bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoxanthine‐guanine phosphoribosyl‐transferase in childhood leukemia: Relation with immunophenotype, in vitro drug resistance and clinical prognosis
Authors: Pieters R. , Huismans D. R. , Loonen A. H. , Peters G. J. , Hählen K. , van der Does‐van den Berg A. , van Wering E. R. , Veerman A. J. P.
Published: February 2007

Decreased activity of hypoxanthine‐guanine phosphoribosyltransferase (HGPRT), responsible for the conversion of 6‐mercaptopurine and 6‐thioguanine (6‐TG) to their cytotoxic nucleotides, may cause resistance to these thiopurines in experimental leukemic systems. The clinical significance of this mechanism is as yet unclear. In 83 children with untreated acute lymphoblastic leukemia (ALL), we determined the prognostic value of HGPRT activity and the relation between HGPRT activity and resistance to thiopurines. HGPRT activity was determined radiochemically; in vitro resistance to 6‐TG with the MTT assay. HGPRT level was significantly lower in T‐ALL than in B‐lineage ALL; no differences were found between sequential differentiation stages of B‐lineage ALL. HGPRT activity was inversely related to the white‐blood‐cell count (WBC). Among patients with cALL and pre‐B‐ALL with WBC < 50 × 109/I, cases with a low HGPRT had a significantly poorer prognosis than those with a high HGPRT. WBC, age, sex, organomegaly and differentiation stage were comparable in both patient groups. No correlation was found between HGPRT activity and in vitro 6‐TG resistance in cALL and pre‐B‐ALL patients. T‐ALL cases were not more 6‐TG‐resistant than cALL and pre‐B‐ALL cases. Cells from 6 relapsed ALL cases did not show decreased HGPRT activity. We conclude that: (a) HGPRT is lower in T‐ than in B‐lineage ALL and is constant in sequential differentiation stages of B‐lineage ALL; (b) HGPRT activity is inversely related to tumor load; (c) low HGPRT activities are correlated with a poorer prognosis in precursor B‐ALL but this cannot be explained by thiopurine resistance because (d) there is no relation between HGPRT activity and in vitro 6‐TG resistance.
Doxorubicin: monoclonal antibody conjugate for therapy of human cervical carcinoma
Authors: Yeh Ming‐Yang , Roffler Steve R. , Yu Mu‐Hsien
Published: February 2007

Doxorubicin (Dox) was conjugated via a dextran linker to the F(ab′)2 fragment of monoclonal antibody (MAb) IH10 which recognizes an antigen expressed on the surface of human cervical carcinoma cells and tissues. Drug‐antibody conjugates (IH10‐Dox) with a molar ratio of Dox to MAb ranging from 40:1 to 60:1 retained antigen‐binding and pharmacological activities. Anti‐tumor activity of the conjugate in vitro was evaluated by measuring inhibition of [5‐3H]‐uridine incorporation into cellular RNA. IH10‐Dox was found to be 30 times more toxic to cervical tumor cells than a control MAb‐Dox conjugate and 150 times more potent than Dox coupled to dextran. In addition, IH10‐Dox was less toxic to antigen‐negative cells in vitro, suggesting that IH10‐Dox killing of cervical carcinoma cells was antibody‐mediated. 125I‐labeled IH10‐Dox preferentially localized in solid human cervical carcinoma xenografts in athymic mice with tumor‐to‐blood ratios of IH10‐Dox reaching 17.9 after 24 hr and 32.8 after 48 hr. Treatment of athymic mice bearing human cervical tumors with IH10‐Dox resulted in a dose‐dependent inhibition of tumor growth. Multiple administrations of IH10‐Dox at a dose corresponding to 20 μg doxorubicin significantly suppressed the growth of human cervical tumors in nude mice without significant side effects (weight loss), and this suppression was antibody specific. Both i.p. and i.v. administration of IH10‐Dox were found to be equally effective. Our results suggest that IH10‐Dox may be useful for the treatment of human cervical carcinoma.
Human renal‐cell carcinoma cells are able to activate natural killer cells
Authors: Hayakawa Kazuhiro , Morita Tatsuo , Augustus Lazel B. , von Eschenbach Andrew C. , Itoh Kyogo
Published: February 2007

We previously reported that natural killer (NK) cells that had infiltrated renal‐cell carcinoma (RCC) proliferated vigorously in culture with interleukin‐2 (IL‐2) and lysed autologous tumor cells. In this study, we investigate the susceptibility of RCC cells to NK‐cell lysis and their ability to stimulate proliferation and increase phenotypic expression and function of NK cells. Cells from primary culture of RCC (p‐RCC cells) were significantly more susceptible to the lysis mediated by human NK3.3 clones than were cells from primary culture of metastatic melanomas. Both RCC‐cell clones and cells from primary culture of non‐tumorous kidneys were also susceptible to lysis by NK3.3 clones and IL‐2‐activated peripheral blood lymphocytes (PBLs). Incubation of NK3.3 clones with p‐RCC cells in the absence of IL‐2 induced proliferation of NK3.3 clones, whereas incubation with cells from primary culture of metastatic melanomas, K562 cells, or any others tested did not. The p‐RCC cells from earlier passages were more potent inducers of NK‐cell proliferation than were those from older passages. Cell‐free culture superna‐tants of p‐RCC cells with or without NK3.3 clones failed to induce NK‐cell proliferation. Incubation of CD16+ NK cells purified from PBLs with p‐RCC cells induced higher proliferation of the NK cells only in the presence of IL‐2, whereas incubation with cells from primary culture of metastatic melanomas did not. Incubation of NK3.3 clones with p‐RCC cells resulted in an increase in CD16, CD25 (IL‐2 receptor‐α), and HLA‐DR antigen expression and cytotoxicity in NK3.3 clones. In summary, these results suggest that RCC cells are able to activate NK cells, potentially through cell‐to‐cell interaction.
Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times
Authors: de Bruijn Ernst A. , Sleeboom Harm P. , van Helsdingen Peter J. R. O. , van Oosterom Allan T. , Tjaden Ubbo R. , Maes Robert A. A.
Published: February 2007

The schedule in dosing of intravesical chemotherapy has thus far received little attention. Correlation of optimal contact time with bladder toxicity, as well as maximal chemotherapeutic effect for one of the drugs of first choice for intravesical instillation, i.e. mitomycin C (MMC), is a particularly important question. In a randomized study, we treated bladder cancer patients with intravesical MMC using 30‐min and 60‐min dwelling times. There were 28 evaluable patients in each of the 2 groups. The groups were comparable with respect to mean age, sex ratio and distribution of primary or recurrent and single or multiple tumors. Stages and grades of tumors were also comparable over both treatment groups. Pharmacokinetics of MMC and degradation/metabolism were monitored during the first 4 cycles and the last (8th) cycle using HPLC and mass spectrometry. Recurrence was significantly lower in the 60‐min treatment group (35.7% vs. 14.3%, x2 test; 0.01 < p < 0.05). No recurrences were found in patients with Ta and Tl tumors when the 60‐min dwelling time was used. Toxicity was mild and transient; the incidence was, surprisingly, lower in the 60‐min group but the difference failed to reach the level of significance. Pharmacokinetics of systemic MMC and recovery in the urine was comparable over both groups and systemic absorption was calculated to be in the range of 1–5%.
High protein, saturated fat and cholesterol diet, and low levels of serum lipids in colorectal cancer
Authors: Trichopoulou A. , Tzonou A. , Hsieh C. C. , Toupadaki N. , Manousos O. , Trichopoulos D.
Published: February 2007

In a case‐control study probing the role of diet on the occurrence of colorectal cancer and undertaken in Athens, Greece, sera were collected from 100 cases and 100 controls, and serum total cholesterol, high‐density‐lipoprotein (HDL) cholesterol and triglycerides were determined. The biochemical results were analyzed in conjunction with nutrient intakes and a dietary score that summarizes in a linear way the dietary contrast between high‐risk (high protein, saturated fat and dietary cholesterol; low vegetable) and low‐risk (low protein, saturated fat and cholesterol; high vegetable) patterns. Cases with colorectal cancer had significantly (p < 0.001) and substantially lower values of serum total cholesterol and particularly HDL cholesterol, but these associations did not reflect dietary practices, since protein intake and, to a lesser (and nonsignificant) extent, saturated fat and dietary cholesterol intake were higher among cases than among controls. In absolute terms, the dietary effect (as summarized in the linear dietary score) is more evident among persons with low serum total cholesterol and HDL cholesterol than among those with high levels of these serum lipids. These results indicate that a diet beneficial with respect to the risk of coronary heart disease is also likely to reduce the risk of colorectal cancer, even though low levels of serum total cholesterol and particularly HDL cholesterol represent important independent correlates of clinically overt colorectal cancer.
Independent clinical, histological and quantitative prognostic factors in transitional‐cell bladder tumours, with special reference to mitotic frequency
Authors: Lipponen P. K. , Eskelinen M. J. , Jauhiainen K. , Harju E. , Terho R. , Haapasalo H.
Published: February 2007

A cohort of 537 transitional‐cell bladder cancers (TCC) was followed up for a mean of 9 years. Clinical stage, WHO grade, papillary status, 6 nuclear factors and volume‐corrected mitotic index (M/V index) were related to progression and survival. Classic and quantitative prognostic factors were significantly interrelated (p< 0.001). In Ta‐TI tumours M/V index predicted progression independently (p< 0.001) and in the entire cohort progression was related independently to the M/V index (p= 0.0001) and to the WHO grade (p= 0.0022). In survival analysis, clinical stage (p< 0.0001), M/V index (p< 0.0001), WHO grade (p< 0.0001), papillary status (p< 0.0001) and nuclear factors (p< 0.0001) were significant predictors. In papillary tumours, clinical stage (p< 0.0001), M/V index (p< 0.0001), WHO grade (p< 0.0001) and nuclear factors (p= 0.0001–0.0133) were related to survival. In a multivariate analysis T‐category (p< 0.001), WHO grade (p< 0.001), M/V index (p= 0.002) and papillary status (p= 0.034) predicted survival independently in the entire cohort whereas in papillary tumours T‐category (p< 0.001) and M/V index (p< 0.001) were independent predictors. If tumours with pelvic lymphnode metastases or distant metastases at diagnosis were excluded from the analysis, T‐category (p< 0.001), M/V index (p< 0.001) and WHO grade (p< 0.001) were independent predictors. In papillary tumours T‐category (p< 0.001), M/V index (p< 0.001) and WHO grade (p= 0.048) predicted survival. The results emphasize the importance of mitotic activity as a most important histological prognostic factor in TCC, second only to clinical stage. In Ta‐TI tumours quantitative mitotic frequency analysis includes all the available independent prognostic information. Accordingly, TCC can be graded by mitotic frequency analysis in place of subjective grading systems.
Capacity of adipose tissue to promote growth and metastasis of a murine mammary carcinoma: Effect of estrogen and progesterone
Authors: Elliott Bruce E. , Tam S.‐P. , Dexter D. , Chen Z. Q.
Published: February 2007

Previously we have shown that a murine mammary carcinoma cell line, designated SPI, grows and metastasizes more efficiently in the mammary gland than in the subcutis. In this report, we examine the tissue specificity of this phenomenon. Our results show that SPI cells grow best in the mesenteric and ovarian fat pads and well in the mammary gland, but very poorly in the subcutis or peritoneal cavity. Massive dissemination of tumors from the ovarian and mesenteric sites occurs to the liver, spleen and diaphragm. In contrast, metastases from the mammary site occur primarily in the lung. Co‐transplantation of a threshold number of SPI cells with mammary or ovarian fat fragments into the subcutis results in increased tumor growth, whereas very few tumors form in sham controls receiving no fat fragments. Removal of the ovaries of donor and recipient mice abrogates tumor growth in adipose tissue transplants. Estrogen can stimulate growth of SPI in adipose tissue sites, whereas progesterone inhibits growth. In contrast, in vivo growth of a stable metastatic variant selected from SPI cells was not inhibited by progesterone. SPI cells growing in ovarian and mesenteric fat pads showed increased expression of estrogen receptors and progesterone receptors, as well as detectable levels of epidermal‐growth‐factor receptors, whereas receptor levels decreased to baseline on tumors in the subcutis. The levels of estrogen‐receptor mRNA reflect the corresponding functional expression of receptors; this finding suggests that the regulation of estrogen‐receptor expression in this system is, at least in part, at the mRNA level. Our results are consistent with the model that adipose tissue exerts an estrogen‐dependent positive regulatory effect on primary SPI tumor growth, and promotes the formation of metastases.
Pharmacologic interactions between the resistance‐modifying cyclosporine sdz psc 833 and etoposide (VP 16–213) enhance In Vivo cytostatic activity and toxicity
Authors: Keller Roland P. , Altermatt Hans J. , Donatsch Peter , Zihlmann Hans , Laissue Jean A. , Hiestand Peter C.
Published: February 2007

Cyclosporin A reverses multidrug resistance (MDR) and increases the in vivo cytostatic activity and toxicity of the anticancer agent etoposide (VP 16–213). SDZ PSC 833 (PSC 833), a non‐immunosuppressive, non‐toxic cyclosporin and very active modifier of P‐gp 170‐mediated MDR, elicits similar effects when administered with adriamycin. The underlying mechanisms, however, are not yet understood. The present pharmacological interaction study with PSC 833 and VP 16–213 was carried out to reveal the nature of this enhancement of cytostatic activity and toxicity. Rats pre‐treated with either PSC‐833 or solvent received a single dose of VP 16–213. Plasma levels of VP 16–213 were measured by high‐performance liquid chromatography (HPLC). The resulting increase in cytostatic activity and toxicity of VP 16–213 mediated by PSC 833 was paralleled by marked changes in the pharmacokinetic parameters of VP 16–213 in vivo. Bioavailability and blood levels of VP 16–213 were significantly increased 30 min after administration if PSC 833 had been given before. The disappearance rate of VP 16–213 from the intravascular compartment was considerably slowed down by PSC 833. In drug‐sensitive xenografts of human colon carcinoma, the PSC‐833‐induced pharmacologic changes in vivo could be counteracted by dose reduction of VP 16–213 while a full therapeutic potential was maintained. Doses of VP 16–213, 1.5 to 2 times smaller, combined with PSC 833, were as effective in terms of tumor‐growth inhibition as the maximum tolerated dose of VP 16–213 alone. Thus, pharmacologic interactions between PSC 833 or other resistance modifiers and VP 16–213 and other cytostatic agents require careful attention if they are to be used in humans to overcome MDR.
Pleiotropic actions of suramin on the proliferation of human breast‐cancer cells in vitro
Authors: Foekens John A. , Sieuwerts Anieta M. , Stuurman‐Smeets Elisabeth M. J. , Dorssers Lambert C. J. , Berns Els M. J. J. , Klijn Jan G. M.
Published: February 2007

Suramin, a non‐specific growth factor antagonist, is currently under investigation for treatment of cancer patients. We studied its action on 6 different human breast‐cancer cell lines in vitro. In complete growth medium, pleiotropic effects were observed with respect to cell proliferation, i.e. suramin is stimulatory at low concentrations and inhibitory at higher concentrations, for 4 of the 6 cell lines studied. The various cell lines showed marked differences with respect to the antiproliferative action of suramin, the Evsa‐T cells being by far the most sensitive ones. A suramin concentration of 100 μg/ml brought about a 100% stimulation of the proliferation of ZR/HERc cells, ZR 75.1 cells ectopically expressing a human epidermal growth factor receptor (EGF‐R) cDNA. Although less pronounced (10 to 60% stimulation), a similar response was observed for the parent ZR 75.1 cells, as well as for T‐47D and MDA‐MB‐231 cells. The non‐specificity of the action of suramin was established by the observation that suramin‐induced inhibition of cell proliferation could be abolished by insulin‐like growth factor‐1 (IGF‐I) or basic fibroblast growth factor (bFGF), and even by estradiol, both in complete growth medium and under defined serum‐free conditions. Our data indicate that suramin exerts pleiotropic effects on the proliferation of human breast cancer cells in vitro, and confirm the non‐specific nature of its action. The stimulatory effect of low concentrations of suramin on the proliferation of breast cancer cells may have important consequences for breast cancer patients treated with suramin.
Expression of integrins and other adhesion molecules in epstein‐barr virus‐transformed B lymphoblastoid cells and Burkitt's lymphoma cells
Authors: Rincon Jorge , Prieto Jacqueline , Patarroyo Manuel
Published: February 2007

Lymphocytes adhere to cells or extracellular matrices to perform functions relating to cytotoxicity, extravasation and tissue localization, as well as modulation of lymphocyte growth and maturation. This adherence is mainly mediated by 3 families of cell‐surface adhesion molecules: integrins, immunoglobulin‐related molecules and selectins. Since variations in the degree of adherence may affect the pathophysiology of lymphoproliferative disorders, the expression of a large number of adhesion molecules was analysed on Epstein‐Barr virus (EBV)‐transformed lymphoblastoid cell lines (LCLs), and on EBV‐positive or EBV‐negative Burkitt's lymphoma (BL) lines, by immunofluorescence flow cytometry and immunoprecipitation with monoclonal antibodies. With regard to the β1, β2 and β3 integrin subfamilies, LCLs strongly expressed CD49d/CD29 (VLA‐4), CDIIa/CD18 (Leu‐CAMa, LFA‐1) and CD5I/CD6I (vitronectin receptor). These cells also abundantly expressed CD54 (ICAM‐I) and CD58 (LFA‐3) as well as the „homing receptors”︁ L‐selectin (LECAM‐I) and CD44, BL lines had considerably lower amounts of VLA‐4 than LCLs, and ICAM‐1 was expressed only by some of the tumor lines. All other adhesion molecules were absent or minimally expressed in the BL cells.
SOD2: A new type of tumor‐suppressor gene?
Authors: Bravard A. , Sabatier L. , Hoffschir F. , Ricoul M. , Luccioni C. , Dutrillaux B.
Published: February 2007

The activity of superoxide dismutases (SOD) I and 2 was analysed in correlation with mRNA and chromosome content in 6 SV40‐transformed (TF) and in non‐transformed (NF) human fibroblast cell lines. Total SOD activity was fairly constant, whereas the ratio SOD2/SOD I was much lower in TF than in NF. The decrease in SOD2 activity was correlated with a low mRNA content, and with the presence of various chromosomal rearrangements leading to deletions of the long arm of chromosome 6 where the gene is mapped. In contrast, chromosome 21, carrying the gene for SODI, was not found to be deficient and the SODI activity was high. This shows that in TF, the activity of SOD2 is largely determined by gene dosage. It has been proposed that SOD activity could be inversely correlated with cell proliferation, and that SOD2 activity, in particular, was related to cell differentiation. Thus, there is a cascade of events occurring in cell transformation, involving gene deregulation, chromosome (gene) deletion, low mRNA and protein content, low enzyme activity, and acquisition of growth advantage which makes the SOD2 gene a possible new type of tumor‐suppressor gene.
Expression of mRNA for cytokines in tumor‐infiltrating mononuclear cells in ovarian adenocarcinoma and invasive breast cancer
Authors: Vitolo Domenico , Zerbe Tony , Kanbour Anisa , Dahl Carol , Herberman Ronald B. , Whiteside Theresa L.
Published: February 2007

Cytokine gene expression in tumor‐infiltrating lymphocytes (TIL) in frozen‐tissue sections of 2 types of human solid tumor—ovarian adenocarcinoma and invasive breast cancer—was examined by in situ hybridization with 35S‐labeled cDNA probes for human cytokines. The proportion of cells containing mRNA able to hybridize to the antisense c‐DNA probes for interleukin 2 (IL‐2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ) or receptors for IL‐2 (either p55 or p70) was also determined in human normal peripheral lymphoid tissues and inflammatory tissues. Few cells were positive for IL2 and TNFα mRNA in reactive human lymph nodes and tonsils. Inflammatory lesions, such as salpingitis or chronic active hepatitis, contained 10‐20 times more cells positive for cytokine mRNA than reactive lymphoid tissue. In contrast, tumor‐infiltrating lymphocytes (TIL) in the stroma of ovarian carcinomas or most ductal breast tumors only rarely expressed mRNA for TNFα, IL2 or IFNγ. The intensity of mononuclear cell infiltration in these tumors correlated positively with the percentage of cells which expressed mRNA for IL‐2, TNFa and IL‐2R. In those ductal breast carcinomas which contained intracellular or intraductal mucins, up to 30% of lymphoid cells in the tumor stroma were positive for IL‐2, TNFα, IFNγ and IL‐2R. Thus, strong evidence for local activation of mononuclear cells in situ, exemplified by the expression of genes for cytokines, was obtained only in inflammatory lesions and in mucin‐producing breast carcinomas. In most carcinomas studied, few TIL expressed genes for cytokines as measured by in situ hybridization. Thus, human solid tumors appear to differ in their ability to induce gene expression for cytokines in TIL.
Prevalence of human papillomavirus (HPV) infection in basque country women using slot‐blot hybridization: A survey of women at low risk of developing cervical cancer
Authors: Herckenrode Carmen Mugica‐Van , Malcolm Alan D. B. , Coleman Dulcie V.
Published: February 2007

Cervical smears from 1, 178 women with cytologically normal cervices and 67 women with cervical intra‐epithelial neoplasia (CIN) or cervical carcinoma were analyzed for the presence of HPV 6, 11, 16 and 18 DNA by slot‐blot hybridization. HPV DNA was detected in 17% (95% CI: 14%‐19%) of the women with a normal smear; 11% of infected women harboured HPV 16 and 18 (95% CI: 9%‐13%, each). HPV DNA was detected in 54% (95% CI: 41 %‐66%) of patients with abnormal smear; the most prevalent virus type in this group was HPV 16 (45%; 95% CI: 32%‐38%). In order to verify the slot‐blot results, a proportion of the samples was also investigated by PCR. There was 88% correlation between the 2 tests. The high prevalence of HPV 16 and 18 infection demonstrated in our low‐cervical‐cancer‐risk area further support the role of as yet unidentified co‐factors as determinants of the different geographic rates of cervical‐cancer incidence.
Unusual expression and localization of heat‐shock proteins in human tumor cells
Authors: Ferrarini Marina , Heltai Silvia , Zocchi M. Raffaella , Rugarli Claudio
Published: February 2007

It has been suggested that members of HSP families represent the surface target of immune responses leading to tumor rejection in mice. Here we report that tumor cells, compared with normal cells, constitutively expressed 2‐ to 10‐fold higher levels of intracellular HSP90. Moreover, in the absence of environmental stress, 2 lines (out of 6) expressed the “inducible” HSP72, which was also detectable in fresh tumor cells. HSP72 expression was not regulated during the cell cycle, in contrast with what has been observed with normal cells. Both HSP90 and HSP72 proteins exhibited a heterogeneous pattern of intracellular distribution in most cells, HSP72 being confined mainly to the nuclear compartment. Finally, we could detect both HSP90 and, to a lesser extent, HSP72 (that are generally believed to be located intracellularly) at the surface of some tumor cell lines. We conclude that tumor cells differ from normal cells in their pattern of HSP expression; this might imply a role of HSPs in eliciting an immune response against cancer.
Inhibition of tumor‐induced angiogenesis by the administration of recombinant interferon‐γ followed by a synthetic lipid‐a subunit analogue (GLA‐60)
Authors: Saiki I. , Sato K. , Yoo Y. C. , Murata J. , Yoneda Junya , Kiso M. , Hasegawa A. , Azuma I.
Published: February 2007

The effect of the administration of recombinant interferon‐γ. (rlFN‐γ) and a synthetic lipid A subunit analog (GLA‐60) on angiogenesis induced by B16‐BL6 melanoma was examined in syngeneic C57BLJ.6 mice. Intravenous administration of rlFN‐γ followed by GLA‐60 (referred to as rIFN‐γ/GLA‐60) induced endogenous production of tumor necrosis factor (TNF). This treatment on day 3 after tumor inoculation caused a marked decrease in the number of vessels oriented towards the tumor mass (angiogenic response) and tumor size over a period of 9 days. In contrast, neither rlFN‐γ nor GLA‐60 alone, nor GLA‐60/ rIFN‐γ (reverse sequence of administration), which is unable to induce the production of TNF in the serum, had any effect. Sera induced by the treatment with rIFN‐γJ.GLA‐60, and recombinant TNF, inhibited the in vitro growth of lung endothelial cells which is considered to be one of the essential events in tumor neovascularization. Multiple i.v. treatments with rIFN‐γ/ GLA‐60 on days 5, 8 and 11 after s.c. implantation of tumor, significantly inhibited primary tumor growth by the amputation time (day 20) and lung metastasis of BI6‐BL6 cells on day 34, while other treatment modalities had no such effect. Our results indicate that inhibition of lung‐tumor metastasis by rlFN‐γ/GLA‐60 treatment may be partly due to the inhibition of tumor‐associated angiogenesis.
The effect of retinoic acid on chemosensitivity of PA‐1 human teratocarcinoma cells and its modulation by an activated N‐ras oncogene
Authors: Le‐Ruppert Kim , Masters John R. W. , Knuechel Ruth , Seegers Silvia , Tainsky Michael A. , Hofstaedter F. , Buettner Reinhard
Published: February 2007

Combination of chemotherapeutic drugs with agents that induce cell differentiation is a possible means of improving cancer chemotherapy. To explore this approach we used 4 cell lines established from the human teratocarcinoma‐derived cell line PA‐1; 2 retinoic acid (RA)‐sensitive lines compared to 2 RA‐resistant lines transformed by an activated N‐ras oncogene. Equal numbers of colony‐forming cells were exposed for 72 hr to 10−6M RA and subsequently to a range of concentrations of cisplatinum, etoposide or bleomycin. Enhanced cytotoxicity of cisplatin and etoposide (3‐ to 5‐fold) was observed in the N‐ras‐transformed cell lines compared to the non‐transformed lines. Treatment with RA caused an increase in the cytotoxicity of all 3 drugs to the 2 RA‐sensitive cell lines. In contrast, a reduction of cytotoxicity was observed in the 2 N‐ras‐transformed lines. Our results indicate that sensitivity to cytotoxic agents can be increased by RA in RA‐sensitive cells, but the opposite effect is seen in N‐ras transformed, RA‐resistant cells. Therefore, a general rationale for combination therapy with RA and cytotoxic drugs cannot be inferred.
Overexpression of a synthetic phosphotyrosine protein phosphatase gene inhibits normal and transformed cell growth
Authors: Ramponi Giampietro , Ruggiero Marco , Raugei Giovanni , Berti Andrea , Modesti Alessandra , Innocenti Donatella Degl' , Magnelli Lucia , Pazzagli Claudia , Chiarugi Vincenzo P. , Camici Guido
Published: February 2007

We studied the level of the cytosolic phosphotyrosine protein phosphatase (PTPase) (originally termed low‐Mr acid phosphatase) in normal NIH/3T3 and in v‐erb B‐transformed fibroblasts. The level of the enzyme, assayed by ELISA, was inversely related to cell proliferation, normally growing cells had less enzyme than their contact‐inhibited counterparts and v‐erbB transformants had less enzyme than normal NIH/3T3. In order to overexpress the enzyme and study its effects in normal and transformed cells, we transfected a synthetic gene coding for the PTPase in control NIH/3T3 and v‐erbB transformants. The overexpressed enzyme was recognized by antibodies raised against the native enzyme and, in cells overexpressing the PTPase, we observed a marked dephosphorylation of tyrosyl residues of cellular proteins. Cell proliferation, in both normal and v‐erbB transformants overexpressing the PTPase, was measured. We observed that PTPase overexpression was accompanied by significantly reduced thymidine incorporation in both cell types, either serum‐starved or serum‐stimulated. The ability of transformed v‐erbB cells to grow in soft agar was also markedly decreased by overexpression of the enzyme. Taken together, our results indicate that overexpression of PTPase might interfere with mitogenic signalling pathways in both normal and transformed cells, and propose a role for PTPase in the control of cell proliferation.
Menstrual and reproductive factors and breast cancer in women with family history of the disease
Authors: Parazzini Fabio , La Vecchia Carlo , Negri Eva , Franceschi Silvia , Bocciolone Luca
Published: February 2007

The relationship between socio‐economic indicators, body mass, reproductive and menstrual factors and risk of “familial” breast cancer has been analyzed using data from a large case‐control study of breast cancer conducted in Italy. A total of 3,037 breast‐cancer patients aged 75 years or less admitted to a network of hospitals in the Greater Milan area were interviewed. Controls were 2,569 women aged 75 or less, admitted for acute conditions to the same network of hospitals where cases had been identified. Women were not included as controls if they had been admitted for gynecological, hormonal or neoplastic diseases. A total of 331 cases and 121 controls reported a family history of breast cancer in their first‐degree relatives, with a family history tended to be more educated and of higher social class than controls with family history, but these differences were not statistically significant. No relationship emerged with marital status and body‐mass index. The estimated multivariate relative risks were, compared with nulliparous women, respectively 0.9, 1.2 and 1.2 for women reporting 1, 2 and 3 or more births. The risk of breast cancer was also greater in women reporting one or more spontaneous abortions: compared with those who did not, the estimated relative risk was 1.9 (95% confidence interval 0.8 to 3.7). Relative to women reporting their first birth below age 25, the estimated relative risks were 1.3 and 0.9 in those reporting it at age 25 to 29 and 30 or more respectively. Likewise, no consistent relationship emerged with lifelong menstrual pattern and menopausal status. These results suggest that menstrual and reproductive factors do not play an important role in the risk of breast cancer in women with a history of the disease in first‐degree relatives. © 1992 Wifey‐Liss, Inc.
Appearance and detection of multiple copies of the mdr‐1 gene in clinical samples of mammary carcinoma
Authors: Lönn Ulf , Lönn Sigrid , Nylen Urban , Stenkvist Björn
Published: February 2007

To examine the presence of multiple copies of the mdr‐1 gene in clinical tumor samples we have developed an approach where the cells are obtained by fine‐needle biopsies and the number of gene copies determined by PCR. The temporal appearance of amplified mdr‐1 was examined in 20 breast‐cancer patients with clinical stage‐IV disease receiving endocrine treatment. Tumor samples were obtained every 2nd to 3rd month from the same tumor lesion. None of the initial samples from each patient contained multiple copies of mdr‐1. Of 16 patients who showed increased tumor size, 4 developed multiple gene copies, showing that the event occurs without cytotoxic selection of cells with chemotherapy. © 1992 Wifey‐Liss, Inc.
The changing importance of prognostic factors in breast cancer during long‐term follow‐up
Authors: Lipponen P. , Aaltomaa S. , Eskelinen M. , Kosma V.‐M. , Marin S. , Syrjänen K.
Published: February 2007

A cohort of 464 breast‐cancer patients were followed up for over 10 years and the clinical, histological and morphometric factors were related to survival within different time periods during follow‐up. Tumor diameter, axillary lymph‐node status (pN), tubule formation and the fraction of intraductal growth as determined from the primary tumor biopsy specimen had prognostic value up to 5 years. Histological grade, morphometric nuclear factors and the M/V index had only short‐term prognostic value immediately after the primary therapy. In axillary lymph‐node‐negative (ANN) tumors tubule formation, intraductal growth, tumor necrosis and tumor diameter had prognostic value during the first 3 postoperative years. In axillary lymph‐node‐positive (ANP) tumors, tumor diameter, intraductal growth and tubule formation had long‐term prognostic value whereas the M/V index had prognostic value only for 1 postoperative year. Tumor diameter, axillary lymph‐node status, tubule formation and the proportion of intraductal growth also had independent long‐term prognostic value in a multivariate analysis and accordingly these factors can categorize breast‐cancer patients into prognostic groups after several years of follow‐up. In contrast, mitotic frequency loses its prognostic power within 2 postoperative years, while morphometric nuclear factors and histological grade have no practical prognostic value after 1 year of follow‐up.© 1992 Wifey‐Liss, Inc.
Risk factors for gallbladder cancer: A polish case‐control study
Authors: Zatonski Witold A. , La Vecchia Carlo , Przewozniak Krzysztof , Maisonneuve Patrick , Lowenfels Al B. , Boyle Peter
Published: February 2007

A population‐based case‐control study of gallbladder cancer was conducted in the south‐west of Poland, within the framework of the SEARCH Programme of the International Agency for Research on Cancer. A total of 73 cases and 186 controls were interviewed using a questionnaire including demographic and socio‐economic factors, education, smoking, alcohol, tea and coffee consumption, and past medical history. A validated diet history was used to estimate the daily intake of calories, fats, carbohydrates, proteins, cholesterol, fibres and vitamins C and E. Gallbladder disease was the major determinant of subsequent gallbladder cancer: 41 cases (56%) vs. 15 (8%) controls had a past history of gallbladder disease, corresponding to an odds ratio (OR) of 12.5 (95% confidence interval, 5.8 to 26.6), and the OR was 12.1 for gallbladder problems dating back 20 years or more in the past. There was an inverse relationship with education, the OR being 0.3 (95% CI 0.1 to 1.2) for 13 years of education or more vs. less than 7. Gallbladder cancer risk was positively associated with total calorie intake, with ORs of 1.4, 1.5,4.1 for the 3 upper quartiles compared with the lowest one (trend, p < 0.01). Weaker direct associations were observed for proteins, carbohydrates and cholesterol. There was some suggestion of inverse associations with fibre intake, and a more consistent one with vitamins C and E. These results further quantify the role of gallstones, and suggest that total calorie intake and other dietary factors potentially linked with benign gallbladder conditions are involved in the aetiology of gallbladder cancer. © 1992 Wifey‐Liss, Inc.
Two antigens detected on human ocular melanomas with the mouse monoclonal antibodies 2/10sn and 10/12SN
Authors: Safi Nour , Kantor Raphe R. S. , Atkinson Barbara , Moratz Chantal , Wilt Allen R. , Pancake Sam , Reba Richard , Mathieson Bonnie J. , Desgrez Alex
Published: February 2007

Seven human ocular melanoma cell lines were established in vitro and 3 of these, GU‐4, LLN‐40 and its subline C17‐11, were characterized. Mice were immunized with these ocular melanoma cell lines, and 2 hybridomas producing monoclonal IgG1antibodies (MAb) were produced. MAb 2/10SN recognizes a 44‐kDa monomeric protein, whereas MAb 10/12SN reacts with an 83/65‐kDa heterodimeric protein. These melanoma‐associated antigens (MAA) are detected at high concentrations in the cytoplasm of ocular melanoma cells. However, cell‐surface labelling techniques suggest that these MAA are also associated with the cell‐surface membrane. These 2 ocular MAA are also expressed by several skin melanoma cell lines. Immunohistochemical studies have localized these antigens to ocular and skin melanomas, to sweat ducts and basal squamous cells in normal skin, with limited expression in several other normal tissues and some carcinomas. Biodistribution studies in nude mice with human ocular melanomas have demonstrated good localization of 125I‐labeled MAb 2/10SN at the tumor sites. Therefore, these 2 MAbs, 2/10SN and 10/12SN, recognize MAA which appear to be unique and may prove useful for imaging purposes. © 1992 Wifey‐Liss, Inc.
Potentiation by novobiocin of the cytotoxic activity of etoposide (VP‐16) and teniposide (VM‐26)
Authors: Rappa Germana , Lorico Aurelio , Sartorelli Alan C.
Published: February 2007

The coumermycin antibiotic novobiocin, which interacts with the nuclear enzyme topoisomerase II, produced supra‐additive toxicity to WEHI‐3B D+ leukemia cells at clinically achievable concentrations, when combined with teniposide (VM‐26) or etoposide (VP‐16). Simultaneous exposure of cells to both agents was required for maximum efficacy of the combination. Novobiocin also produced supra‐additive toxicity to A549 human lung carcinoma cells when combined with VM‐26 or VP‐16. At concentrations above the peak plasma levels achievable in patients, novobiocin lost its potentiating activity. Exposure of WEHI‐3B D+ cells to novobiocin did not modify the cytotoxicity produced by the topoisomerase II inhibitor m‐AMSA, whereas, in contrast, novobiocin antagonized the cytotoxicity of m‐AMSA in A549 cells. Although it has been suggested that inhibitors of the syntheses of DNA and RNA interfere with the cytotoxic activity of the epipodophyllotoxins, maximum potentiation of the cytotoxicities of VP‐16 and VM‐26 occurred at novobiocin concentrations that decreased the rates of synthesis of both DNA and RNA in WEHI‐3B D+ cells by about 50%. The number of DNA‐topoisomerase‐ll covalent complexes stabilized by VM‐26 in WEHI‐3B D+ cells was greatly increased when cells were exposed simultaneously to VM‐26 and novobiocin for 1 hr, but not when cells were treated with m‐AMSA and novobiocin for the same period of time. Novobiocin did not affect the amount of covalent complexes produced by VM‐26 in isolated nuclei, suggesting that the potentiating activity of novobiocin was not due to its direct interaction with the nuclear topoisomerase II enzyme. Our findings suggest that therapeutic levels of novobiocin may be capable of enhancing the clinical activities of VP‐16 and VM‐26. © 1992 Wifey‐Liss, Inc.
Polyethylene‐glycol‐modified interleukin‐2 is superior to interleukin‐2 in locoregional immunotherapy of established guinea‐pig tumors
Authors: Mattijssen Vera , Balemans Lianne T. M. , Steerenberg Peter A. , de Mulder Pieter H. M.
Published: February 2007

Polyethylene glycol‐modified recombinant human interleukin‐2 (PEG‐IL‐2) represents a cytokine with prolonged circulatory half‐life and increased antitumor activity as compared to recombinant interleukin‐2 (rIL‐2) after systemic administration. We studied whether PEG‐IL‐2 would also be advantageous in locoregional immunotherapy using a syngeneic tumor model. Intradermal inoculation of line‐10 tumor cells into the flanks of strain‐2 guinea‐pigs results in a fast‐growing tumor and regional lymph‐node metastases. Treatment schedules were started on day 7 after inoculation in animals with established tumors. First, groups of 5‐6 animals were treated with repeated intratumoral and perilymphatic rIL‐2 or PEG‐IL‐2 injections. PEG‐IL‐2 caused significant growth inhibition of both the primary tumor and the regional lymph‐node metastases at lower doses and with less frequent administration than rIL‐2. The best schedule for PEG‐IL‐2 was 3 injections a week for 5 weeks, resulting in cure of 4/17 and 5/5 (ρ < 0.01) animals at the 2 most efficient dose levels tested. Subsequent experiments indicated that the intratumoral and not the perilymphatic injection route was essential for the obtained antitumor effect. Furthermore, 12/12 animals cured after PEG‐IL‐2 treatment rejected a rechallenge with line‐10 tumor cells, whereas no cures were seen after rIL‐2 injections. PEG‐IL‐2 therefore appears to be a valuable substance for intratumoral immunotherapy. © 1992 Wifey‐Liss, Inc.
Insulin‐like growth‐factor‐binding protein gene expression and protein production by human tumour cell lines
Authors: Reeve Julie G. , Kirby Lemuel B. , Brinkman Ad , Hughes Stephanie A. , Schwander Jurg , Bleehen Norman M.
Published: February 2007

The secretion of insulin‐like growth‐factor‐binding proteins (IGFBPs) and expression of the genes encoding IGFBP‐I, IGFBP‐2 and IGFBP‐3 have been studied in a panel of cell lines derived from breast carcinomas, Wilms' tumour, neuroblastoma, retinoblastoma, colon carcinoma, liver adenocarcinoma, Burkitt's lymphoma and a non‐small‐cell lung carcinoma. All cell lines, with the exception of the Burkitt's lymphoma cell line, secreted IGFBPs, as detected by affinity labelling. A 34‐kDa BP was present in the conditioned media of all IGFBP‐secreting cell lines, whereas BPs ranging from 18 kDa to 53 kDa were variably secreted. All IGFBP‐secreting cell lines expressed the IGFBP‐2 gene as determined by Northern blot analysis. The Wilms' tumour, the neuroblastoma and the retinoblastoma cell line expressed the IGFBP‐2 gene only. All other cell lines, with the exception of the Burkitt's lymphoma, expressed the IGFBP‐2 gene and, in addition, either the IGFBP‐I gene and/or the IGFBP‐3 gene. IGFBP‐I gene expression could be detected by reverse transcriptase polymerase chain reaction only. IGFBP‐3 gene expression was detected by Northern blot analysis, but transcripts were less abundant than IGFBP‐2 mRNAs. These findings indicate that the expression of multiple BP genes and the secretion of BPs may be a common property of tumour cells. © 1992 Wifey‐Liss, Inc.
Reduced tumorigenicity of fibrosarcomas which constitutively generate il‐1α either spontaneously or following il‐1α gene transfer
Authors: Douvdevani Amos , Huleihel Mahmoud , Zöller Margot , Segal Shraga , Apte Ron N.
Published: February 2007

Interleukin‐I (IL‐I) is a major immunoregulatory/proinflammatory cytokine which also affects fibroblast proliferation and function and therefore it was of interest to investigate whether its constitutive expression influences the in vivo tumorigenic potential of transformed fibroblastoid cell lines. Here we report on a strong correlation between the constitutive expression of IL‐1α and reduced tumorigenicity, using various series of oncogene‐transformed NIH/3T3‐derived cell lines which produce the cytokine spontaneously or upon gene transfer, following transfection with the IL‐1α cDNA. Reduced tumorigenicity of the constitutive IL‐1α producing cell lines was manifested either by inability to grow in animals or by regressions of initially growing tumors, within 2 to 3 weeks from cell inoculation. In contrast, mice inoculated with non‐IL‐1‐producing cell lines developed progressive tumors which ultimately killed the animals. Clones obtained from a non‐IL‐1‐producing met‐transformed cell line shifted from a progressive to a regressive phenotype, following transfection with an IL‐1α‐encoding gene, inserted into an appropriate expression vector, resulting in constitutive expression of the cytokine. The effects of constitutive IL‐1 expression on tumor development were observed both in histocompatible (NFS/N) and partially allogeneic (BALB/c) mice; however, they were more pronounced in the allogeneic environment. Fibrosarcomas which are non‐IL‐1 producers induced progressive tumors in both strains of mice at the same growth rate. The differences between the growth characteristics of the fibrosarcomas in histocompatible vs. partially allogeneic mice suggest that IL‐1 exerts adjuvant‐like effects which increase the immunogenicity of tumor‐cell antigens, and they also argue against the possibility that an IL‐1‐mediated local non‐specific inflammatory response is the major effector mechanism of tumor rejection. Indeed, in subsequent studies we shall report on the importance of specific cellular immune responses, especially cytotoxic T lymphocytes (CTLs), in the eradication of constitutive IL‐1‐producing fibrosarcomas. Thus, our findings may serve as the basis for novel immunotherapy strategies aimed at the induction of IL‐1 expression by cells comprising the neoplasm or alternatively by local application of the cytokine in the vicinity of the tumor. © 1992 Wifey‐Liss, Inc.
Prevalence and expression of human papillomavirus in tonsillar carcinomas, indicating a possible viral etiology
Authors: Snijders Peter J. F. , Cromme Frans V. , Van Brule Adriaan J. C. Den , Schrijnemakers Henri F. J. , Snow Gordon B. , Meijer Chris J. L. M. , Walboomers Jan M. M.
Published: February 2007

The presence of human papillomavirus (HPV) DNA was assessed in biopsies of tonsillar carcinomas (n = 10) and cases of tonsillitis (n = 7), serving as controls, by general‐primer‐mediated PCR (GP‐PCR). All carcinomas appeared HPV‐positive, whereas all cases of tonsillitis were HPV‐negative. Additional type‐specific PCR for HPV 6, 11, 16, 18, 31 and 33 revealed that 4 carcinomas contained HPV 16 DNA, 4 contained HPV 33 DNA and I contained an HPV 16/33 double infection. False positivity was excluded by additional Southern blot analysis of type‐specific PCR‐positive samples (n = 4). Further characterization of GP‐PCR products by sequence analysis revealed that 2 carcinomas contained still uncharacter‐ized HPV genotypes; one of these also contained HPV 33 DNA and one was negative by type‐specific PCR. Application of RNA PCR revealed expression of HPV 16 or HPV 33 E7 encoding spliced E6*l transcripts in all tonsillar carcinomas (n = 4) examined. Additional non‐radioactive RNA in situ hybridization performed on 3 biopsies revealed the presence of HPV 16 or HPV 33 E7 transcripts exclusively localized within the carcinoma cells, whereas stroma stained negative. These findings strongly support a role for certain HPV types in the pathogenesis of tonsillar carcinomas.
Colon cancer in argentina. I: Risk from intake of dietary items
Authors: Iscovich J. M. , L'Abbé K. A. , Castelleto R. , Calzona A. , Bernedo A. , Chopita N. A. , Jmelnitzsky A. C. , Kaldor J.
Published: February 2007

A case‐control study has been conducted to investigate the relationship between dietary components and risk of colon cancer in the La Plata area of Argentina. Cases are 110 patients newly diagnosed with colon cancer in 10 major hospitals between 1985 and 1986. Two neighbourhood controls per case were individually matched by age, sex and place of residence. Personal interviews elicited information on frequency of consumption of 140 food items during the 5‐year period up to 6 months prior to interview. Risk is analyzed by quartiles of individual food items and groups of items. Multivariate conditional logistic regression modelling indicates that consumption of eggs is associated with increased risk for colon cancer (odds ratios by quartile: 1.0, 1.58, 2.02, 4.66), as are some dairy products (ORs of 1.93 for the highest quartile of consumption of cheese). Intake of vegetables, fish and poultry is associated with statistically significant decreasing risk (ORs of 0.075, 0.39 and 0.39, for the highest categories of consumption of vegetables, fish and poultry, respectively). The risk for red meat does not consistently increase as consumption increases. Risks are not altered by the inclusion of potential confounders such as education or body mass index. These findings confirm those of several previous studies and are of particular interest, since the Argentinean diet typically includes a high intake of red meat.