bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumoricidal activity and cytokine secretion by tumor‐infiltrating macrophages
Authors: Brunda Michael J. , Sulich Viveca , Wright Rosemary B. , Palleroni Alicia V.
Published: February 2007

Murine macrophages from different anatomical sites were compared for their ability to become tumoricidal and to secrete interleukin‐l (IL‐I) and tumor necrosis factor (TNF) following stimulation in vitro by several biological response modifiers (BRM). Peritoneal macrophages (PM), alveolar macrophages (AM), and tumor‐infiltrating‐macrophages (TIM), isolated from B16F10 melanoma colonies in the lung, were incubated overnight with BRM [recombinant murine in‐terferon gamma (rMulFN‐γ), lipopolysaccharide (LPS), muramyl dipeptide (MDP)], either alone or in combination. PM exhibited an increased cytotoxic response following incubation with LPS or rMulFN‐γ but not with MDP. Both AM and TIM were induced to become tumoricidal following incubation with rMulFN‐γ plus LPS or rMulFN‐γ plus MDP but not after stimulation with any BRM alone; the level of cytotoxicity obtained with TIM incubated with rMulFN‐γ plus LPS was slightly lower than that observed with PM or AM, while with rMulFN‐γ plus MDP both AM and TIM had lower cytotoxicity than PM. Secretion of IL‐I and TNF was observed in PM stimulated with LPS or MDP but not with rMulFN‐γ. Likewise, secretion of IL‐I by AM or TIM was also induced with LPS, although Jess than that obtained with PM. AM stimulated with LPS secreted larger amounts of TNF than PM while TIM secreted very low amounts of TNF. However, this result may be a consequence of the enzymatic isolation procedure used to obtain TIM since TNF secretion was also impaired in LPS‐stimulated normal lung macrophages isolated by a similar enzymatic procedure, or enzyme‐treated PM. Our results suggest that TIM obtained from lung metastases share certain functional characteristics with normal AM and respond to BRM in like manner with respect to induction of tumoricidal activity and cytokine secretion.
A secreted Mr ∼ 40,000 glycoprotein specifically induced by glucocorticoids in a rat colon carcinoma cell line
Authors: Denis Marc G. , Chadeneau Corinne , Pleignet Corinne , Lustenberger Patrick
Published: February 2007

Glucocorticoid hormones are thought to play a role in car‐cinogenesis, as they regulate cell differentiation and proliferation. We have previously shown that dexamethasone inhibits the growth of a rat colon carcinoma cell line, and induces the secretion of an Mr ∼ 40,000 protein. We now report that the synthesis and the release in the culture medium of this protein is stimulated specifically by glucocorticoid agonists, and not by other steroid hormones. The anti‐glucocorticoid RU 38486 is inefficient and suppresses the induction of this protein by dexamethasone. Induction is sensitive to actinomycin D, suggesting that regulation may be exerted by altering the rate of mRNA synthesis. Characterization of culture medium from dexamethasone‐treated cells revealed that the Mr ∼ 40,000 protein is glycosylated, and can be further separated from other secreted proteins by high‐performance anion‐exchange chromatography.
Occupation and risk of hodgkin's disease in north‐east Italy
Authors: Franceschi Silvia , Serraing Diego , Bidoli Ettore , La Vecchia Carlo , Tirelli Umberto
Published: February 2007

The relationship between occupation and exposure to several occupational agents and Hodgkin's disease (HD) was investigated in a case‐control study of 152 cases and 613 controls with acute diseases admitted to all hospitals in Pordenone province, north‐east Italy. Among cases, there was a significant excess of individuals occupied in agriculture (odds ratio, OR for > 10 years = 2.2, 95% confidence interval, CI:1.3‐3.7), Who were exposed to livestock and meat processing (OR‐3.4, 95% CI:1.7‐6.6), herbicides and pesticides (OR = 3.2, 95% CI:1.6‐6.5). When the relationship between agriculture and specific exposures was assessed, it appeared that contact with some still unidentified animal‐related agent involved in livestock farming and meat processing may be at least as important in determining HD risk as exposure to herbicides and pesticides and, probably, more important than occupation in agriculture per se.
in vitro “progression” of bovine papillomavirus‐transformed cells: Loss of contact sensitivity after multiple rounds of selection
Authors: Naito A. , Kitamura Y. , Yoshikura H. , Sudoh K.
Published: February 2007

The transformed phenotype of C127 cells harboring bovine papillomavirus shuttle vector pdBPVMMTneo(342–12) was suppressed by direct contact with untransformed C127 cells. By repeated selections of rare foci developing on untransformed cell monolayers, we obtained a cellular clone of BPV transformants which formed foci on the untransformed C127 cells as efficiently as on plastic surface. The BPV genome in the mutant cells showed extensive genetic rearrangements, duplication of upstream regulatory region and deletion of pBR322‐derived sequence and its flanking. There was an increase in BPV transcripts per cell. Culture of the parental BPV‐transformant in contact with the untransformed C127 cells resulted in a marked reduction of the BPV transcripts, while in the case of the mutant transformant the reduction was much slighter. This indicates that the transcription level of the BPV genome was controlled by a cell‐cell contact signal.
Inhibition of DNA repair and the enhancement of cytotoxicity of alkylating agents
Authors: Frankfurt Oskar S.
Published: February 2007

DNA damage was evaluated by flow cytometric (FCM) analysis of cells treated with L‐phenylalanine mustard (L‐PAM) and stained with anti‐DNA monoclonal antibody (MAb) F7–26. DNA damage was rapidly repaired, as indicated by the loss of DNA immunoreactivity after removal of L‐PAM. Two types of drug combinations were found to inhibit DNA repair. Combinations containing inhibitors of DNA polymerase (ara‐C, aphidicolin) or these inhibitors and hydroxyurea inhibited DNA repair in A2780/PAM and A549 cells. The inhibition of DNA repair by combinations of DNA‐damaging agents thloTEPA or cisplatln and DNA polymerase inhibitors is a novel observation based on the specificity of DNA damage assay with MAb F7–26. Combinations containing thioTEPA or cisplatin inhibited DNA repair in A549 but not in A2780/PAM cells. Drug combinations which inhibited DNA repair also significantly enhanced cell killing by L‐PAM. Cell survival in cultures treated with L‐PAM and efficient inhibitors was 2 to 3 orders of magnitude lower than was expected for additive survival. ThioTEPA and cisplatin play a dual role in combination chemotherapy by inducing DNA damage and inhibiting repair of DNA damage. FCM analysis of DNA repair may be a useful component of drug evaluation and could be applied to determine cell‐type specific sensitivity to inhibitors of DNA repair.
The interrelationship between the anti‐mitotic action of the somatostatin analog octreotide and that of cytostatic drugs and suramin
Authors: Lamberts S. W. J. , Van Koetsveld P. , Hofland L. J.
Published: February 2007

In the present study we used the model of cultured somatostatin‐receptor‐positive prolactin (PRL)‐secreting rat pituitary tumor cells to investigate the possible interrelationships between the anti‐mitotic and hormone‐release‐inhibitory effects of the somatostatin analog octreotide (SMS 201–955) and the effects of vincristine, methotrexate, fluo‐ uracil and suramin. Dose‐dependent inhibitory effects of all compounds were shown both on the DNA content and on PRL release. Octreotide and these cytostatic compounds were slightly additive in their anti‐proliferative and anti‐secretory effects. The somatostatin analog did not alter drug sensitivity in these tumor cells, however. The data obtained in this tumor model suggest that octreotide can be effectively administered in combination with cytostatic drugs and/or suramin.
Human papillomavirus infection and other risk factors for cervical neoplasia: A case‐control study
Authors: Morrison Ellen A. B. , Ho Gloria Y. F. , Vermund Sten H. , Goldberg Gary L. , Kadish Anna S. , Kelley Karen F. , Burk Robert D.
Published: February 2007

A case control design has been used to investigate risk factors associated with the development of cervical squamous intraepithelial lesions (SIL) in a population of urban women in which non‐affluent minority groups were heavily represented. Eighty‐five women with histologically confirmed SIL were compared to a control group of 70 cytologically normal women. HPV infection was determined using both Southern blot hybridization and polymerase chain reaction (PCR) amplification specific for HPV types 16, 18, and 33. When Southern blot was used to detect HPV, logistic regression analysis identified HPV infection (odds ratio (OR) = 17.9, 95% confidence interval (CI) = 6.2‐51.6) and low educational achievement (OR = 3.4, 95% CI = 1.2‐10.1) as major independent risk factors. When PCR was employed to detect HPV, the logistic regression model suggested that HPV infection (OR = 10.4, 95% CI = 3.6‐30.4) and Hispanic ethnicity (OR = 5.0, 95% CI = 1.2‐20.5) represented independent risk factors; low educational achievement and Black ethnicity were risk factors of borderline significance. PCR detection of simultaneous co‐infection with more than one HPV type was associated with a very high risk of SIL (OR for one type = 7.2, 95% CI = 2.4‐21.9; OR for >1 type = 43.0, 95% CI = 6.9‐266.6). Furthermore, increased viral load determined by either method carried an increased risk of disease. HPV infection with viral types previously reported to be related to neo‐plastic or dysplastic lesions carried the highest risk of SIL. The association of HPV detected by Southern blot and SIL in women < 35 years old had an OR of 10.1, whereas in women ≦35 the OR was 74.5 (p = 0.09 for homogeneity of ORs). We conclude that infection with HPV is the major risk factor for cervical SIL and suggest that targeted HPV screening of women over age 35 may represent an innovative strategy to detect women at high risk of cervical neoplasia.
Functional characterization of tumor‐infiltrating lymphocytes, lymph‐node lymphocytes and peripheral‐blood lymphocytes from patients with breast cancer
Authors: Rubbert Andrea , Manger Bernhard , Lang Norbert , Kalden Joachim R. , Platzer Erich
Published: February 2007

Mononuclear cell infiltration is frequently seen within human solid tumors. Effector cells within the tumor site usually fail to exhibit cytotoxic or natural killer activity when freshly isolated; however, they develop potent and sometimes specific cytotoxicity after expansion in IL2. Thus, local tumor environment may influence lymphocyte function. In our study, we disaggregated human breast‐cancer and lymph‐node tissue to obtain lymphocyte‐enriched cell fractions. Besides phenotypic analysis, functional characterization with regard to proliferation and cytokine production of tumor‐infiltrating lymphocytes (TIL), peripheral‐blood lymphocytes (PBL) and lymph‐node lymphocytes (LNL) was the aim of our study. TIL showed an enrichment of CD8+ cells with a corresponding decrease in CD4+ cells in comparison with PBL and LNL. In response to PHA, TIL showed decreased 3H‐thymidine uptake, but TIL were significantly stimulated by rhlL2. TIL produced low levels of ID, TNF and IFNγ upon mitogen/phorbol ester stimulation, while PBL produce high levels of TNF and IFNγ but low levels of IL2. Under the same experimental conditions, LNL produce high levels of TNF and IL2 but low levels of IFNγ. Mitogen‐mediated TNF secretion was increased after addition of autologous tumor cells in TIL and LNL, whereas IFNγ secretion tended to be suppressed. Our results indicate different patterns of activities of TIL, LNL and PBL from breast‐cancer patients.
A population‐based case‐control study of endometrial cancer in shanghai, china
Authors: Shu Xiao‐Ou , Brinton Louise A. , Zheng Wei , Gao Yu Tang , Fan Jin , Fraumeni Joseph F.
Published: February 2007

A case‐control study of 268 patients with endometrial cancer and 268 population controls was conducted during 1988–1990 in Shanghai, China, to evaluate etiologic factors in a population whose risk had not been substantially altered by the use of exogenous estrogens. In spite of this, the major risk factors resembled those found in other studies. The risk of endometrial cancer was significantly elevated among nulli‐gravidas (OR = 5.4, 95% CI = 2.0‐14.6) and decreased with number of pregnancies (p < 0.01). Late age at menopause was associated with increased risk, while early age at menarche was unrelated. Use of oral contraceptives for more than 2 years was associated with a reduction in endometrial cancer risk (OR = 0.4, 95% CI = 0.1‐1.2). while short‐term use of oral contraceptives and other methods of contraception were unrelated. Obesity was a strong predictor of risk, with women in the highest quartile of weight having 2.5 times the risk of those in the lowest quartile. In contrast to many other studies, cigarette smokers were at elevated risk (OR = 1.7. 95% CI = 0.9‐3.0). Risk was also elevated among women reporting a history of gall‐bladder disease, polycystic ovaries, menstrual symptoms, and non‐estrogen hormone use.
Pooled analysis of 3 european case‐control studies: I. Reproductive factors and risk of epithelial ovarian cancer
Authors: Negri Eva , Franceschi Silvia , Tzonou Anastasia , Booth Margaret , La Vecchia Carlo , Parazzini Fabio , Beral Valerie , Boyle Peter , Trichopoulos Dimitrios
Published: February 2007

The role of reproductive factors in the aetiology of epithelial ovarian cancer has been re‐assessed in a meta‐analysis of 3 hospital‐based case‐control studies conducted in Europe (i.e. Italy, the United Kingdom and Greece), providing a total dataset of 1,140 cases and 2,724 controls. Multiple logistic regression models were used to obtain relative risk (RR) estimates adjusted for study centre, age, socio‐cultural indicators, age at menopause, and oral contraceptive use. The risk decreased with increasing number of births and the trend in risk was significant (X = 7.50, p < 0.01). In comparison to nulliparous women, those who reported 4 or more births had a 40% reduction in risk of ovarian cancer (RR = 0.6, 95% confidence interval, CI: 0.4‐0.8). An RR estimate of 1.4 (95% CI: 1.1‐1.7) was found, overall, for age of 35 or more at first birth compared to age of 25 or less at first birth. In each stratum and overall, nulliparous women did not appear to be at increased risk compared to those who delayed birth of their first child until age 35 or more. In each study, as well as in the overall dataset, an inverse association between number of abortions and ovarian cancer risk emerged. Overall, the inverse relationship was highly significant, RR estimates for 1 and 2 or more abortions, as compared to none, being 0.9 (95% CI: 0.8 and 1.1) and 0.7 (95% CI: 0.60.9) respectively. The effects of parity, age at first birth and number of abortions emerged consistently in various strata of study centre and age.
Derivatives of butyric acid as potential anti‐neoplastic agents
Authors: Rephaeli Ada , Rabizadeh Ester , Aviram Adina , Shaklai Mati , Ruse Margaretta , Nudelman Abraham
Published: February 2007

A novel derivative of butyric acid, pivalyloxymethyl butyrate (AN‐9) has been shown, in vitro, to: (a) induce cytodifferentiation and inhibit the proliferation of leukemic cells; (b) inhibit the growth and formation of Lewis lung carcinoma colonies in semi‐solid agar. AN‐9 affect cells at about 10‐fold lower concentration and at a faster rate than does butyric acid. The pivalyloxymethyl esters of propionic, isobutyric and valeric acids do not elicit effects similar to those of AN‐9, while the isobutyryloxymethyl butyrate does, which strongly suggests that the activity of AN‐9 stems from intracellular metabolic degradation of the pro‐drug to butyric acid. In vivo, AN‐9, increased the survival of mice in Lewis lung carcinoma primary cancer model and significantly decreased the number of lung lesions of the animals inoculated with highly meta‐static cells, but did not affect their life span. Acute LD50, studies have shown that AN‐9 possesses low toxicity. These results suggest that AN‐9 is a potential anti‐neoplastic agent ar well as a tool for investigation of the differentiation induction mechanism.
Epidermal growth factor reduces resistance to doxorubicin
Authors: Kwok Tim T. , Sutherland Robert M.
Published: February 2007

Epidermal growth factor (EGF) increased the sensitivity to doxorubicin (DOX) of a human squamous carcinoma cell line, A431. The relative enhancement of sensitivity by EGF was greater in 2 DOX‐resistant sublines, A431/A5 and A431/A10, established by growing cells from surviving colonies after treatment of A43I cells with DOX. A greater number of EGF receptors (both high‐ and low‐affinity binding sites) was found for resistant A431/A5 and A431/A10 cells than for parental cells. The enhanced drug responsiveness is not directly related to EGF effects on growth, as growth inhibition by EGF appears to be similar among the 3 sublines.
Induction of mammary adenocarcinomas in metallothionein promoter‐human growth hormone transgenic mice
Authors: Törnell Jan , Rymo Lars , Isaksson Olle G. P.
Published: February 2007

To develop transgenic mice, a mouse metallothionein promoter–human growth hormone (Mt‐hGH) gene fragment was injected into the pronucleus of C57BI × DBN/2J F2 one‐cell embryos. Six founder animals grew larger (1.3‐2.2 times) than littermate controls and had higher levels of hGH in plasma (4.6‐279 mU/I). At 27‐43 weeks of age, 3 of the 4 female transgenic founders developed malignant papillary adenocarcinomas of mammary origin. One of the male trantgenic founders was successfully mated and 2 of 3 female transgenic offspring developed mammary tumors. Forty‐two female mice with the same genetic background as the transgenic animals and older than 43 weeks served as controls. No palpable tumor was found in this group. Five of the control animals were killed and examined histologically, revealing only normal mammary tissue. Earlier studies have shown that GH is important for growth and development of the mammary gland. Our study suggests that markedly elevated endogenous levels of GH cause mammary carcinoma in a specific strain of transgenic mice. The present animal model might be useful for studying molecular mechanisms that are involved in the development of hormonally induced mammary tumors.
Characterization of the new bladder cancer cell line HOK‐I: Expression of transitional, squamous and glandular differentiation patterns
Authors: Offner Felix Albert , Ott German , Povey Susan , Knuechel Ruth , Preisler Verena , Fuezesi Laszlo , Klosterhalfen Bemd , Ruebben Herbert , Hofstaedter Ferdinand , Kirkpatrick Charles James
Published: February 2007

The new continuous cell line HOK‐I derived from a grade‐III transitional‐cell bladder carcinoma with foci of squamous and glandular differentiation was shown to retain this pheno‐typical heterogeneity for more than 45 passages in vitro. Electron microscopy revealed transitional as well as a considerable proportion of squamous carcinoma and adenocarcinoma cells. PAS‐positive mucus was detected in numerous cells. These features were principally maintained when grown as multicellular spheroids and in nude mice. More pronounced signs of differentiation (i.e., expression of cytokeratins 10 and 11, formation of glandular structures) were found in xenograft tumours. Independently, cytokeratins 13, 18 and 19 were detected in vitro and in vivo, reflecting the urothelial origin. The line forms distinct colonies in soft agar, expresses Lewis‐x and Lewis‐y antigens and reacts with monoclonal antibodies (MAbs) against CEA, β‐HCG and URO‐5. Cytogenetic analysis revealed several related clones with a rearrangement at chromosome I and loss of one X chromosome as common karyotypic changes in all clones. DNA content, as quantified by image analysis, showed a DNA stemline close to 2c. The new cell line HOK‐I can be used as an in vitro model to study the mechanisms of heterogeneous differentiation patterns in bladder cancer.
Nad(P)H:Quinone oxidoreductase (DT‐Diaphorase) activity and mRNA content in normal and neoplastic mouse lung epithelia
Authors: Thaete Larty G. , Siegel David , Malkinson Alvin M. , Forrest Gerald L. , Ross David
Published: February 2007

DT‐diaphorase (DTD) is a flavoprotein which catalyzes obligate two‐electron reduction of a diverse group of substrates. We have reported previously that non‐tumorigenic mouse lung alveolar type‐II pneumocytes have high DTD activity, while cell lines derived from lung tumors do not. In contrast, other investigators, using human lung tissue, reported increased DTD activity in tumors compared with normal tissue. We therefore investigated DTD associated with mouse lung neoplasia in vivo as well as in vitro. Pulmonary tumors had far less DTD activity compared with normal mouse lung. Correspondingly, a tumorigenic mouse lung cell line which arose as a spontaneous transformant of a normal cell line had very low DTD activity compared with non‐tumorigenic lung cells. DTD‐specific mRNA levels were also much higher in normal cell lines than in neoplastic ones. DTD was localized histo‐chemically in type‐ll pneumocytes in situ, but was not observed by this technique in normal bronchiolar epithelia or in tumor cells. These data show that, unlike what has been observed in human lung cancer, a marked decrease in DTD content and activity accompanied mouse lung tumorigenesis in vivo and neoplastic transformation in vitro.
Incidence and prognostic significance of vascular invasion in 529 gastric‐cancer patients
Authors: Gabbert H. E. , Meier S. , Gerharz C. D. , Hommel G.
Published: February 2007

The prognostic significance of blood‐vessel invasion (BVI) and lymphatic‐vessel invasion (LVI) was evaluated in a retrospective series of 529 gastric‐cancer patients who underwent potentially curative surgery. Evidence for BVI was found in 127 patients (24.0%), while LVI was demonstrated in 245 patients (46.3%). The incidence of both BVI and LVI run parallel to increasing tumor size and tumor stage as well as to decreasing grade of tumor differentiation. The incidence of BVI and LVI was higher in lymph‐node‐positive patients than in lymph‐node‐negative patients. The 5‐year‐survival rate was significantly lower (p < 0.0001) in patients with BVI or LVI (14.9% and 22.2% respectively) than in patients without BVI or LVI (54.7% and 64.1% respectively). Both BVI and LVI were shown to be prognostic factors independent of tumor stage, grade of differentiation or lymph‐node involvement. In a multivariate Cox regression analysis, the gain of prognostic information provided by the evidence of BVI and LVI was shown to exceed the information obtained by the combination of tumor stage, grade of differentiation and lymph‐node involvement. A careful search for vascular invasion in gastric cancer may therefore provide additional useful information for identifying patients who are at high risk and who may be candidates for adjuvant therapy in future clinical trials.
Leanness and lung‐cancer risk
Authors: Knekt Paul , Heliövaara Markku , Rissanen Aila , Aromaa Arpo , Seppänen Ritva , Teppo Lyly , Pukkala Eero
Published: February 2007

Body mass index (weight/height2) was studied for its prediction of lung cancer in Finnish men examined by the Social Insurance Institution's Mobile Clinic and followed up by the Finnish Cancer Registry. Among 25,994 participants aged 20 to 75 years and free from cancer at the start of the study, 504 lung‐cancer cases were diagnosed during a maximum follow‐up of 19 years. There was a significant inverse gradient between body mass index and the incidence of lung cancer. This association was not due to confounding by age, smoking, social class, self‐perceived general health, history of stress symptoms, chronic cough or chest X‐ray findings, although these factors correlated with body mass index and were also significantly predictive of lung cancer. After adjustment for these factors, the relative risks of lung cancer were 1.0, 1.4, 1.5 and 1.8 (pfor trend < 0.001) from the highest to the lowest quartiles of body mass index. The association was noted among current smokers, but it was most obvious among men who had never smoked, the relative risk of lung cancer between the lowest and highest quartiles of body mass index being 7.6 (95% confidence interval = 2.0 to 29.4). The inverse gradient persisted throughout the entire follow‐up period, and was most distinct after the first 10 years of follow‐up, the relative risks for the quartiles of body mass index being 1.0, 1.9, 2.3 and 2.6 (p< 0,001). The present study shows that the thinner the man, the more liable he is to develop lung cancer. Leanness, or some factor or cluster of factors closely correlated to it, may play an aetiological role in lung cancer.
The biological effects of macrophage‐colony‐stimulating factor induced by progestin on growth and differentiation of endometrial adenocarcinoma cells
Authors: Kimura Tadashi , Azuma Chihiro , Saji Fumitaka , Tokugawa Yoshihio , Takemura Masahiko , Miki Mariko , Ono Masaaki , Tanizawa Osamu
Published: February 2007

Progestins have biological effects of regression and differentiation on human endometrial adenocarcinoma. We investigated the effects of progestin on the induction of macrophage‐colony‐stimulating factor (M‐CSF) and its receptor messenger RNAs in the human endometrial adenocarcinoma cell line Ishikawa which has receptors for both estrogen and progesterone. Poly(A)+RNA extracted from lshikawa cells cultured with or without synthetic progestin R5020 was subjected to Northern blot hybridization using M‐CSF and c‐fms cDNA probes. The expression of M‐CSF mRNA in Ishikawa cells increased about 2.3 times following treatment with R5020 at 10−7 M. Induction of M‐CSF mRNA by RS020 was antagonized by anti‐progestin RU486 in a dose‐dependent manner. However, c‐fms mRNA, coding the M‐CSF receptor, was expressed constitutively in Ishikawa cells and its expression was not affected by hormonal treatment. We further examined the biological effects of M‐CSF on endometrial cancer cells. Colony formation of Ishikawa cells in soft agar, which represents anchorage‐independent cell growth, was inhibited by M‐CSF treatment. On the other hand, accumulation of glycogen granules in cytoplasm detected by periodicacid‐Schiff staining was observed in lshikawa cells treated with M‐CSF. These results indicate that M‐CSF, whose gene expression was enhanced by progestin, suppressed growth and induced differentiation of endometrial adenocarcinoma cells. These effects of M‐CSF on endometrial cancer cells are similar to those of progestins, so the effects of progestins on these cells are, at least in part, probably mediated by M‐CSF in an autocrine or paracrine manner.
Radiosensitivity of small‐cell lung cancer xenografts compared with activity of c‐myc, N‐myc, L‐myc, c‐raf‐1 and K‐ras proto‐oncogenes
Authors: Rygaard Kåre , Slebos Robert J. C. , Spang‐Thomsen Mogens
Published: February 2007

Oncogenes of the myc family c‐raf‐I and K‐ras have been reported to modulate radiosensitivity. We examined the possible relationship between in vivo radiosensitivity to single‐dose irradiation with 3‐10 Gy, and activity of these proto‐oncogenes in 2 sets of small‐cell lung cancer (SCLC) xenografts, the CPH and the GLC series. CPH‐54A and CPH‐54B are in vitro‐derived subclones of a SCLC cell line, while the GLC tumours were established as cell lines from a patient during longitudinal follow‐up. Both tumours were later transferred into nude mice. CPH‐54A was more sensitive to single‐dose irradiation than CPH‐54B, while, with respect to the 3 GLC tumours examined, GLC‐16 was most sensitive, followed by GLC‐14 and GLC‐19. The CPH tumours expressed similar amounts of c‐myc and c‐raf‐I mRNA, and neither expressed N‐myc or L‐myc. GLC‐14 expressed N‐myc and c‐raf‐I mRNA but no c‐myc. GLC‐16 and GLC‐19 expressed identical amounts of c‐raf‐I and high levels of c‐myc mRNA, but neither expressed N‐myc or L‐myc. None of the tumours was mutated at codon 12 of K‐ras. Our results show that SCLC xenografts with different radiosensitivity may express identical amounts of some of the proto‐oncogenes reported to modulate radiosensitivity. Thus, factors other than activation of the examined proto‐oncogenes must be involved in causing the differences in radiosensitivity found in the SCLC xenografts. Possible long‐term effects of irradiation on proto‐oncogene expression was examined in xenografts of GLC‐16, following regrowth after single‐dose irradiation. No long‐term difference in expression of c‐raf‐I or c‐myc mRNA was detected between control tumours and tumours irradiated with 5 or 10 Gy.
Incidence of histologic types of uterine sarcoma in relation to menstrual and reproductive history
Authors: Schwartz Stephen M. , Weiss Noel S. , Daling Janet R. , Newcomb Polly A. , Liff Jonathan M. , Gammon Marilee D. , Douglas Thompson W. , Watt Janice D. , Armstrong Bruce K. , Weyer Peter , Isaacson Peter , Ek Marit
Published: February 2007

To determine whether the occurrence of one or more histologic types of uterine sarcoma is related to events in a woman's reproductive life, a population‐based case‐control study was conducted. One‐hundred sixty‐seven women newly diagnosed with uterine sarcoma among residents of 6 geographic regions were compared to 208 women selected at random from the same populations with regard to histories of menstruation, pregnancy and childbearing, and breast feeding, as reported during a telephone interview. Compared to women whose menstrual periods began at age 13, women whose menses began earlier were at increased risk of leiomyosarcoma (OR = 2.0, 95% CI 0.9, 4.3); other histologic types were less strongly associated with early age at menarche. Women with leiomyosarcoma and endometrial stromal sarcoma, but not malignant mixed Müllerian tumors, tended to have ceased menstruating 2‐3 years later than controls. None of the histologic types was clearly related to parity or to age at first live birth, but each was inversely related to age at last live birth. Associations were observed between leiomyosarcoma and histories of an induced abortion (OR = 4.2, 95% CI 1.2, 14.2) and of breast feeding after a live birth (OR = 0.5, 95% CI 0.3, 1.0); these relationships were not observed for other morphologic variants. These results suggest possible similarities and differences in menstrual and reproductive risk factors among histologic types of uterine sarcoma, and between these malignancies and the more common breast, endometrial and ovarian carcinomas.
Re‐transformation of non‐transformed hybrids between c‐myc‐activating mouse plasmacytoma cells and normal fibroblasts by transfection with activated c‐Ha‐ras but not c‐myc
Authors: Satoh Chiharu , Oikawa Tsuneyuki , Kondoh Nobuo , Kuzumaki Noboru
Published: February 2007

In a mouse plasmacytoma S194, c‐myc oncogene is rearranged with Ig gene by chromosomal translocation and consequently activated. We previously reported that transformation of phenotype and expression of rearranged c‐myc were repressed in independently isolated hybrid clones, I‐1 and IV‐10, between S194 and normal fibroblasts. In order to investigate the relationship between transformation of phenotype and oncogene expression, transcriptionally enhanced c‐myc or activated c‐Ha‐ras was transfected into I‐1 or IV‐101, a subclone IV‐10. Transfectants expressing high levels of c‐myc were found to retain the non‐transformed phenotypes. On the other hand, transfectants expressing activated c‐Ha‐ras showed the transformed phenotypes. These results suggest that enhanced expression of c‐myc is not sufficient for re‐transformation of the non‐transformed hybrid clones between c‐myc‐activating plasmacytoma cells and normal fibroblasts, but expression of activated c‐Ha‐ras could diminish or overcome the tumor‐suppressive activity of normal fibroblasts.
Immunomodulation in an apparently non‐immunogenic murine tumor
Authors: Bursuker Isia , Petty Barbara A. , Neddermann Kim M. , Keller Lynn S.
Published: February 2007

Madison lung carcinoma (M 109), a murine tumor of spontaneous origin, appears to be non‐immunogenic, according to commonly employed tests for tumor immunogenicity. However, C.parvum‐induced immunopotentiation during the growth of M109 tumor results in post‐excision anti‐tumor immunity to M109 tumor implants. The C.parvum‐potentiated post‐excision immunity to M109 is tumor‐specific and T‐cell‐dependent. T cells from mice whose progressive M109 tumors have been excised are capable, on passive transfer, of inhibiting adoptive immunotherapy of T‐cell‐deficient recipients by spleen cells from mice immunized with an admixture of M109 cells and C.parvum. The data are interpreted as evidence supporting the hypothesis that the apparent lack of anti‐tumor immunity in this tumor model is not due to the absence of tumor‐associated antigens. We suggest that, instead, in this model the balance between the effector and suppressor arms of the immune response favors tumor‐induced immunosuppression, resulting in a magnitude of anti‐tumor immunity insufficient for detection by commonly employed tests for tumor immunogenicity. Our study shows that shifting the balance in favor of the effector arm by means of immunopotentiation results in a measurable immune response to an apparently non‐immunogenic tumor.
Macrophage infiltration and growth of sarcoma clones expressing different amounts of monocyte chemotactic protein/JE
Authors: Walter Sabine , Bottazzi Barbara , Govoni Deanna , Colotta Francesco , Mantovani Alberto
Published: February 2007

Tumor‐derived chemotactic factors (TDCF) have been identified and thought to play a role in the regulation of macrophage infiltration in neoplastic tissues. The present study was designed to assess the in vivo relevance of the TDCF molecularly identified as monocyte chemotactic protein/JE, by investigating murine sarcoma clones expressing diffevent levels of MCP/JE. The ID3 clone derived from the 677 RSV‐induced sarcoma expressed appreciable levels of MCP/JE mRNA and, concomitantly, chemotactic activity for mononuclear phagocytes. In contrast, the 5BII clone from the same tumor had undetectable levels of MCP/JE transcripts and little or no chemotactic activity. The chemotactic activity of ID3 cells was blocked by an appropriate specific antiserum. The in vitro growth rate of the 2 sarcoma lines was identical. Upon in vivo transplantation, the ID3 clone showed a substantially higher level of tumor‐associated macrophages (28.9%; range 21%‐34%) than the 5BII clone (16.6%; range 13%‐20%). 5BII‐induced tumors appeared earlier and grew faster than those induced by ID3. The difference in growth rate and in macrophage infiltration between ID3 and 5BII clones was also evident upon transplantation into nude mice. These results are consistent with the hypothesis that TDCF, identified as MCP/JE, is one important determinant of macrophage infiltration in tumors.
Human tumor spontaneous metastasis in immunosuppressed newborn rats. I. Characterization of the bioassay
Authors: Bailly Maryse , Bertrand Suzanne , Doré Jean‐François
Published: February 2007

We characterize a new model of spontaneous metastasis of human tumor cells using anti‐thymocyte serum (ATS) immunosuppressed newborn rats. We analyzed the intrinsic value of the bioassay of measurement of tumorigenicity and metastatic capacity using 17 human tumor cell lines, of which were 9 human malignant melanomas. Most of these cell lines revealed as tumorigenic and metastatic in lungs and/or lymph nodes 3 weeks after s.c. injection in the ventral flank of newborn rats, irrespective of their origin. All the melanoma cell lines that we injected were tumorigenic and 77% were metastatic, whereas the same cell lines grafted in nude mice showed no evidence of metastases after 6 weeks′ examination. We were not able to show any relationship between tumorigenicity in nude mice and the malignant behavior of these cells in ATS‐treated newborn rats. Likewise, neither chromosome abnormalities, nor anti‐genic marker expression were found to be related to tumor growth in nude mice or newborn rats. Two intrinsic parameters of the model were studied: number of cells injected vs. dose of ATS injected for one melanoma cell line; and role of the 3rd and 4th injections of ATS in the establishment and development of pulmonary metastases. Moreover, we show that s.c. injection in the ATS‐treated newborn rat may represent a suitable method for studying melanoma cell tumor growth and spontaneous dissemination.
Effects of the ras‐related rap2 protein on cellular proliferation
Authors: Jimenez Benilde , Pizon Véronique , Lerosey Isabelle , Béranger Florence , Tavitian Armand , De Gunzburg Jean
Published: February 2007

Ras oncogenes encode 21‐kDa (p21s) GTP binding proteins that are capable of transforming immortalized cells in culture. The ras‐related rap 1A/Krev‐1/smgp21A protein, that exhibits a similar structural organization and contains the same effector domain as ras proteins, antagonizes ras‐transformation. In order to investigate whether the closely related (61% identical) rap2 protein had similar capacities, the corresponding cDNA was inserted into constitutive as well as inducible mammalian expression vectors. Neither the wild‐type, nor an „activated”︁ mutant carrying a glycine‐to‐valine substitution at position 12, had any transforming activity. Several independent lines of evidence demonstrate that the rap2 protein exhibits neither growth‐promoting nor growth‐inhibitory effects, and that its over‐expression does not interfere with ras‐induced transformation. Thus, in spite of their great similarities, the rap 1A/Krev‐1/smgp21A and rap2 proteins have distinct physiological properties.
Univariate and multivariate analyses of the relationship between adenocarcinoma and solitary and multiple adenomas in colorectal adenoma patients
Authors: Gatteschi B. , Costantini M. , Bruzzi P. , Merlo F. , Torcoli R. , Nicolo G.
Published: February 2007

In 584 consecutive patients with no previous history of cancer or polypectomy, 769 adenomas were excised endoscopically and classified retrospectively according to the following parameters: macroscopic growth pattern, size, histological type, grade of dysplasia, anatomical site, presence of adenocarcinoma (ADK), number of adenomas and sex and age of the patient. A multivariate logistic analysis confirmed that size and histological type are the 2 most important predictors of ADK, both solitary and in multiple adenomas. Adenomas located in the sigmoid portion and in the rectum have an increased probability of ADK, independent of size and histology. Multiple polyps, when compared to solitary polyps, were more frequent in males (p < 0.01) and were more often larger than 2 cm. Significant similarities in histology, morphology and degree of dysplasia were observed among multiple adenomas from the same patient.
Breast cancer screening and cost‐effectiveness; Policy alternatives, quality of life considerations and the possible impact of uncertain factors
Authors: de Koning Harry J. , Martin van Ineveld B. , van Oortmarssen Gerrit J. , de Haes J. C. J. M. , Collette Hubertine J. A. , Hendriks Jan H. C. L. , van der Maas Paul J.
Published: February 2007

Mammographic screening for women aged 50‐70 is effective in reducing breast cancer mortality, but the impact on quality of life and the attainable mortality reduction remain t o be discussed. The consequences of expanding screening programmes to include women in other age groups are uncertain. We have predicted the effects and costs for 5 popular screening variants, differing in age group and screening interval, on the basis of our analysis of the Dutch screening trials and of the reported mortality reductions in other trials. We have also investigated the influence of a large number of uncertain factors. Screening for women aged 50 and over with a 2‐ or 3‐year interval is very cost‐effective and will result in reductions of respectively 16% or 10% in breast cancer mortality in a real population. Variation of most variables keeps the cost‐effectiveness (CE) ratio limited to the range of US $3,000 to 5,000 per life‐year gained. A 2‐ to 3‐fold change in CE ratio would only occur if the extreme estimates of mortality reduction in the Swedish screening trials were applied. The impact on quality of life (QoL) is limited: for the 2‐yearly screening policy for women aged 50‐70, the cost per Quality‐Adjusted Life‐Year (QALY) gained is 4,050, whereas the cost per life‐year gained is US $3,825. The CE ratio for 2‐yearly screening of women aged 40‐70 is 5,400, but the additional cost per additional life‐year gained is US $35,000. It would be preferable by far to extend the screening programme to women over the age of 70 or to shorten the screening interval for women aged 50‐70. Screening performances, the demand for mammograms outside screening and the possibility of a survival improvement irrespective of screening have a strong impact on QoL and CE.
An analysis of T‐cell‐receptor variable‐region genes in tumor‐infiltrating lymphocytes within malignant tumors
Authors: Nitta Taizo , Sato Kiyoshi , Okumura Ko , Steinman Lawrence
Published: February 2007

Expression of T‐cell‐receptor (TCR) Vα and Vβ genes in tumor‐infiltrating lymphocytes (TILs) of 29 patients, 15 melanomas and 14 malignant glial tumors (glioma and medulloblastoma), was investigated. The identification and propagation of T cells with anti‐tumor reactivity is crucial to the understanding of the human immune response to tumors, which may possibly be useful in the successful implementation of adoptive immunotherapy against cancer. Despite clinical evidence that a more favorable prognosis is associated with the degree of lymphocyte infiltration within a tumor, the actual role of TIL remains uncertain. In order to address this question, we examined the diversity of the RNA transcripts of TCR genes in TlLs within 29 specimens obtained at surgery. Using the polymerase‐chain‐reaction (PCR) method and primers for 18 different human TCR Vα and 21 Vβ families to analyze TCR V‐(D)‐J‐C gene rearrangements, we detected a limited expression of TCR variable‐region Vα genes of TILs. TCR Vβ gene rearrangements were more diverse than those for Vα. In addition to restricted usage of TCR Vα genes, preferential expression of Vα 7 genes was found in 20 out of 29 cases (69%). Predominant usage of Vα 7 genes was more remarkable in melanoma TlLs (14/15) than in glial tumor TILs (6/14). These findings were also confirmed by Southern blot analysis with oligonucleotide probes for the constant (C) region of TCR α and β chains. We suspect that some specific T‐cell populations may be directed to antigenic determinants in melanoma cells.
Sero‐epidemiological investigations on human herpesvirus 6 (HHV‐6) infections using a newly developed early antigen assay
Authors: Iyengar Sujatha , Levine Paul H. , Ablashi Dharam , Neequaye Janet , Pearson Gary R.
Published: February 2007

Monoclonal antibodies (MAbs) were developed against immunodominant HHV‐6 (GS isolate) late and early proteins. The major late protein was identified as a probable glycoprotein with a molecular weight of approximately 110 kDa (gp 110). Immunoblotting of the early antigen yielded proteins of 41 and 38 kDa (p41/38). The MAb to the early protein reacted with cells infected with 14 different HHV‐6 isolates. In contrast, the MAb against the late protein reacted with only 10 of these isolates, indicating that there was strain variation in this glycoprotein. The percentage of antibody‐positive sera reactive with gp110 in the ELISA ranged from 56% to 96% among the different serum donor categories. In contrast, only 10‐30% of the sera were positive for antibodies to p41/38 with the exception of sera from patients with African Burkitt's lymphoma (ABL) and Hodgkin's disease (HD). These antibody patterns denote the presence of active HHV‐6 replication in patients with ABL and HD.
Efficacy and selectivity of monoclonal‐antibody‐targeted drugs and free methotrexate in fluorescence‐labelled mixed tumour‐cell monolayer cultures and multicellular spheroids
Authors: Embleton M. J. , Charleston Angela , Affleck Karen
Published: February 2007

Free methotrexate (MTX) and 2 monoclonal antibody (MAb)‐MTX conjugates were tested against mixed human tumour‐cell cultures, in which 2 cell lines of differing antigenicity or drug sensitivity, pre‐labelled with fluorescent dyes, were added together in microtitre wells. Conjugates were selectively cytotoxic for cells bearing high concentrations of the relevant antigen, and MTX was preferentially cytotoxic for wild‐type cells rather than MTX‐resistant variants when tested on separate cultures. In mixed cultures these selectivities were substantially retained, although there was a varying tendency towards intermediate cytotoxicity for each cell line of the pair. MTX was cytotoxic for cell line 791T grown as multicellular spheroids, but MAb‐MTX conjugate and a MAb‐RTA immunotoxin showed little cytotoxicity against spheroids at the highest concentrations tested, although they were highly effective against monolayer cells. Mixed spheroids could be formed efficiently from most cell lines, although in some cases cell distribution was non‐random. In mixed spheroids prepared between wild‐type and MTX‐resistant 791T variants, relative MTX sensitivities conformed broadly to those seen in separate monolayer cultures. Fluorescence‐labelling was a reliable method for determining cell behaviour under the above conditions. We conclude that selectivity of therapeutic agents in mixed cultures was partially, but not completely, impaired compared to that observed in separate cultures, and (b) that low Mr drugs are effective against 3‐dimensional tumour‐cell structures but antibody‐targeted conjugates are not.
Kinetics of biochemical, electrophysiological and morphological events (including lysosomal disorder) during the course of suramin‐induced differentiation of the human colon‐cancer cell clone HT29‐D4
Authors: Baghdiguian Stephen , Verrier Bernard , Marvaldi Jacques , Fantini Jacques
Published: February 2007

Suramin, a polysulfonated naphtylurea, has been shown to bind to a wide variety of tumor growth factors, and to exhibit anti‐proliferative effects on several cell lines. We have followed the suramin‐induced (100 μg/ml) evolution of morphological, biochemical and electrophysiological changes in HT29‐D4 human colonic adenocarcinoma cell clone as a function of culture time. After 5 days of culture in the presence of the drug the cells were polarized and exhibited apical brush border and tight junctions. The polarization process of carcino‐embryonic antigen (CEA) in the apical membrane domain was achieved after 8 days of treatment, while the correct localization of HLA class‐I molecules in the basolateral membrane domain occurred after 14 days of culture in the presence of suramin. Spontaneous potential difference (PD) and transepithelial resistance (Rt) were recorded from the 9th day of treatment and reached maximum values at day 15 (PD = 3 mV; RT = 450 Ωcm2), giving evidence that the differentiation process triggered by suramin concerned virtually all cells in the monolayer. Untreated cells were consistently found to be electrically inactive. Finally, from day 10 of suramin treatment, the lysosomal system was perturbed including accumulation of large autophagic vacuoles and, later, typical lamellar inclusion bodies. These structures were never seen when cells were induced to differentiate in suramin‐containing serum‐free medium. Moreover, similar perturbations of the lysosomal system could be obtained by adding BSA in the suramin‐containing defined medium, suggesting that the lysosomal storage disorder occurring upon suramin treatment was due to endocytosis of suramin‐BSA complexes. We conclude that lysosomal impairment due to the presence of BSA in the culture medium did not prevent HT29‐D4 cells from differentiating and that it was not an early event which could be involved in the mechanism of action of suramin. However, this perturbation might account for some of the toxic effects occurring during chronic suramin treatment in humans.