiley‐Liss, Inc.
Anti‐tumor efficacy of an anti‐epidermal‐growth‐factor‐ receptor monoclonal antibody and its F(ab′)2 fragment against high‐ and low‐egfr‐expressing carcinomas in nude mice
Authors: Tosi Emanuela , Valota Olga , Negri Donatella R. M. , Adobati Elena , Mazzoni Alessandra , Meazza Raffaella , Ferrini Silvano , Colnaghi Maria I. , Canevari Silvana
Published: February 2007

Monoclonal antibody (MAb) MINTS specifically detects the epidermal‐growth‐factor receptor (EGFR). In vitro analyses of intact MINTS (IgG,) and its F(ab′)2 fragment indicated that both forms of the MAb inhibited binding of ′25l‐mEGF to EGFR, induced receptor internalization and blocked EGF‐induced EGFR tyrosine‐kinase activation in A431 cells. Both forms of the MAb also inhibited to the same extent the proliferation of the carcinoma cell lines A431 and IGROVI, despite the difference in EGFR levels on the cells. The detection of TGFα mRNA and the inhibition of cell growth in EGF‐free conditions by anti‐EGFR MAb indicated the involvement of an EGFR/TGFα autocrine/ paracrine pathway in the in vitro growth of both cell lines. Analysis of mice xenotransplanted s.c. with A43I cells and treated with MINTS revealed a block in A431 tumor take in 6 of 10 animals when intact MAb was administered from day 0 to day 11. On a molar basis, F(ab)2 at the same dose was ineffective, although at a 7‐fold higher dose F(ab′)2 reduced s.c. tumor growth by 80%. At the same dose, intact MINTS MAb reduced s.c. growth of the EGFR‐negative MeWo cell line by 5%. Survival of mice bearing IGROV I i.p. xenotransplants and treated locally with either form of MAb was significantly prolonged even when treatment was initiated on day 3. Corrected doses of intact and F(ab′)2 fragment, which accounted for the difference in serum half‐lives of the MAb forms, resulted in similar survival rates in the tumor‐bearing mice. These pre‐clinical results suggest that MINTS MAb might be safely used for systemic therapy of EGFR‐over‐expressing tumors. Loco‐regional therapy might be contemplated in the case of tumors with moderate/low EGFR expression. © 1995 Wiley‐Liss, Inc.
Detection of an epstein‐barr‐virus variant in T‐cell‐lymphoma tissues identical to the distinct strain observed in nasopharyngeal carcinoma in the taiwanese population
Authors: Chang Yu‐Sun , Su Ih‐Jen , Chung Pei‐Jung , Shu Chih‐Hung , Ng Cheng‐Koon , Wu Shao‐Jung , Liu Shih‐Tung
Published: February 2007

An EBV variant has been identified in NPC tissues in Taiwan. This EBV variant contains a point mutation in exon I of the LMP I gene. This mutation results in the loss of an Xhol site at nt 169,426, which is present in strain B9S‐8. In addition, this variant contains a 30‐bp deletion in exon 3 of the gene. The recent demonstration of the prevalence of EBV‐containing nasal and peripheral T‐cell lymphoma in this region drove us to evaluate the presence of this NPC‐EBV strain in 7 cases of T‐cell lymphoma, as well as in 48 NPC tissues, 2 cases of Hodgkin's disease and I B‐cell lymphoma. Four samples of normal lymph‐ node tissue, 40 of normal nasopharynx tissue and 78 throat washings of healthy individuals were included for comparison. We used sequence‐specific primers and the polymerase chain reaction (PCR) method to amplify LMP I gene fragments containing these variations. Mutations were then confirmed by restriction‐enzyme digestion and the DNA sequencing analysis. Our results showed that 57 of 58 tumor‐tissues samples were EBV‐positive. Among them, 56, including 6 T‐cell‐lymphoma samples, belonged to the NPC strain. This strain of EBV was also present in 92% of EBV‐positive normal nasopharynx tissues and in 84% of EBV‐positive throat washings of the healthy individuals tested. These results suggest that the NPC‐EBV strain is prominently present in Taiwan. © 1995 Wiley‐Liss, Inc.
Interleukin‐6 inhibits the potent stimulatory action of androgens, glucocorticoids and interleukin‐1α on apolipoprotein D and GCDFP‐15 expression in human breast cancer cells
Authors: Blais Yves , Sugimoto Keiko , Carrière Marie‐Claude , Haagensen Darrow E. , Labrie Fernand , Simard Jacques
Published: February 2007

Our study was designed to investigate the potential interaction between steroid hormones and interleukin‐6 (IL‐6) in the regulation of apolipoprotein D (apo‐D) and gross cystic disease fluid protein 15 (GCDFP‐15) expression in ZR‐75‐1 human breast cancer cells. We first observed that exposure to IL‐6 for 6–14 days decreased basal apo‐D and GCDFP‐15 secretion by 50% and 23%, respectively. In the same experiment, such treatment with IL‐6 decreased cell proliferation by approximately 40% after 6 and 14 days of incubation. Exposure to IL‐6 markedly decreased dihydrotestosterone (DHT)‐induced apo‐D and GCDFP‐15 release, with a half‐maximal effect measured at 13 U/ml. A similar inhibitory action of IL‐6 was observed on the glucocorticoid dexamethasone (DEX)‐induced apo‐D and GCDFP‐15 secretion. The sensitivity of the apo‐D and GCDFP‐15 response to the stimulatory action of DHT or DEX was, however, not changed by concomitant exposure to IL‐6. The inhibitory effect of IL‐6 on the secretion of these two biochemical markers was additive to that of 17β‐estradiol. In addition, IL‐6 blocked the stimulatory effect of interleukin‐1α (IL‐1α) on apo‐D and GCDFP‐15 secretion. Our results show that IL‐6 is a potent inhibitor of basal as well as androgen‐, glucocorticoid‐ and IL‐1α‐induced apo‐D and GCDFP‐15 secretion in ZR‐75‐1 human breast cancer cells, while cell proliferation is inhibited by this cytokine. © 1995 Wiley‐Liss, Inc.
Modulation of heparan‐sulphate/chondroitin‐sulphate ratio by glycosaminoglycan biosynthesis inhibitors affects liver metastatic potential of tumor cells
Authors: Tímár József , Diczházi Csaba , Bartha Irén , Pogány Gábor , Paku SÁNdor , Rásó Erzsébet , Tóvári József , Ladányi Andrea , Lapis Károly , Kopper László , Jeney András
Published: February 2007

Previous data have indicated that the proteoglycan (PG) pattern is different on tumor cells with different liver metastatic potential. We selected “conventional” glycosaminoglycan (GAG) biosynthesis inhibitors, β T‐D‐xyloside (BX), 2‐deoxy‐D‐glucose (2‐DG), ethane‐1‐hydroxy‐1, 1‐diphosphonate (ETDP) and the newly discovered 5‐hexyl‐2‐deoxyuridine (HUdR), to modulate PGs on highly metastatic/liver‐specific 3LL‐HH murine carcinoma and HT168 human melanoma cells and to influence their liver colonization potential. These compounds all induced remarkable changes in GAG biosynthesis, but to varying degrees: glucosamine labelling was affected mainly by 2‐DG, and HUdR and sulphation by BX and HUdR. Furthermore, the ratio of he paran sulphate/chondroitin sulphate (HS/CS) of PGs was increased by ETDP and decreased after treatment by HUdR. In addition to changes in PG metabolism, tumor‐cell proliferation and adhesion to fibronectin were affected; BX and 2‐DG stimulated cell proliferation and adhesion, while HUdR inhibited both proliferation and adhesion. Most interestingly, HUdR, the most effective inhibitor of HS/HSPG, depressed the formation of liver colonies, while ETDP, the most effective inhibitor of CS/CSPG, stimulated the appearance of liver colonies. These observations indicated that, at least in these experimental systems, tumor cells with a high HS/CS ratio are more likely to form liver metastases; consequently, anti‐HS agents could also be anti‐metastatic. © 1995 Wiley‐Liss, Inc.
Amphiregulin anti‐sense oligodeoxynucleotides inhibit growth and transformation of a human colon carcinoma cell line
Authors: Normanno Nicola , Selvam Mouna P. , Bianco Caterina , Damiano Vincenzo , de Angelis Ernesto , Grassi Michele , Magliulo Gabriella , Tortora Giampaolo , Salomon David S. , Ciardiello Fortunato
Published: February 2007

Amphiregulin (AR) is a secreted heparin‐binding growth factor that is structurally and functionally related to epidermal growth factor (EGF) and transforming growth factor a (TGFα). GEO cells are from a human colon cancer cell line that expresses high levels of AR protein and mRNA. To assess the role of AR in colon‐cancer cell proliferation and transformation, 2 different anti‐sense 20‐mer phosphorothioate oligodeoxy‐nucleotides (AR AS‐1 and AR AS‐2 S‐oligos) complementary to the 5′ sequence of AR mRNA were synthesized. Both AR AS S‐oligos were able to inhibit the anchorage‐dependent growth (ADG) of GEO cells. The 2 AR AS S‐oligos were equipotent when used in equimolar concentrations. In particular, a 40% growth inhibition was observed at a concentration of 10 μM, while a mis‐sense S‐oligo used as control had no effect on GEO cell growth. The AR AS‐1 S‐oligo used at the same concentration also inhibited by 40% the 3H‐thymidine incorporation by DNA of GEO cells. The anchorage‐independent growth (AIG) of GEO cells was even more significantly affected by AR AS S‐oligo treatment. In fact, up to 80% inhibition of the AIG of GEO cells was observed when cells were treated with 10 μM of both AR AS S‐oligos. Finally, the AR AS S‐oligos were able to specifically inhibit AR protein expression in GEO cells, as assessed by immunocytochemistry. These data suggest that AR is involved in colon‐cancer cell transformation, and that AR may represent a suitable target for gene therapy in human colon carcinomas. © 1995 Wiley‐Liss, Inc.
Paradoxical effects of bleomycin and heavy water (D2O) in mice
Authors: Gaeng Dominique P. , Geiser Marianne , Cruz‐Orive Luis‐Manuel , Larsen Soren E. , Schaffner Thomas , Laissue Jean A. , Altermatt Hans J.
Published: February 2007

Bleomycin (BLM) lacks many side effects of other cytostatic drugs. Pulmonary toxicity is the major dose‐limiting effect of BLM. This is based in part on generation of free radicals. It is conceivable that deuterium in body fluids lessens the production of free radicals, thus preventing or diminishing the morphologic expression of pulmonary BLM toxicity. We therefore studied the effect of moderate deuteration of body fluids on BLM‐induced lung damage in BALB/c‐mice. In addition to conventional histopathological methods, we used a vertical sectioning design for stereological estimation of pulmonary volumes and surface areas. BLM (low/medium/high dose: 25/50/75 IU/kg body weight) was injected i.p. once a week for 6 weeks. Half the mice drank deuterated water before, during and after BLM treatment. Three weeks after the last injection, the lungs were fixed by airway instillation. Deuterated animals treated with BLM lacked signs of irreversible BLM‐induced pulmonary damage. Conversely, focal sub‐pleural fibrosis and fibrosing alveolitis were present in BLM‐treated mice drinking tap water. Deuterated mice had stereological values for almost all lung parameters that were lower than in non‐deuterated mice. The organ‐specific advantage of deuteration was offset by marked enhancement of systemic toxicity of BLM. We conclude that (I) moderate concentrations of deuterium may prevent the development of fibrosing alveolitis in BLM‐treated mice, possibly by reducing proliferation of alveolar fibroblasts, and, less probably, by impairing generation or enhancing capture of free radicals; (2) the toxicity of BLM was enhanced by ingestion of deuterium, resulting in morphological liver alterations and increased mortality. © 1995 Wiley‐Liss, Inc.
Irradiation induces Up‐regulation of E9 protein (CD105) in human vascular endothelial cells
Authors: Wang Ji‐Min , Kumar Shant , Van Agthoven Andre , Kumar Pat , Pye David , Hunter Robin D.
Published: February 2007

The use of MAb E‐9 raised against tissue‐cultured endothelial cells (EC) has shown marked heterogeneity in vascular EC lining the blood vessels of normal and tumour tissues. MAb E‐9 is human EC‐specific and the protein recognized by it is a homodimer with a molecular mass of 97 kDa. The E‐9 protein is resistant to treatment by 3 mM sodium periodate, but is sensitive to 10% trichloroacetic acid and 70% ethanol. E‐9 protein has been assigned to a new cluster, CD 105, and mapped to human chromosome 9q3. It has approximately 70% homology with type‐III cell‐surface receptor for transforming growth factor beta (TGF‐β). Recently CD 105 has been reported to be the gene in patients with hereditary haemorrhagic telangiecta‐sia. We have examined the effects of radiation on its expression in normal human umbilical‐vein endothelial cells (HUVEC) and brain‐tumour‐derived endothelial cells (BTEC). Irradiation induced dose‐and time‐dependent up‐regulation in the expression of the E‐9 protein on the plasma membranes of EC, and also resulted in greater increase in the expression of the E‐9 protein in semi‐confluent (proliferating) as compared with confluent (non‐proliferating) EC. It may well be that, following radio‐therapy in cancer patients, E‐9 protein is also up‐regulated. The presence of increased amounts of E‐9 protein in EC makes it an attractive target in the control of angiogenesis, especially after radiotherapy in cancer patients. The time scale involved in the up‐regulation of E‐9 protein following irradiation has led us to suggest that it may be a secondary event, the primary being the production and release of mitogenic factors (such as basic fibroblast growth factor) from irradiated EC. © 1995 Wiley‐Liss, Inc.
Cancer in the european population of harare, Zimbabwe, 1990–1992
Authors: Bassett M. T. , Levy L. , Chokunonga E. , Mauchaza B. , Ferlay J. , Parkin D. M.
Published: February 2007

The data presented from the population‐based cancer registry in Harare, Zimbabwe, represent the first information on the incidence of cancer in a population of European origin living in Southern Africa for over 30 years. Their cancer pattern is more or less typical of white populations of high socio‐economic status living in Europe or North America, with elevated incidence rates of breast cancer, large‐bowel cancer and, in women, lung cancer. However, there are also several unusual features, with extremely high incidence rates of skin cancers, including melanomas, and higher rates of liver and bladder cancer than normally seen in white populations.
Cancer in the african population of harare, Zimbabwe, 1990–1992
Authors: Bassett M. T. , Chokunonga E. , Mauchaza B. , Levy L. , Ferlay J. , Parkin D. M.
Published: February 2007

The data presented from the population‐based cancer registry in Harare, Zimbabwe, represent the first information on the incidence of cancer in Southern Africa for almost 20 years. In the African population in Zimbabwe there are several features in common with other countries in sub‐Saharan Africa: high rates of liver, prostate and cervix cancer, low rates of large‐bowel cancer and breast cancer. Also, as reported from southern and south‐eastern Africa, there are relatively high incidence rates of cancers of the oesophagus, bladder and (in men) lung. The AIDS epidemic has given rise to a striking increase in incidence of Kaposi's sarcoma (now the commonest cancer of African men), but there is not much evidence for an increase in incidence of non‐Hodgkin lymphomas nor, although rates are very high, of cervical cancer.
Association of herpesvirus infection with the development of genital cancer
Authors: Koffa Maria , Koumantakis Eugenios , Ergazaki Maria , Tsatsanis Christos , Spandidos Demetrios A.
Published: February 2007

Clinical observations and epidemiological studies on genital cancer have revealed an association with sexual behavior, thus motivating research into sexually transmitted agents which may be responsible for the neoplasia. In this study, we used the PCR technique to examine the presence of CMV, HSV and EBV viruses in 187 cases of human genital lesions and found that infection with CMV or HSV was associated with cervical cancer. When we stratified according to HPV status this association was found only for HPV‐DNA‐negative cases. These findings indicate that past infection with CMV or HSV could be interpreted as a surrogate marker of HPV infection. However, these viruses may play an important role themselves in cervical cancer.
Enhancement of in vitro tumor—cell transcellular migration by tumor—cell—secreted endothelial—cell—retraction factor
Authors: Kusama Toshiyuki , Nakamori Shoji , Ohigashi Hiroaki , Mukai Mutsuko , Shinkai Kiyoko , Ishikawa Osamu , Imaoka Shingi , Matsumoto Yoshirou , Akedo Hitoshi
Published: February 2007

To investigate the factors affecting endothelial‐cell retraction, we have studied the interaction of tumor cells with endothelial cells in 2 human pancreatic cancer cell lines, PSN‐1 and MiaPaca‐2. The extent of endothelial‐cell retraction measured by the amount of intercellular junctional transport of F1TC‐dextran through an endothelial monolayer was increased by the addition of a conditioned medium (CM) from both cell lines, while CM from PSN‐I cells was 2 to 3 times more potent than that from MiaPaca‐2 cells. After the treatment of endothelial monolayer with CM of PSN‐1 cells, the ability of both PSN‐1 cells and MiaPaca cells to adhere to or invade the monolayer increased. The addition of CM from PSN‐1 cells did not affect the growth rate of either the endothelial or the tumor cells. The activity in the CM was heat‐stable and bound to heparin‐Sepharose, but was inactivated when treated by 0.5% trypsin. Protease inhibitors did not influence the activity. Pre‐treatment of PSN‐I cells by an inhibitor of protein synthesis, cyclohexi‐mide, or of protein processing, benzyl‐N‐acetyl‐a‐D‐galactos‐aminide, reduced endothelial‐cell‐retraction activity in the CM. The active substance in the CM fractionated in the molecular‐weight range of 10,000 to 50,000. These results suggest that PSN‐1 cells produce and secrete (a) soluble factor(s) that can induce endothelial‐cell retraction, thus facilitating tumor‐cell invasion.
Increased susceptibility of ras‐transformed cells to phenylacetate is associated with inhibition of p21ras isoprenylation and phenotypic reversion
Authors: Shack Sonsoles , Chen Li‐Chuan , Miller Alexandra C. , Danesi Romano , Samid Dvorit
Published: February 2007

Alterations in the expression of ras oncogenes are characteristic of a wide variety of human neoplasms. Accumulating evidence has linked elevated ras expression with disease progression and with failure of tumors to respond to conventional therapies, including radiotherapy and certain chemotherapies. These observations led us to investigate the response of ras‐transformed cells to the differentiation‐inducer phenylacetate (PA). Using gene transfer models, we show that PA caused cytostasis in ras‐transformed mesenchymal cells, associated with increased expression of 2′,5′‐oligoadenylate synthetase, an enzyme implicated in negative growth control. PA also induced phenotypic reversion characterized by loss of anchorage‐independent growth, reduced invasiveness and increased expression of collagen a type 1, a marker of cell differentiation. The anti‐tumor activity of PA was observed in cases involving either Ha‐ or Ki‐ras and was independent of the mode of oncogene activation. Interestingly, in contrast to their relative resistance to radiation and doxorubicin, ras‐transformed cells were significantly more sensitive to PA than their parental cells. The profound changes in tumor cell and molecular biology were associated with reduced isoprenylation of the ras‐encoded p21. Our results indicate that PA can suppress the growth of ras‐transformed cells, resistant otherwise to free‐radical based therapies, through interference with p21ras isoprenylation, critical to signal transduction and maintenance of the malignant phenotype.
Efficacy of tnf‐α gene‐transduced tumor cells in treatment of established in vivo tumor
Authors: Koshita Yoshikazu , Lu Yue , Fujii Shigeyuki , Neda Hiroshi , Matsuyama Tomohiko , Satoh Yasushi , Itoh Yoshinori , Takahashi Minoru , Kato Junji , Sakamaki Sumio , Watanabe Naoki , Kohgo Yutaka , Niitsu Yoshiro
Published: February 2007

The therapeutic effect of TNF gene‐transduced mouse fibro‐sarcoma cells (Meth‐A: C5) on pre‐inoculated parental cells (Meth‐A: MO) was studied. Subcutaneous (s.c.) transplantation of MO cells into one flank of syngeneic BALB/c mice was followed by s.c. injection of irradiated MO or C5 into the opposite flank I week later. The initial MO tumor (T‐MO) completely regressed in C5‐vaccinated mice, whereas in Mo‐vaccinated mice continuous growth of T‐MO was observed. When a similar experiment was carried out in SCID mice, no regression of T‐MO was observed, suggesting that the tumor regression in BALB/c mice was not due to direct anti‐tumor activity of TNF secreted from C5, but to systemic immunity. Regression of the rechallenged MO tumor was observed in mice which had shown T‐MO regression by C5 vaccination, but rechallenged Colon 26 cells (syngeneic to BALB/c mice) continued to grow, indicating a specific immunity to Meth‐A cells. The systemic immunity evoked in C5‐vaccinated mice was directly demonstrated by enhanced killer activities of LAK and CTL with a proliferation of T‐cell population in their splenocytes. Abrogation of the therapeutic effect of C5 vaccination with anti‐Thy I and anti‐Lyt 2 also demonstrates the involvement of cellular immunity in tumor regression.
Differential inactivation of O6‐methylguanine‐dna methyltransferase activity by O6‐arylmethylguanines
Authors: Mineura Katsuyoshi , Fukuchi Masahito , Kowada Masayoshi , Terashima Isamu , Kohda Kohfuku
Published: February 2007

Activity of O6‐methylguanine‐DNA methyltransferase (MGMT) is well related with drug resistance of tumor cells to chloroethylnitrosoureas (CENUs), because MGMT removes CENU‐induced O6‐alkylguanines in DNA by accepting the alkyl group at a cysteine moiety. Inactivation of MGMT is a feasible way to overcome MGMT‐related resistance of tumor cells to CENUs. O6‐Benzylguanine is known to be a strong depleter of MGMT. We previously reported the potentiation effect of O6‐arylmethylguanine derivatives on cytotoxicity of 1 ‐(4‐amino‐2‐methyl‐5‐pyrimidinyl)methyl‐3‐(2‐chloroethyl)‐3‐nitrosourea hydrochloride (ACNU), a CENU, for HeLa S3 cells. In this study, we tested the activity of these O6‐arylmethylguanine derivatives as depleters of MGMT using HeLa S3 cell‐free extract. The O6‐arylmethylguanine derivatives tested were O6‐benzylguanine (I), O6‐(4‐, 3‐, and 2‐fluorobenzyl)guanines (2–4), O6‐(4, 3‐, and 2‐trifluoromethylbenzyl)guanines (5–7), O6‐(4‐, 3‐, and 2‐pyridylmethyl)guanines (8–10), and O6‐(2‐ and 1 ‐naphtylmethyl)guanines (11, 12). Among these, compounds 1–3, 5, 8, 9 and 11 showed a strong MGMT depletion activity, whereas compounds 4, 6, 7, 10 and 12 were inactive. These inactive compounds, except for 6, have a substituent at the a position of the benzyl group (4, 7, 12) or are an α nitrogen analogue of 1 (10). There was a good relation (r = ‐0.856, p 0.001) between the MGMT depletion activity of O6‐arylmethylguanine derivatives and their potentiation activity of ACNU cytotoxicity. These results suggest that the a position of the benzyl group plays an important role in the interaction of O6‐arylmethylguanine derivatives with MGMT to result in the inactivation of MGMT. Potent MGMT inactivators (1–3, 5, 8, 9, 11) sensitize tumor cells to CENU chemotherapy.
Novel muteins of human tumor necrosis factor with potent antitumor activity and less lethal toxicity in mice
Authors: Kuroda Kensei , Miyata Keizo , Shikama Hiroshi , Kawagoe Tomoko , Nishimura Koji , Takeda Ken , Sakae Nahoko , Kato Masanari
Published: February 2007

Eight muteins of recombinant human tumor necrosis factor‐α (rhTNF; SSSRTP … 29RR … 155L), in which 29Arg was replaced by another amino acid, were prepared and their anti‐tumor effects in BALB/c mice bearing Meth A fibrosarcoma were evaluated. The therapeutic indices, which mark the extent of the therapeutically effective dose, of V29 (29Arg ± Val) and D29 (± Asp) were 3.5 and 3.2, respectively, whereas that of rhTNF was 1.4. Clearly, the therapeutically effective range of these muteins was extended along with a decrease in lethal toxicity. V29 did not produce hypotension in the rat system, but D29 did. In addition, V29 showed potent anti‐tumor activity (Tumor Volume Inhibition Rate = 81% on day 15 after implantation) in 3 consecutive injection schedules despite the decreases in toxicity compared with rhTNF. The relative receptor binding constant was determined using HEp‐2 cells (expressing mainly 55‐kDa‐TNF receptor; p55R) and HL60 cells (expressing mainly 75‐kDa‐TNF receptor; p75R), and revealed that the reduced toxicity of V29 in mice was due to the reduced binding to p55R (34% of rhTNF). On the other hand, the ratio of the constants HEp‐2/HL60 of V29 was 11 in comparison with the value of 1.0 for rhTNF, suggesting that this mutein binds preferentially to p55R. The biological activities in human cell lines (HEp‐2 and HL60 cells) correlated well with the binding activities to each receptor in vitro. Therefore, the much lower toxicity and the potent anti‐tumor activity of this mutein suggest that V29 merits further investigation in pre‐clinical and clinical trials.
Membrane fatty acids of breast carcinoma: Contribution of host fatty acids and tumor properties
Authors: Chajès Véronique , Lanson Monique , Fetissof Frank , Lhuillery Claude , Bougnoux Philippe
Published: February 2007

To assess the part that host fatty‐acid supply and tumor‐specific fatty‐acid utilization contribute to the membrane lipid composition of tumor tissue, intra‐individual comparisons of membrane fatty acids were carried out between breast‐carcinoma tissue and non‐tumorous breast tissue adjacent to the tumor and taken as reference. Phospholipids were purified by thin‐layer chromatography from tumor biopsies obtained from 59 patients with a localized presentation of breast cancer, and fatty acids analyzed by capillary gas chromatography. Elevated levels of palmitic, palmitoleic and arachidonic acids, along with a low level of linoleic acid, were observed in membrane phospholipids of tumors with poor histoprognostic grade. The level of mono‐unsaturated fatty acids was higher, and the level of essential fatty acids was lower in the tumor than in the reference breast tissue. Fatty‐acid‐desaturating activity was not detectable in tumors. A positive relationship was observed among patients for most of the fatty acids between carcinoma and non‐tumorous breast tissue, except for mono‐unsaturated and essential fatty‐acid levels, which were not correlated between both tissues. These data suggest that mechanisms specifically related to malignant transformation and tumor progression influence the membrane fatty‐acid profile of breast carcinoma. Fatty acid supply to the tumor, possibly modified by metabolic conditions related to the host, also seems to play a decisive role in this composition.
Expression of resistance‐related proteins in nephroblastoma after chemotherapy
Authors: Volm Manfred , Mattern Jürgen , Stammler Gerd , Royer‐Pokora Brigitte , Schneider Susanne , Weirich Angela , Ludwig Rolf
Published: February 2007

Tumor tissues of untreated and cytostatic‐agent‐treated patients with nephroblastomas were investigated for expression of resistance‐related proteins (P‐glycoprotein, glutathione S‐transferase‐π, glutathione peroxidase and topoisomerase II) to ascertain whether resistance proteins are changed after treatment. Tumor tissue was analyzed by means of mRNA. Twenty‐three children were treated with actinomycin D and vincristine for 4 to 8 weeks. Eight children received no pre‐operative chemotherapy. In untreated patients, no expression of P‐glycoprotein was seen, whereas, in the patients who were treated with actinomycin D and vincristine, 12 out of 23 tumors showed increased P‐glycoprotein expression (> mean value). Although we found no difference between treated and untreated tumors for glutathione S‐transferase‐π, we found significant differences in the expression of glutathione peroxidase. In the 8 untreated patients, 7 tumors showed low glutathione peroxidase (< mean value) and one high (> mean value) glutathione‐peroxidase‐mRNA content. With treatment, 11 tumors expressed low levels and 12 tumors high levels of mRNA. A significant positive correlation between P‐glycoprotein and glutathione peroxidase was found. In addition, of the 8 untreated patients, 2 had low topoisomerase‐ll expression, and 6 high expression. With treatment, the expression was reduced in 18 tumors, and only 5 tumors had high levels of this protein. These results were confirmed by PCR and immunohistochemistry.
Clinical pharmacokinetic studies of tetra(meta‐hydroxyphenyl)chlorin in squamous cell carcinoma by fluorescence spectroscopy at 2 wavelengths
Authors: Braichotte Daniel , Savary Jean‐François , Glanzmann Thomas , Westermann Patrick , Folli Silvio , Wagnieres Georges , Monnier Philippe , Van Den Bergh Hubert
Published: February 2007

To optimize photodynamic therapy (PDT) and photodetection of cancer with second‐generation photosensitizers, knowledge of important variables such as the uptake of the dye and the dye contrast between normal and tumoral tissue after injection is necessary. The pharmacokinetics of a second‐generation photosensitizer, tetra(meta‐hydroxyphenyl)chlorin (mTHPC), is presented. To study this in a clinical context, an apparatus based on fluorescence spectroscopy and a non‐invasive optical fiber probe has been used. The mTHPC fluorescence is induced at 2 excitation wavelengths (420 and 520 nm) with different penetration depth. The pharmacokinetics of mTHPC in patients with a squamous‐cell carcinoma in the oral cavity show a signal selectivity as high as 16 about 3 hr after i.v. injection for the more advanced carcinomas. The magnitude of this selectivity appears to correlate with the staging of the cancer, the more invasive tumors showing the highest selectivity. Results obtained at 420 and 520 nm show little difference. These pharmacokinetics can be used directly for optimizing photodetection with mTHPC. However, complementary information on the localization of the drug by fluorescence microscopy, and a correlation of this data with tumor necrosis efficacy, are needed to optimize PDT timing.
International renal‐cell cancer study. VIII. Role of diuretics, other anti‐hypertensive medications and hypertension
Authors: McLaughlin Joseph K. , Chow Wong Ho , Mandel Jack S. , Mellemgaard Anders , McCredie Margaret , Lindblad Per , Schlehofer Brigitte , Pommer Wolfgang , Niwa Shelley , Adami Hans‐Olov
Published: February 2007

Risk of renal‐cell cancer in relation to use of diuretics, other anti‐hypertensive medications and hypertension was assessed in a multi‐center, population‐based, case‐control study conducted in Australia, Denmark, Germany, Sweden and the United States, using a shared protocol and questionnaire. A total of 1,732 histologically confirmed cases and 2,309 controls, frequency‐matched to cases by age and sex, were interviewed. The association between renal‐cell cancer and the drugs was estimated by relative risks (RRs) and 95% confidence intervals (CIs). Risks were increased among users of diuretics and other anti‐hypertensive medications. After adjustment for hypertension, risk for diuretics was reduced to unity, except among long‐term (15+ years) users. Risk for use of non‐diuretic anti‐hypertensive drugs remained significantly elevated and increased further with duration of use. Overall risk was not enhanced when both classes of medications were used. Excess risk was not restricted to any specific type of diuretic or anti‐hypertensive drug and no trend was observed with estimated lifetime consumption of any particular type of product. The RR for hypertension after adjustment for diuretics and other anti‐hypertensive medications was 1.4 (95% Cl = 1.2–1.7), although among non‐users of any anti‐hypertensive medications, there was little excess risk associated with a history of hypertension. Exclusion of drug use that first occurred within 5 years of cancer diagnosis or interview did not alter the associations. Our findings suggest small effects on renal‐cell cancer risk associated with hypertension and use of diuretics and other anti‐hypertensive medications. However, because of potential misclassifications of these highly correlated variables, it is difficult to distinguish the effect of treatment from its indication, hypertension.
Intracellular uptake and catabolism of anti‐IgM antibodies and BI‐specific antibody‐targeted hapten by B‐lymphoma cells
Authors: Manetti Corine , Doussal Jean Marc Le , Rouvier Eric , Gruaz‐Guyon Anne , Barbet Jacques
Published: February 2007

The efficiency of radioimmunotherapy with iodine‐labelled antibodies is often limited by intracellular internalisation and catabolism after initial binding to the cellular targets. We have developed a technique called affinity enhancement system (AES) which uses bi‐specific antibodies to target radiolabelled bivalent haptens to cells. This targeting method has been applied successfully to tumour imaging in colorectal cancer patients and is now considered for therapy. We have investigated the potential of this technique to target iodine radioisotopes by comparing it to targeting with covalently iodine‐labelled antibodies in a rapidly internalising antigenic system, the surface IgM of a B‐lymphoma cell line. A 5‐fold increase in the intracellular retention time of activity as compared to l25l‐labelled F(ab')2 or IgG was observed. The radiolabelled hapten did not undergo any catabolism after internalisation. Resistance to cellular proteases and failure of recognition of the hapten by amino acid transporter systems may be potential explanations for these observations. This should make non‐covalent targeting, particularly the AES, a method of choice to target modulating antigens for the therapy of malignant hemopathies.
Antagonists of bombesin/gastrin‐releasing peptide inhibit growth of SW‐1990 human pancreatic adenocarcinoma and production of cyclic AMP
Authors: Qin Yunfeng , Ertl Tibor , Cai Ren‐Zhi , Horváth Judit E. , Groot Kate , Schally Andrew V.
Published: February 2007

We investigated the effects of bombesin/GRP antagonists RC‐3095 and RC‐3940‐II on the growth of SW‐1990 human pancreatic adenocarcinoma cells xenografted into nude mice or cultured in vitro. Nude mice implanted with SW‐1990 tumors received s.c. injections of RC‐3095 and RC‐3940‐II or the vehicle (control) for 28 days. Chronic administration of RC‐3940‐II inhibited the growth of SW‐1990 tumors, as shown by a reduction in tumor volume during the treatment and a significant increase in tumor doubling time. RC‐3940‐II decreased final tumor volume by 57.7% and tumor growth rate by 65%. Final tumor weights in mice treated with RC‐3940‐II were 75% lower than in controls. Treatment with RC‐3095 induced smaller, and not significant, decreases in tumor volume and weight. In cell cultures, both RC‐3095 and RC‐3940‐II effectively inhibited the proliferation of SW‐1990 cells, inducing a dose‐ and time‐dependent decrease in the number of cells. RC‐3940‐II again suppressed in vitro growth of SW‐1990 cells more effectively than RC‐3095. After 72 hr of culture, RC‐3940‐II and RC‐3095 at I μM concentrations decreased cell numbers by 45.7% and 27.7%, respectively. The estimated EC50 value for RC‐3940‐II was I nM. When SW‐1990 cells were cultured in the presence of I nM and 10 nM RC‐3095 for 72 hr, cAMP levels in the incubation medium were decreased to 77.3% and 26.9% of the control value. Our results indicate that bombesin/GRP antagonist RC‐3940‐II can inhibit the proliferation of SW‐1990 human pancreatic adenocarcinoma cells in vivo and in vitro. Our findings also suggest that this effect may involve the intracellular cAMP pathway.
Decreased biotolerability for ivermectin and cyclosporin a in mice exposed to potent P‐glycoprotein inhibitors
Authors: Didier Agnès D. , Loor Francis
Published: February 2007

SDZ PSC 833 or SDZ 280‐446 are strong blockers of the function of class 1 mdr gene‐encoded P‐glycoprotein molecules, which were developed for the reversal of multi‐drug‐resistance of tumor cells. When treated with such drugs, normal mice may display hypersensitivity to cyclosporin A and ivermectin. The recorded signs of acute toxicity are compatible with alterations of the murine central nervous system functions and with earlier data suggesting that P‐glycoprotein expressed at the murine blood‐brain barrier might be involved in the exclusion of cyclosporin A or ivermectin from brain tissue.
Cellular pharmacology of azatoxins (topoisomerase‐II and tubulin inhibitors) in P‐glycoprotein‐positive and ‐negative cell lines
Authors: Eymin Beatrice , Solary Eric , Chevillard Sylvie , Dubrez Laurence , Goldwasser François , Duchamp Olivier , Genne Philippe , Leteurtre François , Pommier Yves
Published: February 2007

Azatoxin (NSC 640737), a synthetic molecule, was rationally designed as a topoisomerase‐ll inhibitor and was shown to be a potent cytotoxic agent that inhibits both tubulin and topoisom‐erase II. A structure‐activity relationship study allowed to select 3 derivatives that inhibit either tubulin (methylazatoxin) only or topoisomerase II (fluoroanilinoazatoxin and nitroanilino‐azatoxin) in MTT assays performed on K562 and K562/ADM cells; the latter, expressing P‐glycoprotein, indicated cross‐resistance of K562/ADM cells to all 4 compounds. DNA double‐strand breaks induced by the 3 azatoxins that inhibit topoisomerase II in vitro were decreased in K562/ADM as compared with K562 cells. Nitroanilino‐azatoxin was the only compound for which resistance and reduced DNA damage observed in K562/ADM cells was partially reversed by verapamil, suggesting that nitroanilinoazatoxin was a substrate for P‐glycoprotein. These results were confirmed by testing the cytotoxic activity of azatoxins on P‐glycoprotein‐expressing rat colon‐carcinoma DHDKI2/TRb cells in the absence and the presence of verapamil. Cell‐cycle and mitotic‐index studies indicated that azatoxin‐ and methylazatoxin‐induced M‐phase arrest was less in K562/ADM than in KS62 cells. The G2 block induced by fluoro‐ and nitroanilino‐azatoxins was delayed in K562/ADM cells. Verapamil increased cell‐cycle inhibition induced by nitroanilinoazatoxin in K562/ ADM cells without modifying cell‐cycle effects of fluoroanilinoazatoxin. These results (i) are consistent with the specific inhibition of topoisomerase II or tubulin by azatoxin derivatives in cells; (ii) indicate that the nitro group of nitroanilinoazatoxin allows recognition and efflux by the P‐glycoprotein; and (iii) suggest that cross‐resistance of K562/ADM cells to other azatoxin derivatives is not mediated by P‐glycoprotein.
Prior immunity‐related medical conditions and pancreatic‐cancer risk in Shanghai
Authors: Dai Qi , Zheng Wei , Ji Bu‐Tian , Shu Xiao‐Ou , Jin Fan , Zhu Jin‐Liang , Gao Yu‐Tang
Published: February 2007

To investigate the role of immunity‐related medical conditions in the etiology of pancreatic cancer, we analyzed data from a population‐based case‐control study of pancreatic cancer conducted in Shanghai during 1992 and 1993. Information on prior histories of selected auto‐immune diseases and allergic conditions was obtained from 108 incident pancreatic‐cancer cases and 275 age‐ and gender‐frequency matched controls by face‐to‐face interviews using a structured questionnaire. A prior history of auto‐immune diseases was associated with a 2‐fold elevated risk of pancreatic cancer (95% C1 = 1.0–4.2), with an indication of a dose‐response relation for the number of reported diseases. In contrast, a prior history of allergic condition was related to reduced risk (OR = 0.6,95% C1 = 0.4–1.1). With the possible exception of drug allergy, such an inverse association was seen for virtually all allergic conditions, although none of the OR was statistically significant. This study suggests that host immune function may be involved in the etiology of pancreatic cancer. Further investigations into the mechanism of these observed associations are warranted.
Loss of abh antigen expression in bladder cancer is not caused by loss of heterozygosity of the ABO locus
Authors: Meldgaard Peter , Johnson Philip H. , Langkilde Niels C. , Wolf Hans , Ørntoft Torben F.
Published: February 2007

The significance of loss of heterozygosity (LOH) of chromosome 9 as an early event in human bladder tumors has been demonstrated by several studies. We have studied LOH of the ABO gene locus at 9q34.2 by means of polymerase chain reaction (PCR) genotyping of tumor preparations and leukocytes. Twenty‐two tumors, all of which were immunohistochemically negative for ABH antigens, were examined. Eleven tumors were from blood‐group O individuals, and were examined by denaturing gradient gel electrophoresis (DGGE). They showed normal band patterns with no sign of single base mutations or LOH. All 11 A and B tumors were sorted on a fluorescence‐activated cell sorter (FACS) according to DNA content, thereby making it possible to study differences in genotype between subpopulations of cells in the same tumor. In 2 genotypically AO cases, we found 2 aneuploid subpopulations. In both cases, the most abnormal, with the highest DNA content, showed complete loss of the O allele, leaving the A allele intact. As all tumors were ABH antigen‐negative, this study demonstrates that LOH of the ABO locus on chromosome 9q34 is not the cause of loss of blood‐group ABH expression in human bladder cancer.