bluuebunny/crossref_metadata_2025 huggingface dataset:
Rejection of mouse melanoma elicited by local secretion of interleukin‐2: Implicating macrophages without T cells or natural killer cells in tumor rejection
Authors: Hara Isao , Nguyen Hai , Takechi Yoshizumi , Gansbacher Bernd , Chapman Paul B. , Houghton Alan N.
Published: February 2007

Tumor cells transduced with cytokine genes provide a model to study host‐effector mechanisms involved in tumor rejection. Local IL‐2 production within a tumor site mimics a specific helper‐T‐cell response, bypassing an immunization phase. Growth of mouse B16F10 melanomas transduced with interleukin‐2 (IL‐2) in syngeneic hosts were significantly delayed. IL‐2‐producing B16F10 cells were super‐transduced with inter‐feron‐γ to up‐regulate expression of major‐histocompatibility‐complex (MHC) antigens. Expression of class‐1‐ or class‐11‐MHC molecules did not augment tumor rejection of IL‐2‐secreting tumor cells. Rejection of IL‐2‐transduced B16F10 cells in syngeneic mice was unaffected by depletion of CD8+ T‐cell and NK1.1+ natural‐killer (NK) cell populations. Tumor rejection occurred in SCID mice even after depletion of NK1.1+ cells, confirming that T cells and NK cells were not required for tumor rejection. Histologic examination of sites of tumor rejection showed inflammation, characterized by infiltrates of macrophages, occasional neutrophils, and areas of necrosis. When mice were treated systemically with macrophage‐colony‐stimulating factor to expand monocyte pools, tumor rejection was significantly augmented further. This study shows that in situ IL‐2 production can result in tumor rejection mediated by inflammatory events, possibly involving macrophages, and mimicking a delayed‐type hypersensitivity (DTH) response even in the absence of T cells and NK cells. Furthermore, tumor rejection can be enhanced by systemic administration of a cytokine to expand potential inflammatory cell populations. © 1995 Wiley‐Liss, Inc.
Differential regulation of glycosphingolipid biosynthesis in phenotypically distinct Burkitt's lymphoma cell lines
Authors: Taga Samir , Mangeney Marianne , Tursz Thomas , Wiels Joëlle
Published: February 2007

Earlier studies have shown that Burkitt's lymphoma (BL) cell lines can be divided into 2 major groups: group I, which retain the original BL biopsy phenotype with expression of CD 10 and CD77 antigens and lack of B‐cell activation markers, and group III, which, after several in vitro passages, progress toward an “LCL‐like” phenotype with loss of CD 10 and CD77 expression and up‐regulation of B‐cell activation antigens. In previous studies we have shown that several glycolipid molecules constitute stage‐specific antigens for B cells and that sequential shifts in the 3 major glycolipid series are observed during B‐cell differentiation, these changes being mostly due to sequential activations of the corresponding glycosyltransferases. In the present work, 10 BL cell lines with group I or group III phenotype have been examined for cell surface expression of 5 glycolipid antigens (LacCer, GM3, Gb3/CD77, Gb4 and GM2), total glycolipid content and enzymatic activities of 4 glycosyl‐transferases (GM3, Gb3, Gb4 and GM2 synthetases). We now report that group I and group III BL cells differ in their glycolipid metabolism and express either mostly globoseries or ganglio‐series compounds. Indeed, Gb3 is the major glycolipid of group I cells, whereas GM3 and GM2 are the 2 major components of group III cells, and these phenotypic differences are mainly due to differential activities of the corresponding glycosyltransfer‐ases: group I cells have high Gb3 synthetase activities and low or no GM3 and GM2 synthetase activities, whereas group III cells have high GM3 and GM2 synthetase activities and low Gb3 synthetase activities. Finally, we also show that, unlike LCL, group III BL cells do not synthesize Gb4. © 1995 Wiley‐Liss, Inc.
Establishment of human acute myelogenous leukemia lines secreting interleukin‐1β in SCID mice
Authors: Giavazzi Raffaella , Berardino Cristina Di , Garofalo Angela , Motta Teresio , Gobbi Alberto , Scanziani Eugenio , Giudici Giovanni , Galli Monica , Mayo Joseph G. , Barbui Tiziano , Biondi Andrea , Rambaldi Alessandro
Published: February 2007

A reproducible in vivo model of human acute myelogeneous leukemia (AML) was established in severe combined immunodeficient (SCID) mice. The AML‐CL and AML‐PS lines were originated from leukemic blasts purified respectively from the peripheral blood of a 27‐year‐old woman with previously untreated hyperleukocytotic AML and from the bone marrow of a 61‐year‐old man during the third leukemic relapse. The 2 lines were maintained and serially transplanted i.p. in SCID mice. AML‐PS and AML‐CL produced ascitogenous gross tumors after approximately 4 and 6 weeks, respectively, and all mice died within 6‐8 weeks. Microscopic evaluation of different organs at autopsy showed massive involvement of bone marrow, liver and spleen, though with differences in the tumor burdens for the 2 lines (AML‐CL > AML‐PS). Flow cytometric analysis documented the spread of leukemic cells to bone marrow, peripheral blood and spleen. AML‐PS and AML‐CL cells show an immunophenotypic profile (CDI3+, CD33+) and cytogenetic findings similar to freshly isolated blasts. Interleukin‐1β (1L‐1β) gene expression was observed by Northern blot analysis in leukemic cells from AML‐CL and AML‐PS SCID mice. After 24 hr of culture both lines released IL‐1β in culture supernatants. High levels of circulating IL‐1β were secreted in plasma of tumor‐bearing mice. This AML‐SCID murine model could contribute to an understanding of the mechanisms of AML growth in vivo and the possible role of the autocrine production of IL‐1β in promoting cell growth. © 1995 Wiley‐Liss, Inc.
Cancer survival in Khon Kaen province, Thailand
Authors: Sriamporn Supannee , Black Roger J. , Sankaranarayanan Rengaswamy , Kamsa‐ad Supot , Parkin D. Maxwell , Vatanasapt Vanchai
Published: February 2007

Thailand is one of the few developing countries for which population‐based cancer survival data are available. Using clinical follow‐up information and reply‐paid postal enquiries, 10,333 residents of Khon Kaen province registered with cancer in the period 1985–1992 were followed‐up to the end of 1993. The sites of the most common cancers in the province were liver (5‐year relative survival rate 9.2%), cervix (60.1%), lung (15.4%), breast (48.1%) and large bowel (41.9%). Results for Khon Kaen were compared with age‐standardized survival data for the US and Scotland. Survival was consistently higher for US whites compared to Khon Kaen residents for those cancers whose prognosis is associated with early diagnosis (breast, cervix and large bowel) or the availability of intensive therapy (leukaemia and lymphoma). The main implication of these results for cancer control in Thailand is that the interventions of greatest potential benefit are those designed to promote early detection. More than one‐third of all cancers in Thailand are liver tumours: primary prevention through control of hepatitis‐B infection and liver fluke infestation is the only effective strategy for their control. © 1995 Wiley‐Liss, Inc.
Changes in biological markers after primary chemotherapy for breast cancers
Authors: Daidone Maria Grazia , Silvestrini Rosella , Luisi Antonella , Mastore Marinella , Benini Elvira , Veneroni Silvia , Brambilla Cristina , Ferrari Laura , Greco Marco , Andreola Salvatore , Veronesi Umberto
Published: February 2007

The profiles of functional (proliferative rate and cell distribution in the cell cycle) and phenotypic (nuclear DNA content and hormone receptor status) biological markers and the expression of P53 and Bcl‐2 proteins were prospectively evaluated in breast cancers before and after different regimens of primary chemotherapy. Overall, changes induced on the 2 proliferation indices (3H‐thymidine labelling index, 3H‐dT LI, and flow‐cytometric S‐phase fraction, FCM‐S) mainly consisted of a decrease for rapidly proliferating tumours and an increase or no change for slowly proliferating tumours. However, when considered as a function of treatment type, changes of 3H‐dT LI and FCM‐S were superimposable in rapidly proliferating tumours, regardless of the type of treatment, and in slowly proliferating tumours only after anthracycline‐including regimens. Conversely, following CMF, FCM‐S was increased in 90% of the cases and 3H‐dT LI in only 50%. Our data imply that the 2 proliferation indices could reflect different phenomena: an actual variation of proliferative activity by 3H‐dT LI and an accumulation of cells in the S‐phase by FCM‐S. In addition, a higher accumulation of cells in G2‐M phases could be detected by FCM after anthracycline‐including regimens than after CMF. The fraction of P53‐positive cells was reduced by primary chemotherapy in about 50% of P53‐positive tumours, whereas Bcl‐2 expression was only marginally affected. DNA ploidy and hormone receptor status did not change in about 75% of cases, regardless of the chemotherapeutic regimen. © 1995 Wiley‐Liss, Inc.
Mutations clustered in exon 5 of the p53 gene in primary nasopharyngeal carcinomas from Southeastern Asia
Authors: Chakrani Fatima , Armand Jean‐Pierre , Lenoir Gilbert , Ju Li‐Ya , Liang Jian‐Ping , May Evelyne , May Pierre
Published: February 2007

Mutations in the p53 tumor suppressor gene play an important role in the development of many common human malignancies. In nasopharyngeal carcinomas (NPC), p53 gene mutations were not detected in primary tumors, with one exception for a primary tumor displaying a p53 mutation at codon 280, whereas p53 mutations were identified in some metastatic and nude mouse‐passaged NPC specimens. In the present report, 41 NPC primary tumors of the undifferentiated carcinoma nasopharyngeal type (UCNT; 21 from Hong Kong and 20 from Guangxi, southeastern China) were studied. Four point mutations that result in amino acid substitutions were identified by PCR amplification of exons 2–9 and direct DNA sequencing, combined with PCR‐singfe‐strand conformation polymorphism analysis. The 4 mutations detected were clustered within the DNA stretch from codon 175 to 177. Our data, taken together with those of others, suggest that mutation in p53 may occur in NPC at various points during tumorigenesis. Alternative mechanisms of p53 inactivation in NPC are also possible. © 1995 Wiley‐Liss, Inc.
HPV infection in cervical‐cancer cases in Russia
Authors: Samoylova Ella V. , Shaikhaiev Gadji O. , Petrov Semjon V. , Kisseljova Natalia P. , Kisseljov Fjodor L.
Published: February 2007

The presence of human papillomavirus (HPV) sequences in 21 biopsies from cervical carcinomas, II specimens of tissues adjacent to tumours, 2 specimens of cervical tissues with radiation fibrosis from patients after radiation therapy of cervical cancer and 7 normal epithelial tissues from the patients with other genital tumours were examined by polymerase chain reaction (PCR) and Southern‐blot analysis. All tumours were HPV‐positive by type‐specific PCR and 86% by Southern‐blot analysis. In normal epithelial and adjacent tissues, HPV sequences were detected in 20% of samples by Southern‐blot analysis and in 70% of samples by PCR, including 2 cases of tissues after radiation therapy. HPV 16 was the most prevalent type in tumours (18/21) as well as in normal epithelial tissues (5/7). One HPV‐positive tumour contained HPV18 DNA and 2 were doubly infected with HPVs 16 and 18 (2/21). The persistence of exclusively episomal HPV16 DNA was observed in 5 out of 11 tumours examined: 3 cases of squamous‐cell carcinomas on the early stage of tumour progression and 2 advanced tumours (squamous‐cell carcinoma and adenocarcinoma). The integration of HPV16 genome was detected in 6 out of 11 tumours, but most of them contained episomal forms of viral DNA simultaneously (5 out of 6). The integrative HPV18 genome was found in 2 tumours examined, and the persistence of episomal forms was also observed in one of them. Our data demonstrate that cervical tumours are associated invariably with high‐risk types of HPV in Russia. © 1995 Wiley‐Liss, Inc.
Effects of interferon‐α on human b cells: Repression of apoptosis and prevention of cell growth are independent responses of burkitt lymphoma lines
Authors: Milner Anne E. , Grand Roger J. A. , Gregory Christopher D.
Published: February 2007

We have previously shown that interferon‐α (IFN‐α) can repress apoptosis in Burkitt lymphoma (BL) cells. In this study, we have compared this protective response with a further, well‐established effect of IFN‐α on BL cells, that of growth arrest. Of a panel of BL lines comprising (i) EBV‐positive and ‐negative lines that retain the phenotype of the parental tumour cells and (ii) the prototype IFN‐α‐growth‐inhibited line, Daudi, only Daudi cells were found to undergo substantial growth inhibition in response to the cytokine. By contrast, all lines, with the notable exception of Daudi, were protected by IFN‐α from high‐rate apoptosis initiated by the Ca2+ ionophore ionomycin. lonomycin failed to elicit an IFN‐α‐repressible apoptotic response in either wild‐type Daudi cells or IFN‐resistant sublines that were refractory to the growth‐arresting effects of the cytokine. Analysis of c‐myc protein levels confirmed previous observations that repression of apoptosis in IFN‐α‐rescuable BL cells was associated with an early inhibition of myc that was followed by a return to high‐level expression. Significantly, ionomycin alone induced a comparable transient inhibition of myc protein in Daudi cells. In Daudi cells, but not in IFN‐α‐rescuable BL cells, renewed expression of myc observed after the early, transient down‐regulation was followed by sustained down‐regulation of the protein, which paralleled growth arrest. Our results indicate that long‐term growth arrest and repression of apoptosis in BL are distinct cellular responses to IFN‐α. © 1995 Wiley‐Liss, Inc.
Induction of CD44 expression by the epstein‐barr virus latent membrane protein LMP1 is associated with lymphoma dissemination
Authors: Walter Jürgen , Schirrmacher Volker , Mosier Donald
Published: February 2007

Epstein‐Barr Virus (EBV) is implicated in the pathogenesis of endemic Burkitt's lymphoma (BL), B‐cell lymphomas occuring under immunosuppression, nasopharyngeal carcinoma and Hodgkin's disease. Two distinct patterns of latent EBV gene expression occur in EBV‐associated lymphomas. BLs typically display expression of the nuclear antigen EBNAI only, whereas EBV‐associated, non‐Burkitt B‐cell lymphomas express at least 9 latent viral genes (6 EBNAs and 3 latent membrane proteins), reminiscent of in vitro EBV‐immortalized lymphoblastoid cell lines (LCL). BLs are characterized by local, extra‐nodal growth, whereas EBV‐associated B‐cell lymphomas often disseminate to peripheral lymphoid tissue. We show here that BL cells forming local tumors after xenotransplantation into SCID mice disseminate to lymphoid tissue following introduction of the latent membrane protein 1 (LMP1) gene. Introduction of LMP1 into BL cells induced expression of CD44 on the cell surface, a molecule implicated in enhanced lymphoid tumor growth and dissemination. Introduction of CD44 into LMP1‐/CD44‐BL cells was observed to confer the disseminated tumor growth pattern associated with LMP1 expression. Taken together our results show that expression of LMP1 may regulate expression of CD44 and play an important role in the behavior of EBV‐based lymphomas. © 1995 Wiley‐Liss, Inc.
Induction and characterization of cytotoxic T‐lymphocytes recognizing a mutated p21ras peptide presented by HLA‐A*0201
Authors: Van Elsas Andrea , Nijman Hans W. , Van Der Minne Caroline E. , Mourer Jacqueline S. , Kast W. Martin , Melief Cornelis J. M. , Schrier Peter I.
Published: February 2007

The ras oncogene is frequently found to be activated in human cancer through point mutations at codons 12, 13 or 61. We explored whether these altered p21 ras protein sequences contain peptide sequences that can activate naive CD8+ cytotoxic T lymphocytes (CTL). Several wild‐type and mutated p21 ras peptides were identified that carry a binding motif for human leukocyte antigen (HLA)‐A*0201. Two peptides were found to bind strongly to this allele. CD8* CTL bulk cultures specifically reacting with one of these peptides could be induced, using processing‐defective T2 cells loaded with peptide CLLDILDTAGL as stimulators. The peptide is derived from p21ras, position 51–61, and carries a 61 Gln → Leu mutation. In contrast, a 9‐mer peptide CLLDILDTA corresponding to amino acid sequence 51–59 of wild‐type p21ras did not yield reactive CTL cultures. T‐cell clones with low affinity for the 11‐mer peptide were isolated from CLLDILDTAGL‐reactive bulk cultures. These T cells did not lyse melanoma cells transfected with 61‐Leu N‐ras, although lysis was found when these transfectants were pulsed with the 11‐mer peptide. Possibly, T cells of higher affinity may be required to demonstrate processed peptide on the cell surface. The combined experiments suggest that a peptide derived from mutated p21ras can be recognized by HLA class 1‐restricted CTL, whereas an analogous wild‐type p21ras peptide may not be immunogenic. © 1995 Wiley‐Liss, Inc.
Interleukin‐3: A putative protective factor against breast cancer which is secreted by male but not female breast fibroblasts
Authors: Speirs Valerie , Birch Mark A. , Boyle‐Walsh Eilis , Green Andrew R. , Gallagher James A. , White Michael C.
Published: February 2007

The enzyme 17β‐hydroxysteroid dehydrogenase (17‐HSD) is a key regulator of intracellular 17β‐estradiol (E2), which is associated with breast cancer and is influenced by paracrine factors released by breast‐cancer fibroblasts. Since the incidence of breast cancer is much higher in females than in males, we have used an in vitro ceil culture system to investigate whether male fibroblasts may inhibit breast‐cancer genesis by restricting the intracellular accumulation of E2. Fibroblasts were obtained from normal males and females undergoing reduction mammoplasty, and from females with benign or malignant breast lesions. Fibroblast‐conditioned medium (CM) was incubated with the established breast‐cancer cell line, MCF‐7, and its effects on 17‐HSD activity were assessed. CM (25% v/v) from male breast fibroblasts had a significant inhibitory effect on reductive i 7‐HSD, decreasing E2 production. This was in direct contrast to the effects of CM from female breast fibroblasts, which had a powerful stimulatory effect on reductive 17‐HSD. RT‐PCR allowing simultaneous detection of a range of cytokines was performed on each type of fibroblast. IL‐3 mRNA was consistently detected in fibroblasts from male but not female breast tissue. Addition of rhIL‐3 to cultures of MCF‐7 caused a reduction in 17‐HSD activity and addition of a polyclonal antibody directed against IL‐3 to male CM completely reversed the inhibitory effects of CM. Thus, male breast fibroblasts may be responsible for secreting IL‐3‐like factors which, given the considerably lower incidence rates of breast cancer in men, may have a protective effect against breast cancer. © 1995 Wiley‐Less, Inc.
Increased LDL receptor mRNA expression in colon cancer is correlated with a rise in plasma cholesterol levels after curative surgery
Authors: Niendorf Axel , Nägele Herbert , Gerding Daisy , Meyer‐Pannwitt Udo , Gebhardt Angelika
Published: February 2007

It is currently under debate whether the low serum cholesterol levels that are frequently observed in cancer patients represent a risk factor for/or, rather, are a consequence of the tumour. We postulate that malignant tumours are directly involved in an increased catabolism of cholesterol‐rich low‐density lipoprotein (LDL) particles. In a prospective study of 25 patients with colorectal carcinoma, we measured intra‐individual shifts in serum cholesterol levels after surgery, and the expression of LDL‐receptor mRNA in surgically removed specimens. A significant rise in plasma cholesterol levels was observed in patients 3 and 12 months after curative surgery, but not after non‐curative surgery. In human colon carcinoma tissues LDL receptor mRNA expression, as determined by competitive reverse‐transcriptase‐polymerase‐chain reaction, was found to be significantly increased when compared to tissues from the tumour‐free margin (median values, 1.2 x 106 vs. 2.0 x 105 molecules/μg total cellular RNA, respectively, n = 17). The extent of LDL‐receptor mRNA expression positively correlated to the percentage rise of plasma cholesterol levels 3 months (n = 7, r = 0.8763) and 12 months (n = 6, r = 0.9181) after curative surgery. This finding provides in vivo evidence that the tumour tissue itself contributes to decreased plasma cholesterol levels in patients suffering from colorectal carcinomas. It supports the hypothesis that low cholesterol levels in cancer patients are a consequence, and not the cause, of the malignancy. © 1995 Wiley‐Loss, Inc.
CD69+ and HLA‐DR+ activation antigens on peripheral blood lymphocyte populations in metastatic breast and ovarian cancer patients: Correlations with survival following active specific immunotherapy
Authors: Yacyshyn Mary Beth Bowen , Poppema Sibrand , Berg Ann , Maclean Grant D. , Reddish Mark A. , Meikle Alison , Longenecker B. Michael
Published: February 2007

Lymphocyte activation markers CD69 and HLA‐DR were studied in metastatic breast and ovarian cancer patients who received active specific immunotherapy (ASI) using cancer vaccines containing the synthetic tumor‐associated antigen sialyl‐Tn or the Thomsen‐Friedenreich antigen conjugated to KLH plus DETOX adjuvant. Breast cancer patients who showed prolonged survival following ASI had lower numbers of total CD69+ and CD4+CD69+ cells prior to ASI compared to patients who died. However, following ASI, the surviving patients showed an increase in CD69+ and CD4+CD69+ cells and the deceased patients showed a decrease. A greater than 50% increase in the percentage of cells bearing the activation marker CD69 is associated with an increase in survival in both ovarian and breast cancer patients. In the surviving breast cancer patients there was a significant decrease in the percentage of non‐B lymphocyte HLA‐DR+ (CD20−HLA‐DR+) cells following cyclophosphamide treatment. A strong positive correlation was found between lymphocyte populations CD20− HLA‐DR+ and CD8+CD57+, a putative suppressor cell population. Breast cancer patients who showed a greater than median decrease in CD20−HLA‐DR+ lymphocytes following cyclophosphamide treatment had a survival advantage over patients who had less than the median decrease in the percent CD20−HLA‐DR+ lymphocytes. © 1995 Wiley‐Liss, Inc.
Average intake of anti‐oxidant (PRO)vitamins and subsequent cancer mortality in the 16 cohorts of the seven countries study
Authors: Ocké Marga C. , Kromhout Daan , Menotti Alessandro , Aravanis Christ , Blackburn Henry , Buzina Ratko , Fidanza Flaminio , Jansen Annemarie , Nedeukovic Srecko , Nissinen Aulikki , Pekkarinen Maija , Toshima Hironori
Published: February 2007

This ecologic study aimed to investigate whether differences in population mortality from lung, stomach and colorectal cancer among the 16 cohorts of the Seven Countries Study could be explained by differences in the average intake of anti‐oxidant (pro)vitamins. In the 1960s, detailed dietary information was collected in small sub‐samples of the cohorts by the dietary record method. In 1987, food‐equivalent composites representing the average food intake of each cohort at baseline were collected locally and analyzed in a central laboratory. The vital status of all participants was verified after 25 years of follow‐up. The average intake of vitamin C was strongly inversely related to the 25‐year stomach‐cancer mortality (r = –0.66, p = 0.01), also after adjustment for smoking and intake of salt or nitrate. The average intake of α‐carotene, β‐carotene, and α‐tocopherol were not independently related to mortality from lung, stomach or colorectal cancer, nor was vitamin C related to lung and colorectal cancer. © 1995 Wiley‐Liss, Inc.
IGF‐2 autocrine stimulation in tumorigenic clones of a human colon‐carcinoma cell line
Authors: Lamonerie Thomas , Lavialle Christian , Haddada Hedi , Brison Olivier
Published: February 2007

Clonal analysis has shown that the SW613‐S human colon‐carcinoma cell line is heterogeneous; some cell clones display a high level of amplification of the c‐myc gene and are tumorigenic in nude mice, whereas others have a small number of copies of this gene and are non‐tumorigenic. Tumorigenic clones can proliferate in a chemically defined serum‐free medium, whereas non‐tumorigenic clones cannot. Suramin, like anti‐insulin‐like growth factor (IGF) or anti‐IGF‐1 receptor antibodies, efficiently inhibits the growth of tumorigenic clones in defined medium. Inhibition by suramin or by anti‐IGF antibodies can be reversed by pure IGF‐1 or IGF‐2. Pure IGF‐1 or IGF‐2 or culture medium conditioned by tumorigenic clones can stimulate DNA synthesis in cells of non‐tumorigenic clones. Co‐culture with cells of tumorigenic clones sustains the growth of non‐tumorigenic clones in defined medium. Cells of both tumorigenic and non‐tumorigenic clones express high‐affinity IGF‐1 receptors at their surface but tumorigenic clones produce on average 5 times more IGF‐1 and 25 times more IGF‐2 than non‐tumorigenic ones. These results indicate that autocrine growth stimulation of tumorigenic clones by IGFs through the IGF‐I receptor is essential for their ability to grow in defined medium. Since cells of tumorigenic clones produce IGF‐2 at levels 80 times higher than IGF‐1 and since an antibody strictly specific for IGF‐1 has no effect on DNA synthesis in cells of tumorigenic clones grown in defined medium, IGF‐2 is very likely the main effector in the autocrine loop. © 1995 Wiley‐Liss, Inc.
Cancer incidence and mortality in young adults in vaud, Switzerland, 1974‐1992
Authors: Levi Fabio , La Vecchia Carlo , Randimbison Lalao , Te Van‐Cong
Published: February 2007

Trends in cancer incidence and mortality in young adults (aged 20 to 44 years) over the period 1974‐1992 were analyzed using data from the Vaud Cancer Registry, Switzerland. A total of 1,497 cancers were registered in males, after excluding non melanomatous skin cancers. The most common neoplasms were testis, lymphomas, lung, skin melanoma and oral cavity and pharynx. The overall age‐standardized (world population) incidence was 750 per million males, and increased from 676 in 1974‐1979 to 808 in 1986‐1992. These upward trends were due mainly to cancers of the oral cavity and pharynx, lung, skin melanoma and colorectum, while testicular cancer rates remained stable. For females, a total of 1,899 malignant neoplasms was notified, corresponding to an overall age‐standardized incidence of 914 per million. The overall rate increased from 818 in 1974‐1979 to 1,003 in 1986‐1992. The most frequent neoplasms were breast, skin melanoma, ovary, thyroid and lymphomas. The major types of cancer responsible for these upward trends were breast cancer, skin melanoma and lung cancer. In the period studied there were 458 cancer deaths in males and 408 in females, corresponding to an overall age‐standardized rate of 227 per million males and 193 per million females. Death rates in males tended to decline, to reach 194 per million in 1986‐1992, but no consistent trend was observed in females. The decline in males was essentially due to the fall in rates for testicular cancer and Hodgkin's disease. In females, falls in death rates were observed for cancer of the cervix uteri, ovary and Hodgkin's disease. Death rates were upwards for lung cancer in both sexes, and for skin melanoma and breast cancer in females. © 1995 Wiley‐Liss, Inc.
Up‐regulation of intercellular adhesion molecule 1 (ICAM‐1) on human renal cell carcinoma cells by interleukin‐4
Authors: Obiri Nicholas I. , Tandon Nandita , Puri Raj K.
Published: February 2007

We have previously demonstrated that human renal cell carcinoma (RCC) cells express high‐affinity IL‐4 receptors (IL‐4R). To study the functions of these receptors, we have examined the effect of IL‐4 on the expression of intercellular adhesion molecule‐1 (ICAM‐1 or CD54) on human RCC cells. Following incubation with various concentrations of IL‐4, RCC cells were examined for ICAM‐1 expression by flow cytometric analysis. The 2 primary RCC cell cultures and the 2 cell lines examined expressed varying basal levels of ICAM‐1 on the cell surface. IL‐4 treatment increased ICAM‐1 expression in a time‐dependent manner and maximum augmentation of ICAM‐1 expression was observed after a 48 hr incubation. The increase in ICAM‐1 expression was specific because anti‐hIL‐4 antibody blocked this effect. No enhancement of ICAM‐1 expression was observed when RCC cells were incubated with IL‐4 in the presence of cycloheximide, indicating that the IL‐4 effect requires new protein synthesis. Up‐regulation of ICAM‐1 expression was also observed at the mRNA level and maximum increase in message occurred 8 hr post‐IL‐4 treatment. Both IL‐4 and IFN‐γ also increased soluble ICAM‐1 levels in WS‐RCC culture supernatant. The significance of enhanced soluble and surface ICAM‐1 expression was investigated by examining the lymphokine activated killer (LAK) cell‐mediated lysis of IL‐4‐treated WS‐RCC cells. LAK cells lysed WS‐RCC cells very effectively, but lysis observed in target cells pre‐treated with IL‐4 did not correlate with the increased expression of ICAM‐1 antigen. Our results indicate a previously unknown function of IL‐4 on RCC and further demonstrate that IL‐4R on RCC are functional. © 1995 Wiley‐Liss, Inc.
Retinoic acid induced death of ovarian carcinoma cells correlates with c‐myc stimulation
Authors: Krupitza Georg , Hulla Wolfgang , Harant Hanna , Dittrich Evelyn , Kallay Enikö , Huber Heinz , Grunt Thomas , Dittrich Christian
Published: February 2007

In the ovarian adenocarcinoma subline N.1, all‐trans retinoic acid (ATRA) induced substantial cell death. This response was elicited only at decreased serum levels. Exposure of N.I cells to increasing concentrations of ATRA was accompanied by a considerable up‐regulation of c‐myc transcript levels that correlated with the rate of cell killing, which itself was an active process as judged by sustained transcriptional expression. ATRA‐triggered rounding and detaching of single cells from the substratum was accompanied by degradation of genomic DNA. We show that the N.I model cell line, which is otherwise highly ATRA‐resistant, can undergo an ATRA‐triggered suicide program when serum is limited. The accompanying c‐myc up‐regulation seems to be mediated by retinoic‐acid‐receptor‐independent pathways involving membrane‐associated phospholipases instead, because manoalide partly suppressed c‐myc induction by ATRA but left constitutive c‐myc expression unaffected. © 1995 Wiley‐Liss, Inc.
Effect of vesicle size and lipid composition on the in vivo tumor selectivity and toxicity of the non‐cross‐resistant anthracycline annamycin incorporated in liposomes
Authors: Zou Yiyu , Ling Yi‐He , Reddy Sara , Priebe Waldemar , Perez‐Soler Roman
Published: February 2007

Annamycin (Ann) is a non‐cross‐resistant lipophilic anthracy‐cline antibiotic optimally suited for liposome delivery. We studied how vesicle size and presence of phospholipids with a high phase transition temperature and monosialoganglioside (GM1) in the liposome bilayers affect the pharmacokinetics, tumor selectivity and toxicity of Ann. Entrapment of Ann in multilamellar vesicles (L‐Ann) resulted in a 20% lower heart AUC and a 30–40% higher tumor and liver AUC. Reduction of the liposome size from 1.6 to 0.03 μm increased Ann plasma circulation time and tumor AUC by 2‐fold, enhanced Ann tumor selectivity and decreased Ann subacute toxicity by 2‐fold. The presence of phospholipids with a high phase transition temperature and GM1 in the liposome bilayers further prolonged Ann plasma circulation time by 2‐ to 4‐fold, did not increase Ann tumor AUC and moderately increased Ann subacute toxicity. The anti‐tumor activity of Ann correlated with the tumor AUC achieved with each particular formulation. Our results strongly suggest that vesicle size may be an important determinant of the therapeutic index of liposomal Ann, but they fail to demonstrate a beneficial tumor‐targeting effect of liposomes composed of GM1 and phospholipids with a high phase transition temperature, as has been reported for the hydrophilic parent compound doxorubicin. © 1995 Wiley‐Liss, Inc.
Identification of a highly specific surface marker of T‐cell acute lymphoblastic leukemia and neuroblastoma as a new member of the transmembrane 4 superfamily
Authors: Takagi Shin , Fujikawa Kiyomi , Imai Toshio , Fukuhara Norio , Fukudome Kenji , Minegishi Masayoshi , Tsuchiya Shigeru , Konno Tasuke , Hinuma Yorio , Yoshie Osamu
Published: February 2007

Five monoclonal antibodies detected a surface antigen expressed exclusively on T‐cell acute lymphoblastic leukemia (T‐ALL) in a panel of 45 human hematopoietic cell lines, including T‐cell lines derived from adult T‐cell leukemia and those established by immortalization with human T‐cell leukemia virus type 1 or Herpesvirus saimiri. Peripheral blood mono‐nuclear cells, including fresh and activated T cells, were also completely devoid of this antigen. We designated this antigen as TALLA‐1 (from T‐ALL‐associated antigen 1). By expression cloning, a cDNA clone encoding TALLA‐1 was isolated from T‐ALL cell line Molt‐4. TALLA‐1 was found to be a member of the transmembrane 4 superfamily (TM4SF). The cDNA was also essentially identical to A15, which was isolated from another T‐ALL cell line, HPB‐ALL, by differential hybridization with normal peripheral blood lymphocytes, and to CCG‐B7, which was isolated from a brain cDNA library using CCG repeat as a probe. The gene product was now characterized in detail at the protein level. Northern blot analysis showed that the gene was expressed most strongly in brain, skeletal muscle and spleen. In a panel of 52 non‐hematopoietic human cell lines, the majority of neuroblastoma cell lines were found to be positive for TALLA‐1. Like ME491, CO‐029 and L6, TALLA‐1 may be another TM4SF member behaving as a potential tumor‐associated antigen. © 1995 Wiley‐Liss, Inc.
Liposomal doxorubicin‐induced toxicity: Depletion and impairment of phagocytic activity of liver macrophages
Authors: Daemen Toos , Hofstede Gert , Ten Kate Marian T. , Bakker‐Woudenberg Irma A. J. M. , Scherphof Gerrit L.
Published: February 2007

Doxorubicin entrapped within conventional liposomes (200 nm in diameter; lip‐Dox) has major toxic effects on liver macrophages of the rat for a considerable period of time following i.v. administration, with respect to both specific phagocytic capacity and cell numbers. At different time‐points after injection of lip‐Dox or free doxorubicin, radiolabeled, negatively charged, “empty” test liposomes were injected. Phagocytic capacity was determined by isolating the liver macrophages and measuring the amount of macrophage‐associated radioactivity. Four subfractions of liver macrophages of different cell‐size and with intrinsically different phagocytic capacity were isolated. Twenty‐four hours after injection of lip‐Dox, the phagocytic capacity of the larger‐sized liver macrophages was strongly decreased. The relatively low intrinsic phagocytic capacity of the smaller‐sized macrophages was only slightly impaired. Phagocytic capacity after injection of lip‐Dox was nearly restored to control values after 14 days. Blood clearance of Klebsiella pneumoniae bacteria after pre‐treatment with lip‐Dox was strongly decreased. Pre‐treatment with the free drug and/or placebo liposomes had no effect on phagocytic and bacterial blood‐clearance capacity. A major depletion of the liver macrophage population was observed, as revealed by both macrophage isolation and histology. Only 2 weeks after injection of lip‐Dox, the number of cells had returned to that seen in control animals. In view of the important host‐defense functions of the liver macrophages, especially in the control of tumor growth and infection, the findings reported here should be taken into consideration when lip‐Dox is to be administered in anti‐tumor therapy. © 1995 Wiley‐Liss, Inc.
Sensitization to cisplatin action by step‐down heating in cddp‐sensitive and ‐resistant cells
Authors: Hettinga Judith V. E. , Lemstra Willy , De Vries Elisabeth G. E. , Konings Antonius W. T. , Kampinga Harm H.
Published: February 2007

Hyperthermia treatment (≥ 43°C) has been shown to be able to (partially) reverse acquired cDDP resistance. However, such heat treatment is difficult to achieve in the clinic. Short pre‐treatment at a high temperature (>42°C), immediately before a treatment at a lower temperature (<42°C) can enhance the heat toxicity of the lower temperatures. This “step‐down heating schedule” was explored for its possible drug‐sensitizing potential in in vitro‐cultured cDDP‐sensitive and ‐resistant murine and human tumour cells. A 10‐min pre‐treatment at 44°C enhanced the cytotoxicity of 41°C hyperthermia alone. It also enhanced sensitivity to cDDP when given at 37°C. However, it did not increase the 41°C‐induced cDDP sensitization. Thus, no correlation was found between heat kill and cDDP sensitization for step‐down heating schedules. The observed effects of step‐down heating were comparable in sensitive and in resistant cells, so the step‐down heating schedule, unlike the 43°C treatment, did not lead to a decrease of the cDDP‐resistance factor. Yet the total cytotoxicity caused by this treatment protocol was 10‐fold more than for cDDP with 41°C alone, due to the extra hyperthermic cell killing and the cDDP‐sensitizing effect of the pre‐treatment. This treatment could have a substantial impact on cDDP efficacy in the clinic even when cDDP resistance has developed. © 1995 Wiley‐Liss, Inc.
Isolation of antigenic mimics of MDR1‐P‐glycoprotein by phage‐displayed peptide libraries
Authors: Poloni Francesca , Romagnoli Giulia , Cianfriglia Maurizio , Felici Franco
Published: February 2007

To identify an MC57 epitope which is more efficiently expressed on inactivated forms of P‐glycoprotein we utilized peptide libraries displayed on filamentous phage. Using this technology, we selected specific phage clones blocking the binding of the murine monoclonal (MAb) MC57 with live human multi‐drug‐resistant (MDR) cells, and sequenced and analyzed their DNA. The results we obtained indicate that MAb MC57 epitope could be formed by 2 regions localized on the predicted fourth and sixth extracellular loops of the current 12‐transmembrane‐domain model predicted for MDR1‐P‐glycoprotein. Surprisingly, a third region, defined by residues 800–807 of the MDR1‐P‐glycoprotein sequence and postulated to be intracellular, was also identified as a putative part of the MC57 epitope. This finding adds weight to the interesting hypothesis that a P‐glycoprotein structure different from the current model may exist. © 1995 Wiley‐Liss, Inc.
Influence of an anti‐angiogenic treatment on 9L gliosarcoma: Oxygenation and response to cytotoxic therapy
Authors: Teicher Beverly A. , Holden Sylvia A. , Ara Gulshan , Dupuis Norman P. , Liu Fang , Yuan Jia , Ikebe Masahiko , Kakeji Yoshihiro
Published: February 2007

Tissue oxygen tensions were measured in subcutaneously growing rat 9L gliosarcoma under normal air and carbogen breathing conditions prior to and after i.v. administration of a perflubron emulsion. When these animals were treated with the anti‐angiogenic agents TNP‐470 and minocycline for 5 days prior to oxygen measurement, tumor hypoxia was decreased compared with untreated tumors. Hypoxia, defined as the percent of pO2 readings ≤5 mm Hg, was decreased from 71% in untreated air‐breathing controls to 34% in animals treated with the anti‐angiogenic agents, the perflubron emulsion and carbogen breathing. These effects were manifest in the increased response of the tumor to single‐dose (10, 20 and 30 Gy) radiation therapy. Twenty‐four hours after treatment with BCNU oxygenation of the tumors was not altered; however, 24 hr after administration of adriamycin oxygenation of the tumors was increased such that hypoxia in adriamycin‐treated tumors in animals receiving the perflubron emulsion and carbogen was reduced to 21%. Tumor growth delay in the s.c. tumors was increased by the addition of treatment with the anti‐angiogenic agents from day 4 through day 18 post‐tumor cell implantation along with BCNU or adriamycin on days 7–11. Administration of the perflubron emulsion and carbogen breathing resulted in increased tumor growth delay with the chemotherapeutic agents alone and in combination with the anti‐angiogenic agents. Life span in animals bearing intracranially implanted 9L gliosarcoma progressively increased with administration of the anti‐angiogenic agents and then the anti‐angiogenic agents and perflubron emulsion/carbogen compared to treatment with BCNU or adriamycin. © 1995 Wiley‐Liss, Inc.
Evidence of a chromatin basis for increased mutagen sensitivity associated with multiple primary malignancies of the head and neck
Authors: Pandita Tej K. , Hittelman Walter N.
Published: February 2007

Individuals at increased risk for cancer development have been reported to exhibit increased mutagen sensitivity as detected by the G2 phase chromosome breakage assay. To better understand the basis for such chromosome sensitivity, we examined 4 lymphoblastoid cell lines derived from 4 head and neck cancer patients, 2 of whom were previously shown to have normal bleomycin sensitivity and 2 high bleomycin sensitivity (and multiple primary tumors). These cell lines were studied for cell survival and initial damage and repair at both the DNA and chromosome levels, and the results compared to a normal control cell line and 3 ataxia telangiectasia homozygote cell lines. While all cell lines exhibited nearly equal levels of initial DNA damage and repair throughout the cell cycle, both the ataxia telangiectasia homozygote cell lines and 2 cell lines derived from individuals with multiple head and neck primary tumors showed increased levels of initial chromosome damage (detected by premature chromosome condensation), a reduced fast repair component and higher residual chromosome damage. Our results suggest that one component of the enhanced mutagen sensitivity phenotype observed in cancer‐prone individuals may involve an inherent chromatin alteration that allows a more efficient translation of DNA damage into chromosome damage following mutagen exposure. The degree of such an alteration might then be associated with an increased risk for second primary tumors in other carcinogen‐exposed sites. © 1995 Wiley‐Liss, Inc.
Substance‐P receptors in human primary neoplasms: Tumoral and vascular localization
Authors: Hennig Ivo M. , Laissue Jean A. , Horisberger Ulla , Reubi Jean‐Claude
Published: February 2007

Primary human neoplasms were examined for the presence of substance‐P receptors by receptor autoradiography with 125I‐labelled Bolton‐Hunter substance P. Substance‐P receptors were localized and characterized in the neoplastic cells of 9/12 astrocytomas, 10/10 glioblastomas, 10/12 medullary thyroid carcinomas, 8/16 breast carcinomas and 4/5 ganglioneuroblastomas. Conversely, substance‐P receptors were not or only rarely identified on non‐small‐cell carcinomas of the lung (1/16), neuroblastomas (0/8), adenocarcinomas of the colon (1/21) or the pancreas (1/9), or on malignant lymphomas (3/18). However, in the great majority of the investigated tumours, substance‐P receptors were found on intra‐ and peritumoral blood vessels. All substance‐P receptors detected had the pharmacological characteristics of the neurokinin‐I receptor sub‐type. In addition, the expression of somatostatin receptors was examined in all the neoplastic tissues mentioned above. Both substance‐P and somatostatin receptors were present in astrocytomas and in ganglioneuroblastomas, whereas little or no receptor was found in pancreatic and non‐small‐cell lung carcinomas. The extent of somatostatin‐receptor expression was inversely correlated to that of the substance‐P receptors in glioblastomas, neuroblastomas and non‐Hodgkin's lymphomas. The tumoral and vascular localization of substance‐P receptors in tumours may have clinical implications. The use of radiolabelled substance P for in vivo scintigraphy may supplement the current set of diagnostic tools. Substance‐P antagonists might be used in the treatment of tumours, as their binding to vascular receptors may decrease tumoral blood supply and drainage. © 1995 Wiley‐Liss, Inc.
Inhibition of 3′‐methyl‐4‐dimethylaminoazobenzene‐induced hepatocarcinogenesis in rat by dietary β‐carotene: Changes in hepatic anti‐oxidant defense enzyme levels
Authors: Sarkar Alok , Mukherjee Biswajit , Chatterjee Malay
Published: February 2007

The dietary administration of β‐carotene (BC) daily has been found to be highly effective in reducing hepatocarcinogenesis in male Sprague‐Dawley rats fed 3′‐methyl‐4‐dimethylaminoazo‐benzene (3′‐Met‐DAB). The anti‐cancer efficacy of BC was evaluated by estimating some possible pre‐neoplastic and neo‐plastic hepatic anti‐oxidant markers such as glutathione (GSH) and related enzymes, namely glutathione S‐transferases (GSHT, with varying substrate specificities), γ‐glutamyl transpeptidase (GGT), glutathione peroxidase (GPX) and reductase. BC proved to be an effective anti‐neoplastic substance in long‐term treatment. Furthermore, BC limited the exponential increase of GSH, GGT, GSH‐T and GPX both in the hyperplastic nodules (HNs) and surrounding liver (NNSP) areas compared with carcinogen control (3′‐Met‐DAB) rats during long‐term treatment. Early marginal changes in GSH, GGT and GSHT (with 1‐chloro‐2,4‐dinitrobenzene as a substrate) activities in BC‐treated groups for 10 days compared with carcinogen (3′‐Met‐DAB once) control rats entail the participation of BC in the initial stages of hepatocarcinogenesis. A decrease in the number of hyperplastic nodules and the total liver parenchyma they occupy was observed in BC‐treated groups. HNs and NNSP liver areas are directly correlated with hepatic BC and vitamin A content and with rates and patterns of hepatic anti‐oxidant defense enzymes. Our results confirm that BC is protective in limiting the action of 3′‐Met‐DAB during the initiation phase of hepatocarcinogenesis. © 1995 Wiley‐Liss, Inc.
Vitamin‐D3 derivatives and breast‐tumor cell growth: Effect on intracellular calcium and apoptosis
Authors: Vandewalle Brigitte , Hornez Louis , Wattez Nicole , Revillion Françoise , Lefebvre Jean
Published: February 2007

Vitamin‐D3 derivatives are now well‐recognized growth inhibitors of numerous tumoral cells and in particular breast‐cancer cells. However, the mechanisms by which they operate are not well established. Among the wide range of physiological and biological functions of vitamin‐D3 derivatives, the best described include their action on calcium homeostasis. In this study, we sought to establish whether the effects of vitamin‐D3 derivatives on breast‐cancer cell growth may be in part related to intracellular calcium modulation and induction of apoptosis. To address these questions, we used, in addition to 1,25(OH)2D3, the active metabolite of vitamin D3, a non‐calcemic 1,25(OH)2D3 derivative: Ro 23‐7553 [16‐ene‐23‐yne‐1,25(OH)2D3], which in our hands was more potent than the parent compound in inhibiting breast‐cancer cell growth. We showed that the efficiency of both compounds in growth inhibition was higher in the estradiol‐receptor‐positive‐breast‐tumor MCF‐7 cells than in the estradiol‐receptor‐negative MDA‐MB 231 cells. In MCF‐7 cells in particular, important modifications of intracellular calcium related to the emptying of intracellular pools were observed. The depletion of Ca++ from intracellular stores was followed by the induction of apoptosis. Such a phenomenon was never observed in MDA‐MB 231 cells. Our results suggest that the action of vitamin‐D3 derivatives on the depletion of calcium stores, which was more significant in MCF‐7 than in MDA‐MB 231 cells, may induce apoptosis in the former cells and account for the high efficiency of vitamin‐D3 derivatives on growth inhibition of MCF‐7 breast‐tumor cells. © 1995 Wiley‐Liss, Inc.