bluuebunny/crossref_metadata_2025 huggingface dataset:
Presence of the bcl‐2 protein and apoptosis in non‐hodgkin lymphomas with diffuse growth pattern
Authors: Leoncini Lorenzo , Del Vecchio Maria T. , Spina Donatella , Megha Tiziana , Barbini Paolo , Sabattini Elena , Pileri Stefano , Tosi Piero , Kraft Rainer , Laissue Jean A. , Cottier Hans
Published: February 2007

In an attempt to further clarify the role of the apoptosis‐counteracting protein bcl‐2, non‐Hodgkin lymphomas (NHL, n = 170) were examined immunohistochemically, across the boundaries of histologic classification, for the presence of this oncoprotein, in comparison with apoptotic indices (AI) and percentages of Ki‐67+ cells (growth fraction). The results of this retrospective study revealed a highly significant inverse relationship (“mirror image”) between the proportion of bcl‐2+ cells and the AI per case. Both these parameters, although variable, clearly distinguished low‐ from high‐grade‐malignancy lymphomas according to the Kiel classification. Cluster analysis detected 2 separate groups of high‐grade NHL, one with rather high AI and low percentages of bcl‐2+ cells, comprising most anaplastic large‐cell lymphomas, the other group with reverse characteristics. We found no correlation between the percentage of bcl‐2+ cells per case and overall survival. © 1995 Wiley‐Liss, Inc.
Colon goblet cells lose proliferative response to TGFα as they differentiate
Authors: Sauma Samir , Huang Fei , Winawer Sidney , Friedman Eileen
Published: February 2007

Two cell line models for colon goblet cells expressed 6‐ to 14‐fold elevated levels of the EGF receptor, 3‐ to 5‐fold levels of TGFα and 11‐ to 15‐fold levels of amphiregulin compared with 2 cell lines which model colon enterocytic differentiation, suggesting a role for the EGF receptor and its ligands in goblet cell growth control. Two HT29 colon carcinoma sublines were used to model normal goblet cells at different stages of maturation. TGFα induced a 2‐fold increase in growth of the HD8 subline but inhibited the growth of the more differentiated HD6 subline by 40%. EGF receptors were activated in each line by ligand, but signal transduction varied sharply. Both MAP kinase isoforms, p44 and p42, were markedly activated in HD8 cells for at least 20 min, while only a marginal activation was seen in HD6 cells. In contrast, the more differentiated HD6 cells showed an increase in 105 kDa MBP kinase activity with EGF treatment, while HD8 cells displayed constitutively elevated levels of this kinase. Thus, activated EGF receptors initiated different signalling pathways in model cell lines for colon goblet cells at different stages of maturation. TGFα protein levels have been shown by other investigators to be restricted to the top of the cylinder‐like colonic crypt, where cells terminally differentiate and cease division, an unexpected location for an epithelial cell mitogen. Our data with model cell lines imply that normal colon goblet cells lose proliferative response to TGFα as they differentiate and the elevated levels of TGFα at the top of the colonic crypt in vivo serve to inhibit goblet cell growth. © 1995 Wiley‐Liss, Inc.
Susceptibility of colorectal‐carcinoma cells to natural‐killer‐mediated lysis: Relationship to CEA expression and degree of differentiation
Authors: Prado Ivete B. , Laudanna Antonio A. , Carneiro Célia R. W.
Published: February 2007

This study addresses the relevance of colorectal‐carcinoma‐cell (CRC) CEA expression and degree of differentiation in natural‐killer(NK)‐mediated lysis susceptibility. A 51Cr‐release cytotoxicity assay performed with 5 human CRC lines demonstrated that CRC CEA expression was related to resistance to NK lysis. Moreover, the addition of anti‐CEA Fab fragments to the assay led to a significant increase of lysability of high‐CEA‐producing and NK‐resistant cells (LS 174‐T), whereas purified CEA drastically reduced lysis of low‐CEA‐producing and NK‐susceptible cells (LISP‐1) in a dose‐dependent manner. These results strongly suggest that CEA plays a causal role in CRC resistance to NK lysis. Nevertheless, our data did not demonstrate CEA binding to effector cell surface, suggesting that CEA expression can protect CRC, possibly by preventing NK‐tumor‐cell adhesion to occur. Our results also show that CRC susceptibility to NK lysis was related to a less differentiated phenotype. HCT‐8, which are poorly differentiated and low‐CEA‐producing cells, were cultured in vitro in the presence of the differentiation agent sodium butyrate. Treated cells became less susceptible to NK lysis as they progressed towards a more differentiated phenotype. However, CEA production was not altered upon differentiation. Our study thus demonstrates that both features, CEA expression and degree of cellular differentiation, may individually influence CRC susceptibility to NK lysis. © 1995 Wiley‐Liss, Inc.
Expression of acid cysteine proteinase inhibitor (acpi) in the normal human prostate, benign prostatic hyperplasia and adenocarcinoma
Authors: Söderström Karl‐Ove , Laato Matti , Wu Ping , Hopsu‐Havu Väinä K. , Nurmi Martti , Rinne Ari
Published: February 2007

Acid cysteine proteinase inhibitor (ACPI or cystatin A) is a protein (12 kDa) which inhibits the action of several cysteine proteinases, e.g. cathepsins B, H, L and S. In this study the cellular location of ACPI has been immunohistochemically investigated in the normal human prostate, in benign prostatic hyperplasia (BPH) and in adenocarcinoma. ACPI was found in the basal epithelial cells of the normal prostate. The secretory epithelial cells did not express ACPI. In the hyperplastic prostate, the expression of ACPI was decreased and it was also expressed more focally in the basal cells. Hyperplastic basal cells also expressed ACPI. In prostatic adenocarcinoma, no ACPI expression was found. The absence of ACPI expression was obvious and if the sections contained both benign and malignant cells, only the benign glandular structures always expressed ACPI. The results suggest that expression of ACPI might be related to prostatic epithelial cell proliferation and differentiation. Possibly the detection of ACPI in tissue sections might be helpful in identifying prostatic adenocarcinoma, especially in cases with small carcinomatous foci. © 1995 Wiley‐Liss Inc.
Human and viral interleukin‐10 in Hodgkin's disease, and its influence on CD4+ and CD8+ T lymphocytes
Authors: Ohshima Koichi , Suzumiya Junji , Akamatu Minoru , Takeshjta Morishige , Kikuchi Masahiro
Published: February 2007

The Epstein‐Barr virus (EBV) is closely related to Hodgkin's disease (HD), while the BCRF‐I (viral [v] IL‐10) gene of the EBV is highly homologous to the human interleukin‐10 (h IL‐10) gene. To investigate the relationship of IL‐10 and HD, we performed both immunostaining and in situ hybridization (ISH) in 30 cases of HD. The presence of EBV in Hodgkin (H) and Reed‐Sternberg (RS) cells was seen in 16 of the 30 cases, by ISH of the EBV EBER‐I region and/or immunostaining of latent membrane protein (LMP‐I). Of the 16 EBV‐positive cases, 12 also showed IL‐10 antigen (Ag) in H and RS cells by immunostaining, 5 of the 16 demonstrated hIL‐10 RNA by ISH and 14 of the 16 showed vIL‐10 RNA. But only 2 of the 14 EBV‐negative cases showed IL‐10 Ag, and one of them showed hIL‐10 RNA, while none demonstrated vIL‐10 RNA. The T cells in the HD‐involved tissues were found to be mainly CD4‐positive T cells, and had no association with EBV infection. However, the lymphocytes surrounding H and RS cells were more frequently CD4 cells and rarely CD8 cells in the EBV‐positive cases, in contrast with the EBV‐negative cases. The above results indicate that an EBV infection influenced both cytokine synthesis and the response of T cells in HD. © 1995 Wiley‐Liss Inc.
Second primary cancers in patients with carcinoma in situ of the uterine cervix. The norwegian experience 1970–1992
Authors: Bjørge Tone , Hennig Elin M. , Skare Gry B. , Søreide Odd , Thoresen Steinar Ø.
Published: February 2007

Multiple primary cancers in the same individual occur rarely. Consequently, a large number of cancer patients have to be followed for long periods to obtain adequate information about their risk of subsequent tumour development. Studies of multiple malignancies are of interest, since they may provide information on common or opposite risk factors. In the present study, the risk of second primary cancers following carcinoma in situ of the uterine cervix diagnosed in Norway in the period 1970–1992 was examined and quantified. Altogether, 37,001 patients with carcinoma m situ were followed from the date of diagnosis until 31 December 1992. The follow‐up period was divided into 5‐year intervals. The results were expressed as standardized incidence ratios (SIR = O/E), and their 95% confidence intervals were given. A total of 1,037 second primary cancers in 989 individuals were identified. There was no overall excess of second primary cancers. However, there were differences depending on the site: cancers of the oesophagus, nose, nasal cavities, trachea, bronchus, lung, vulva, vagina, bladder and other urinary organs, and other skin cancers, excluding basal‐cell carcinoma, occurred more frequently. A lower risk than expected was noted for cancer of the cervix uteri and cancer of the corpus uteri. There was a rising trend with time in the observed/expected ratio for cancer of urinary organs. In the group of patients evaluated, the likelihood of subsequent tumour development was no greater than in the general female population. Nevertheless, cancer sites of higher and of lower risk than expected were identified among the carcinoma‐In situ patients. © 1995 Wiley‐Liss Inc.
A novel human monoclonal antibody, TONO‐1, reactive with T‐lymphocytic leukemia cells
Authors: Numasaki Muneo , Fukuoka Yoshihiro , Kudo Toshio , Saeki Hisaaki , Tachibana Takehiko , Motomiya Masakichi , Nukiwa Toshihiro
Published: February 2007

Mononuclear cells from the peripheral blood of patients with systemic lupus erythematosus (SLE) were transformed with the Epstein‐Barr virus (EBV) and the resultant polyclonal B‐lymphoblastoid cell lines were tested for antibody activity to membrane antigens of certain T‐cell lines. B lymphoblastoid cell lines secreting specific antibodies were fused with (mouse x human) heteromyeloma SHM‐D33 cells. Among the large number of hybridomas generated, one which produced a human monoclonal antibody (MAb) TONO‐I (1gM, λ) was selected. MAb TONO‐I proved to be reactive with 4 human T‐cell lines, HPB‐MLT, L‐MAT, MOLT‐3 and MOLT‐4F, but not with B‐leukemia, Burkitt's lymphoma, myelomonocytic leukemia, erythroleukemia or non‐hematopoietic malignant cell lines. MAb TONO‐I reacted positively with fresh leukemia cells from 2 of 7 patients with acute T‐lymphocytic leukemia, but no reaction was observed in non‐T‐cell leukemia cases. Normal lymphocytes, monocytes, granulocytes, red blood cells and platelets in the peripheral blood did not demonstrate remarkable binding. Neither thymocytes nor bone‐marrow cells from healthy volunteers were reactive. The antigens defined by MAb TONO‐I were polypeptides of 57 kDa and 68 kDa. Immunohistological studies revealed no staining of thymocytes in the thymus of a 6‐month‐old child, but showed epithelial reticular cells and Hassall's corpuscles to stain positively. These results suggest that MAb TONO‐I is directed to T‐leukemic cells and some components of thymus tissue. © 1995 Wiley‐Liss Inc.
Sequence specificity on the growth suppression and induction of apoptosis of chronic myeloid leukemia cells by BCR‐ABL anti‐sense oligodeoxynucleoside phosphorothioates
Authors: Maekawa Taira , Kimura Shinya , Hirakawa Kouichi , Murakami Akira , Zon Gerald , Abe Tatsuo
Published: February 2007

Sequence specificity of inhibitory effects of various BCR‐ABL anti‐sense oligodeoxynucleoside phosphorothioates (AS PS‐ODN) on the proliferation of the chronic myeloid‐leukemia cell line BV173 was examined. We confirmed that 26,18, and 16mer B2A2 AS PS‐ODN had strong inhibitory effects on the proliferation of BV173 cells with B2A2 mRNA expression, and that B3A2 AS PS‐ODN were equally inhibitory when cultures were initiated at lower cell concentrations. However, at higher cell concentrations, the inhibitory effects by B3A2 AS PS‐ODN were reduced and B2A2 AS PS‐ODNs could suppress the proliferation of BV173 cells with much more relative sequence specificity. The 26mer B2A2 AS PS‐ODN induced apoptosis of BV173 cells following reduction of BCR‐ABL mRNA expression and p210 protein synthesis. Various sense (S), reverse order, and random sequences had no inhibitory effects except 16mer B2A2 S and B3A2 S that revealed significant suppressive effects. Furthermore, 26mer B3A2 AS also reduced B2A2 mRNA expression and p210 protein synthesis, while 16mer S sequences did not. These results suggest that B2A2 AS may be cross‐reactive with B3A2 AS on the growth suppression of CML cells under certain culture conditions, possibly due to their partial hybridization to the ABL portion of the target mRNA, although other non‐sequence‐specific mechanisms are also possible. © 1995 Wiley‐Liss Inc.
Expression of type a and b tumor necrosis factor (TNF) receptors on melanoma cells can be regulated by dbc‐AMP and IFN‐γ
Authors: Carrel Stefan , Hartmann Françoise , Salvi Suzanne , Albrecht Hugo , Schreyer Magali , Rimoldi Donata
Published: February 2007

Local administration of high‐dose r‐TNFα with IFNγ in the limbs of melanoma patients has proved to be a very promising treatment. To understand the role played by the effect of TNF on melanoma cells in tumor destruction, we have investigated the expression of TNF‐receptors in melanoma cells using monoclonal antibodies specific for the type‐A (75‐kDa) and the type‐B (55‐kDa) TNF receptors. Flow cytometric analysis of cultured melanoma cells indicated the presence of both types of receptor. Quantificative differences in the relative levels of receptors were observed for different cells lines, although the type‐B receptor was generally more strongly expressed. Similar results were obtained by immunohistochemistry on cryosections from tumor samples. Positive staining of variable intensity was observed for the type‐B TNF‐receptor in a high percentage of tumor cells. The type‐A TNF‐receptor was also detected, but with a weaker staining. The total TNF‐binding activity of cultured melanoma cells, as measured by binding of 125l‐labeled TNFα, was up‐regulated between 2‐ and 4‐fold by incubation of cells with activators of protein kinase A or IFNγ. Treatment of cultured melanoma cells with dbc‐AMP resulted in a selective induction of type‐A TNF‐receptors, without affecting the type‐B receptor level. In contrast, IFN‐y was able to induce either type of receptor in a cell‐line‐dependent fashion. Addition of TNFγ to melanoma cells induced the activation of the nuclear transcription factor KB, as measured in an electrophoretic mobility shift assay, thus indicating the biological significance of the TNF‐receptors on these cells. © 1995 Wiley‐Liss Inc.
MRP gene overexpression in a human doxorubicin‐resistant SCLC cell line: Alterations in cellular pharmacokinetics and in pattern of cross‐resistance
Authors: Binaschi Monica , Supino Rosanna , Gambetta Romolo A. , Giaccone Giuseppe , Prosperi Ennio , Capranico Giovanni , Catalog Ignazio , Zunino Franco
Published: February 2007

The development of non‐P‐glycoprotein‐mediated multidrug resistance is a frequent event among lung‐cancer cell lines. In an attempt to understand the underlying mechanisms of this phenotype, we have selected a multi‐drug‐resistant subline (POGB/DX) in vitro for doxorubicin resistance. The original cell line (POGB) was established in vitro from a non‐treated patient with a small‐cell lung cancer. POGB/DX cells were crossresistant to other drugs, associated with MDR phenotype. In contrast, they were not resistant to taxol, camptothecin or melphalan, but were instead hypersensitive to 5‐fluorouracil. Although expression of the mdr‐l gene was not detected in POGB/DX cells, cellular pharmacokinetics showed a reduced drug accumulation and altered intracellular localization in the POGB/DX cell line. This defect in drug accumulation was associated with overexpression and amplification of the MRP gene. Interestingly, verapamil, a known modulator of P‐glycoprotein function, was able to reverse drug resistance and to increase drug accumulation. In Northern‐blot analysis no differences in expression of topoisomerase I and II (α and β), DNA polymerase β, or HSP70 and HSP60 genes were observed between POGB and POGB/DX. Coupled to lack of changes in expression of known resistance factors, over expression of MRP and modulation by verapamil strongly support a role for this gene product in the development of drug resistance in this SCLC cell system. This study provides evidence that (a) altered cellular pharmacokinetics is related to MRP expression; (b) MRP‐mediated phenotype is characterized by a specific pattern of cross‐resistance, which does not involve taxol; and (c) verapamil may be effective in modulating the function of the MRP gene product. © 1995 Wiley‐Liss Inc.
Identification of a novel peptide derived from the melanocyte‐specific gp100 antigen as the dominant epitope recognized by an HLA‐A2.1‐restricted anti‐melanoma CTL line
Authors: Barker Alexander B. H. , Schreurs Marco W. J. , Tafazzul Gaalda , De Boer Annemiek J. , Kawakami Yutaka , Adema Gosse J. , Figdor Carl G.
Published: February 2007

Cytotoxic T lymphocytes (CTL) reactive with human melanoma tumor cells occasionally display cross‐reactivity with normal melanocytes. Previously, we identified the melanocyte lineage‐specific antigen gp100 that is expressed by both melanoma cells and normal melanocytes, as a target antigen for tumor‐infiltrating lymphocytes derived from a melanoma patient (TIL 1200). Here, we demonstrate that the oligoclonal HLA‐A2.1‐restricted TIL 1200 line is reactive with 2 distinct peptides derived from the gpl00 protein. Apart from the peptide corresponding to gpl00 amino acids 457–466, we identified the gpl00 peptide 154–162 as a second epitope recognized by TIL 1200. A 100‐fold lower concentration of this novel gpl00 peptide was required for target‐cell sensitization compared to peptide 457–466, indicating that the 154–162 peptide is the dominant gpl00 epitope for TIL 1200. Together with the recently described gpl00 280–288 epitope, 3 distinct CTL epitopes have now been identified in gpl00, all presented in the context of HLA‐A2.1. Therefore, gpl00 is an attractive target antigen in the development of immuno‐therapeutic protocols against melanoma. © 1995 Wiley‐Liss Inc.
Interferon‐α/β can impede development of carcinogen‐induced squamous‐cell tumors in the esophagus of C57B1 mice
Authors: Fagerberg Jan , Rubio Carlos , Gresser Ion , Kuylenstierna Richard , Munck‐Wikland Eva , Strander Hans
Published: February 2007

The effect of treatment with murine interferon‐α/β preparations on diethylnitrosamine‐induced squamous‐cell tumors in the esophagus of C57B1 mice was investigated. Diethylnitrosamine was administered in the drinking water for 18 weeks. Interferon was given intraperitoneally during the same 18 weeks or from the end of the period of carcinogen exposure until termination of the experiment. In mice given interferon and diethylnitrosamine synchronously, a significantly lower tumor index (number of tumors/cm of esophageal mucosa) was observed as compared to all control groups. Treatment with interferon after the administration of the carcinogen was terminated had no effect on the appearance of tumors. These data suggest that interferon therapy can exert certain effects on carcinogenesis. © 1995 Wiley‐Liss Inc.
Socioeconomic factors and human cancer
Authors: Tomatis Lorenzo
Published: February 2007

In spite of the many attempts made at various periods of human history to arrive at an equalitarian society by reducing differences between the rich and the poor and by redistributing wealth, social inequalities have not disappeared and even seem to be increasing worldwide. Inequalities in health represent some of the social inequalities present in our society and are one of their most convincing indices. In industrialized countries, it has been consistently shown that total incidence of and mortality from cancer are higher in less favored socioeconomic groups, mainly due to increased rates at certain sites. The differences observed between socioeconomic groups within industrialized countries are similar, although not identical, to those prevailing between industrialized and developing countries. Occupational risks are becoming a very serious problem in developing countries, largely as a consequence of the transfer of hazardous industries from highly industrialized countries where certain industries are judged to be unacceptable. A similar double standard is applied toward tobacco advertising and sales in the industrialized and developing countries. © 1995 Wiley‐Liss Inc.
Multiple births and risk of breast cancer
Authors: Dietz Amy Trentham , Newcomb Polly A. , Storer Bany E. , Longnecker Matthew P. , Mittendorf Robert
Published: February 2007

Data from a large, multicenter, population‐based case‐control study were analyzed to investigate the relation between multiple birth pregnancies and subsequent breast‐cancer risk in the gravidas. Women less than 75 years old who had breast cancer were identified from statewide tumor registries in Wisconsin, western Massachusetts, Maine and New Hampshire. Controls aged less than 65 years were selected randomly from lists of licensed drivers, and controls aged between 65 and 74 were selected randomly from lists of Medicare beneficiaries. Information on reproductive history and other factors was obtained by means of telephone interviews. After excluding nulliparous women, 5,880 case subjects and 8,217 controls remained for analysis. Multiple birth pregnancies occurred in 146 cases and 218 controls. Adjusted for the number of full‐term pregnancies and other confounders, the odds ratio (OR) for any multiple birth pregnancy was 0.94 (95% confidence interval, 0.75 to 1.17). The null association between multiple birth pregnancies and breast cancer remained if the mother's first pregnancy or last pregnancy resulted in a multiple birth. In addition, no trend in risk emerged for age at first multiple birth or time since last multiple birth. While other investigators have suggested biological mechanisms to explain both protective and detrimental effects of multiple births and subsequent development of breast cancer, this study does not support either assertion. © 1995 Wley‐Liss, Inc.
Correlation between the sensitivity or resistance to IL‐2 and the response to cyclophosphamide of 4 tumors transplantable in the same murine host
Authors: Greco Giampaolo , Gabriele Lucia , Rozera Carmela , Venditti Massimo , Belardelli Filippo , Proietti Enrico
Published: February 2007

We have studied the anti‐tumor response to cyclophosphamide (CTX) in DBA/2 mice transplanted s.c. with 4 tumors exhibiting different responses to IL‐2: ESb lymphoma and Friend leukemia cells (non‐responsive or poorly responsive, respectively), pI I‐R‐Eb and Eb lymphoma cells (both highly responsive to IL‐2). CTX injections on days 7, 14 and 21 resulted in a significant anti‐tumor response in mice transplanted s.c. with Friend leukemia cells or ESb cells, whereas no anti‐tumor effect was observed in mice injected with Eb or pI I‐R‐Eb cells. All 4 tumor cell lines were equally sensitive to the cytotoxic effects of mafosfamide, an in vitro active analogue of CTX. To define the host mechanisms responsible for the lack of an anti‐tumor effect of CTX in mice transplanted with IL‐2‐responsive tumors, we studied several aspects of the spontaneous or IL‐2‐induced anti‐tumor response in mice transplanted with pI I‐R‐Eb cells. Injection of monoclonal antibodies (MAbs) to IFN‐γ completely abolished the anti‐tumor effects of IL‐2. Using a Winn assay, clear‐cut anti‐tumor activity was found in spleen cells from mice transplanted with the IL‐2‐responsive tumors. This activity was abolished by CTX, which also abrogated the anti‐tumor response to IL‐2 in mice injected with pI I‐R‐Eb cells. Our results indicate an inverse correlation between sensitivity to IL‐2 and response to CTX and emphasize the importance of initial host‐tumor interaction in determining the type of response to IL‐2 or CTX. © 1995 Wiley‐Liss, Inc.
Pharmacokinetics and anti‐tumor activity of vincristine encapsulated in sterically stabilized liposomes
Authors: Allen Theresa M. , Newman Mary S. , Woodle Martin C. , Mayhew Eric , Uster Paul S.
Published: February 2007

Vincristine is used clinically for the treatment of various types of cancer. Recent significant therapeutic improvements obtained by entrapping anthracyclines in sterically stabilized liposomes raised the question whether the therapeutic index of vincristine can be similarly increased by formulation into such long‐circulating liposomes. Encapsulation of vincristine in sterically stabilized liposomes (SL‐VCR) prolonged the drug's distribution phase plasma half‐life in rats from 0.22 to 10.5 hr. There was no significant difference in LD50 (⪋ 2.5 mg/kg, i.v.), but mice given sublethal doses of SL‐VCR experienced significantly less weight loss than those given the same dose of free drug. Compared to free drug, SL‐VCR was most effective against i.p. or s.c. implanted tumors. However, i.v. tumor inoculation nullified the therapeutic advantage of encapsulation. A single i.v. 2 mg/kg dose of SL‐VCR increased the life span of mice bearing i.v. implanted P388 cells by only 44%, while the life span of i.p. P388 implanted mice was increased by 199%. In an s.c. implanted murine colon carcinoma, multiple doses of free drug did little to slow the growth of the tumors, but SL‐VCR was able to produce long‐term survivors in several dose regimens. These results indicate that prolonged circulation time increases the therapeutic index of VCR entrapped in liposomes against s.c. or i.p. implanted tumors, but does not improve the drug's activity against rapidly growing i.v. disseminated leukemias. © 1995 Wiiey‐Liss, Inc.
Composition of ether‐linked sub‐classes of glycerophospholipids in clones with a different metastatic potential isolated from a murine fibrosarcoma line (T3 cells)
Authors: Fallani Anna , Mannori Gianna , Ruggieri Salvatore
Published: February 2007

An increase of ether‐linked sub‐classes of choline and ethanol‐amine glycerophospholipids has been shown in different types of tumor cells, and correlated with some of their specific biological parameters. In the present study, we examined the composition of ether‐linked lipids in a series of clones with a different lung‐colonizing potential isolated in our laboratory from a highly metastatic fibrosarcoma line (T3 cells). We found good correlation between the metastatic potential of T3 isolates and increased proportions of both alkylacyl and alkenylacyl subclasses in choline glycerophospholipids (CGP). Moreover, propagation of a weakly metastatic T3 clone in tissue culture led to the emergence of a sub‐clone which expressed high metastatic potential together with a high level of alkylacyl and alkenylacyl CGP. No differences were found in the alkylacyl and alkenylacyl‐ethanolamine glycerophospholipids (EGP) between the strongly and weakly metastatic T3 clones. We discuss the accumulation of alkylacyl and alkenylacyl CGP in metastatic cells for its possible role in metastatic diffusion by generation of platelet‐activating factor (PAF). © 1995 Wiley‐Liss, Inc.
Differential effects of verapamil and quinine on the reversal of doxorubicin resistance in a human leukemia cell line
Authors: Bennis Sanae , Ichas François , Robert Jacques
Published: February 2007

We studied the restoration of doxorubicin accumulation and sensitivity by verapamil and quinine in a variant of the human erythroleukemia cell line K562 selected for resistance to doxorubicin and presenting a multidrug‐resistance (MDR) phenotype. Verapamil was able to completely restore doxorubicin accumulation in the resistant cells to the level obtained in sensitive cells, but only partially reversed doxorubicin resistance. Quinine, in contrast, had a relatively weak effect on doxorubicin accumulation but was able to completely restore doxorubicin sensitivity in the resistant cells. In addition, verapamil was able to decrease azidopine binding to P‐glycoprotein, whereas quinine was not. Quinine also modified the intracellular tolerance to doxorubicin, which suggests that it is able to modify drug distribution within the cells. Confocal microscopy revealed that verapamil and quinine were able to restore nuclear fluorescence staining of doxorubicin in resistant cells; since this was obtained for quinine without significant increase of doxorubicin accumulation, this observation confirms that quinine acts principally on doxorubicin redistribution within the cells, allowing the drug to reach its nuclear targets. When used in association, verapamil and quinine reversed doxorubicin resistance in a synergistic fashion. We conclude that verapamil and quinine do not share the same targets for reversal of MDR in this cell line; whereas verapamil directly interferes with P‐glycoprotein and mainly governs drug accumulation, quinine has essentially intracellular targets involved in drug redistribution from sequestration compartments. © 1995 Wiley‐Liss Inc.
Engineering high affinity humanized anti‐p185HER2/anti‐CD3 bispecific F(ab′)2 for efficient lysis of p185HER2 overexpressing tumor cells
Authors: Zhu Zhenping , Lewis Gail D. , Carter Paul
Published: February 2007

We previously constructed a humanized anti‐p185HER2/anti‐CD3 bispecific antibody variant, BsF(ab′)2 v1 which retargets the cytotoxic activity of human T cells in vitro against human breast tumor cells which overexpress the p185HER2 product of the HER2/neu (c‐erbB‐2) protooncogene. Subsequently we identified an improved anti‐CD3 variant, v9, which binds to T cells with approx. 100‐fold higher affinity than the original variant, v1. Here we demonstrate that BsF(ab′)2 v9 is more potent than BsF(ab′)2 v1 in stimulating the proliferation of both resting peripheral blood lymphocytes (PBL) and IL‐2‐activated, long‐term cultured T lymphocytes (ATL). In addition, at low concentrations (0.01‐1 ng/ml) BsF(ab′)2 v9 is much more efficient than BsF(ab)2 v1 in directing lysis of p185HER2‐overexpressing tumor cells by IL‐2 activated PBL. In contrast, at higher concentration BsF(ab′)2 v9 and BsF(ab′)2 v1 have similar potency in retargeted cytotoxicity. At BsF(ab′)2 v9 concentrations of ⩾ 1 ng/ml the susceptibility of p185HER2‐expressing tumor cells to lysis is apparently independent of the level of p185HER2 expression. At lower concentrations of BsF(ab′)2 v9 and/or lower ratios of effector to target cells the extent of lysis is reduced, in some cases improving the selectivity of lysis of high p185HER2 expressors over low expressors. Thus selection of a high affinity anti‐CD3 arm is likely important in the design of BsF(ab′)2 for retargeting the cytotoxicity of T cells to tumors. The dose of BsF(ab′)2 v9 in any future clinical evaluation will require optimization to maximize anti‐tumor efficacy whilst minimizing potential toxicity against normal tissue expressing p185HER2. © 1995 Wiley‐Liss Inc.
Identification of differentially expressed genes in T‐lymphoid malignancies in an animal model system
Authors: Starkey Cindi R. , Levy Laura S.
Published: February 2007

The molecular events characterizing lymphoid malignancy have been examined in an animal model system, specifically, the retroviral induction of leukemia and lymphoma in the domestic cat following infection with feline leukemia virus (FeLV). Genes differentially expressed in FeLV‐induced lymphomas were isolated using a strategy of differential hybridization. Six genes were identified which demonstrate a higher level of expression in an FeLV‐induced feline thymic tumor as compared with normal thymus. The differentially expressed genes encode the feline homologues of ribosomal proteins S3a, S4, S17, and L41, elongation factor‐1α, and cytochrome oxidase sub‐unit 1. Northern‐blot analysis and quantification by phosphorimaging demonstrates that these genes are expressed at levels from 1.5‐to 3.1‐fold higher in J5–1 thymic tumor as compared with normal thymus. Expression of the selected ribosomal protein mRNA was further examined in a series of human and feline tissues, including normal tissues, malignant tumors and cell lines. Our data reveal that elevation of the selected ribosomal protein mRNA is associated with all FeLV‐induced thymic lymphomas examined. The differentially expressed ribosomal protein mRNA accumulates in a balanced manner in thymic lymphomas. By contrast, the elevation in ribosomal protein mRNA levels is not associated uniformly with hematopoietic malignancy, T‐lymphoid malignancy, solid tumors or actively proliferating cells. Rather, the elevation appears to be a uniform and distinctive feature of T‐cell malignancy of this particular type. The elevated expression of these genes may be causally related to the neoplastic process. © 1995 Wiley‐Liss Inc.
Cinnamic acid: A natural product with potential use in cancer intervention
Authors: Liu Lei , Hudgins W. Robert , Shack Sonsoles , Yin Mu Quan , Samid Dvorit
Published: February 2007

Cinnamic acid, a naturally occurring aromatic fatty acid of low toxicity, has a long history of human exposure. We now show that cinnamic acid induces cytostasis and a reversal of malignant properties of human tumor cells in vitro. The concentration causing a 50% reduction of cell proliferation (IC50) ranged from 1 to 4.5 mM in glioblastoma, melanoma, prostate and lung carcinoma cells. Using melanoma cells as a model, we found that cinnamic acid induces cell differentiation as evidenced by morphological changes and increased melanin production. Moreover, treated cells had reduced invasive capacity associated with modulation of expression of genes implicated in tumor metastasis (collagenase type IV, and tissue inhibitor metalloproteinase 2) and immunogenicity (HLA‐A3, class‐1 major histocompatibility antigen). Further molecular analysis indicated that the anti‐tumor activity of cinnamic acid may be due in part to the inhibition of protein isoprenylation known to block mitogenic signal transduction. The results presented here identify cinnamic acid as a new member of the aromatic fatty acid class of differentiation‐inducers with potential use in cancer intervention. © 1995 Wiley‐Liss Inc.
Interleukin‐11 protects the clonogenic stem cells in murine small‐intestinal crypts from impairment of their reproductive capacity by radiation
Authors: Potten Christopher S.
Published: February 2007

The rapidly proliferating gastrointestinal mucosa is one of the major limiting tissues in cancer therapy. Because of its short transit time and high sensitivity to radiation and chemotherapeutic drugs, damage is rapidly manifested. Protection of the important stem cells in the tissue could be achieved, in principle, by appropriate prior manipulation with cytokines or growth factors which might make them more resistant to the cytotoxic treatment, for example, by putting them out of cycle. Such strategies might reduce some of the adverse side‐effects of cancer treatment and improve the quality of life of patients, while possibly allowing an escalation of therapeutic dose. The functional capacity of stem cells has been studied for many years using a microcolony assay technique which measures the regenerative capacity of the clonogenic stem cells in crypts. These cells determine the survival of crypts which themselves determine whether or not the mucosal integrity is maintained and ultimately whether the animal or patient survives. Here, we demonstrate that treatment with interleukin‐11 for 2 days prior to radiation exposure can significantly increase the number of surviving crypts. Treatment with IL‐11 both before (for 2 days) and after irradiation (for 3 days) produces a slightly enhanced protection. Up to about 4 times more crypts survive at the highest radiation dose after either of these treatment schedules. These studies may provide a radiobiological explanation for the increased survival of animals when IL‐11 is administered during SFU and radiation exposures. © 1995 Wiley‐Liss Inc.
Risk of cutaneous melanoma associated with a family history of the disease
Authors: Ford Deborah , Bliss Judith M. , Swerdlow Anthony J. , Armstrong Bruce K. , Franceschi Silvia , Green Adèle , Holly Elizabeth A. , Mack Thomas , Mackie Rona M. , Østerlind Anne , Walter Stephen D. , Peto Julian , Easton Douglas F.
Published: February 2007

In a combined analysis of 2952 melanoma patients and 3618 controls from 8 case‐control studies in white populations the risk of cutaneous melanoma was 2.24‐fold higher (95% Cl, 1.76–2.86) in subjects who reported at least one affected first‐degree relative than in subjects who did not. There was no evidence for heterogeneity in the relative risk between the studies, which were from a wide range of latitudes and hence degrees of sun exposure. The effect of family history on melanoma risk was independent of age, naevus count, hair and eye colour, and freckling. There was no evidence for a relationship between family history and primary site of melanoma but there was some suggestion that the familial patients were more likely to have superficial spreading melanoma or lentigo maligna melanoma than acral lentiginous melanoma or nodular melanoma. © 1995 Wiley‐Liss, Inc.
Effects of 1,25‐dihydroxyvitamin D3 on transformed C3H/10T1/2 fibroblasts grown as multicellular spheroids
Authors: Brackman Damien
Published: February 2007

We have previously shown that 1,25‐dihydroxyvitamin D3(1,25‐(OH)2D3) is able to modulate proliferation of C3H/10T1/2 fibroblasts grown in monolayer cell culture. The aim of this study was to investigate the effects of the hormone in a 3‐dimensional culture system, which is considered to better reflect the cellular environment that is found in vivo. Two transformed cell lines of C3H/10T1/2 fibroblasts (C116 and TPA 482) were grown as multicellular spheroids, whereas the non‐tumorigenic C3H/10T1/2 C18 cells failed to form spheroids. The hormone had no effect on spheroids made of TPA 482 cells but had a biphasic effect on C116 spheroid growth with stimulation at low and inhibition at higher concentrations. In C116 spheroids, 10–8M 1,2S‐(OH)2D3 induced complete arrest of spheroid growth. Light and electron microscopic studies and immunocy‐tochemistry showed that 10–8M 1,25‐(OH)2D3 induced morphological changes in C116 spheroids, with a marked reduction in expression of fibronectin, laminin and the gap junction protein connexin 43. These effects were followed by a loosening of the spheroid structure, detachment of viable cells, and finally disaggregation of the spheroids. The results of this study, together with the data previously obtained in monolayer cell cultures, indicate that the effects of 1,25‐(OH)2D3 may be conditioned by the cellular environment. Therefore, the spheroid model is an interesting tool for investigation of the anti‐neoplastic effect of the hormone. © 1995 Wiley‐Liss, Inc.
Comparison of solutol HS 15, cremophor EL and novel ethoxylated fatty acid surfactants as multidrug resistance modification agents
Authors: Buckingham Lela E. , Balasubramanian M. , Emanuele R. Martin , Clodfelter Kathleen E. , Coon John S.
Published: February 2007

Some well‐known fatty acid ester surfactants, e.g., Cremophor EL and Solutol HS 15, are modulators of multidrug resistance in vitro and in vivo. Because they are pelydisperse, and their active component(s) have not been identified, the therapeutic potential of such surfactants is unclear. To better define the active components of Solutol HS 15 and to make more potent surfactant multidrug resistance modulators, highly purified C‐18 fatty acids were esterified with ethylene oxide at 5–200 molar ratios. Unexpectedly, ethylene oxide esters of pure 12‐hydroxy stearic acid, the major components of Solutol HS 15, displayed negligible resistance modification activity compared with Solutol HS 15 itself or to stearic and oleic acid esters synthesized under identical conditions. Since oleic acid esters appeared to have good activity, a series of these compounds was prepared to determine the optimal ethylene oxide J. fatty acid ratio. The optimal ratio was found to be 20 mole ethylene oxide: I mole fatty acid, with a steep decline in activity for products made with ratios above and below the optimum. The most active oleic acid ester, designated CRL 1337, was 8.4‐fold as potent as Solutol HS 15 and over 19‐fold as potent as Cremophor EL in promoting rhodamine 123 accumulation in multidrug‐resistant KB 8–5–11 cells in vitro. Our results show that the structure of the hydrophobic domain (fatty acid) of surfactants as well as its hydrophile‐lipophile balance are critical in determining the potency of surfactants as reversing agents. © 1995 Wiley‐Liss, Inc.
RB and A novel E2F‐1 binding protein in MHC class II deficient B‐cell lines and normal IFN‐γ induction of the class II transactivator ciita in class II non‐inducible RB‐defective tumor lines
Authors: Tschickardt Michael E. , Lu Yanmei , Jacim Mark , de Wayne Ussery G. , Steimle Viktor , Mach Bernard , Blanck George
Published: February 2007

The major histocompatibility (MHC) class II genes encode cell surface proteins that bind antigenic peptide for presentation to T‐cells. The class II proteins are expressed constitutively on B‐cells and EBV‐transformed B‐cells, and are inducible by IFN‐γ on a wide variety of cell types. Retinoblastoma protein (RB) is a tumor suppressor and functions as a transcriptional represser by binding and inactivating the transactivator E2F‐1. RB‐ defective tumor lines are non‐inducible for MHC class II by IFN‐γ, or very weakly inducible, but transfection of 2 different lines with RB expression vectors re‐establishes or substantially enhances class II inducibility. Therefore, we examined the RB status of a series of B‐cell mutants that are defective in class II expression, generated either in vitro or derived from Bare Lymphocyte Syndrome (BLS) patients. Nuclear matrix‐bound RB was detectable in all cases, indicating that loss of RB is not responsible for decreased class II expression in these lines. A second E2F‐1 binding protein, most likely DP‐1, was also apparantly normal in both class II‐positive and ‐negative B‐cell lines. We also examined the IFN‐γ induction of CIITA in RB‐defective lines. CIITA is a class II gene transactivator known to be defective in one form of BLS and to be required for the induction of MHC class II by IFN‐γ. CIITA mRNA is normally inducible by IFN‐γ in class II non‐inducible, RB‐defective lines, and in one line, re‐expression of RB has no effect on CIITA mRNA induction levels. Thus, the block in MHC class II inducibility in RB‐defective cells is not due to a block in CIITA inducibility. © 1995 Wiley‐Liss, Inc.
Risk of lung cancer in pre‐ and post‐menopausal women with ano‐genital malignancies
Authors: Frisch Morten , Melbye Mads
Published: February 2007

Women diagnosed during the period 1943–1990 and reported to the Danish Cancer Registry with invasive squamous‐cell carcinomas of the uterine cervix, vulva, vagina or anus, together with those having pre‐cancerous lesions (CIN III or carcinoma in situ) of the uterine cervix diagnosed in the period 1958–1990, were followed for the occurrence of subsequent lung cancer over 762,000 person‐years. Overall, these patients developed 2 to 2° times more lung cancers than women in the general Danish population. Women in whom cervical cancer was diagnosed recently, and before the age of 45 years, had a 4.6 times elevated risk of developing lung cancer, while young women with vulvar or vaginal cancer were at a 4.0‐fold elevated risk. Similarly, women in whom anal cancer was diagnosed before the age of 60 years were at a 3.5‐fold increased risk of developing lung cancer. The present study supports the hypothesis that smoking is involved in the aetiology of ano‐genital malignancies. The particularly high risk of developing subsequent lung cancers seen in women who were pre‐menopausal (<45 years) at the time of the ano‐genital cancer diagnosis suggests that the effect of smoking in ano‐genital carcinogenesis might be partly mediated through alterations in oestrogen metabolism. Alternatively, patients who developed their initial ano‐genital cancer at a young age might harbour some genetic susceptibility which could explain their excess lung‐cancer risk. © 1995 Wiley‐Liss, Inc.
Non‐Hodgkin's lymphoma and skin malignancies‐shared etiology?
Authors: Hall Per , Rosendahl Ingvar , Mattsson Anders , Einhorn Stefan
Published: February 2007

The Stockholm‐Gotland Cancer Register was used to evaluate the clinical observation that patients with non‐Hodgkin's lymphoma (NHL) had an increased risk of malignant melanoma or squamous‐cell carcinoma of the skin (SCCS) and vice verso. During 1958–1992, NHL was diagnosed in a total of 6,176 patients. Of these patients, 504 developed a second primary cancer of any type except NHL, compared to 301.9 expected, giving a standardized incidence ratio (SIR) of 1.7 [95% confidence interval (Cl) 1.5–1.8]. The risk of SCCS and malignant melanoma in patients with NHL was 4.8 (95% Cl 3.6–6.2; n = 54) and 1.7 (95% Cl 0.8–3.1; n = 10), respectively. The hazard risk for a second malignancy was relatively constant over time, whereas the skin malignancies revealed the highest risks 3–10 years after initial diagnosis. Similarly, the risk of a secondary NHL was studied in patients with malignant melanoma and SCCS during the same period and found to be 1.3 (95% Cl 0.8‐2.1; n = 17) and 1.8 (95% Cl 1.2–2.5; n = 34), respectively. The highest risk for NHL following malignant melanoma was seen 3–10 years after first diagnosis, while the highest risk following SCCS was observed 0‐2 years after initial diagnosis. One of several possible explanations for the development of NHL and a skin malignancy in the same patient is an immunological defect caused by sun exposure. © 1995 Wiley‐Liss, Inc.
Methyl‐p‐Hydroxyphenyllactate‐esterase activity and type‐II estrogen‐binding sites in ovarian cancer: Correlation with biological and clinico‐pathological parameters
Authors: Ranelletti Franco O. , Scambia Giovanni , Panici Pierluigi Benedetti , Piantelu Mauro , Ferrandina Gabriella , D'agostino Giuseppe , De Vincenzo Rosa , Rinelli Alessandro , Isola Giulio , Mancuso Salvatore
Published: February 2007

We examined the levels of activity of methyl‐p‐hydroxyphenyl‐lactate esterase (MeHPLA‐ase) and cytosolic Type‐II‐estrogen‐binding sites (Type‐II EBS) in 61 and 71 cases, respectively, of primary ovarian cancer. MeHPLA‐ase activity and Type‐II EBS were seen to by asymmetrically distributed, in that levels were skewed towards the lower values. A statistically significant direct correlation was found between MeHPLA‐ase activity and Type‐II EBS. MeHPLA‐ase activity and Type‐II EBS were inversely correlated with ER and PR levels and showed a trend towards inverse correlation with the percentage of cells in S‐phase of the cell cycle. MeHPLA‐ase activity and Type‐II EBS did not correlate with clinico‐pathological parameters. The median MeHPLA‐ase activity tended to be higher in responders than in unresponsive patients, but statistical significance was not reached. Higher Type‐II‐EBS levels were found in cases showing complete and partial response to chemotherapy than in cases which did not respond. A statistically significant relationship was found between high MeHPLA‐ase activity and longer overall survival. © 1995 Wiley‐Liss, Inc.