IgE骨髓瘤1例报告及文献复习

目的 报告1例IgE骨髓瘤病例并将其临床特征与文献进行比较。方法 对1例骨髓瘤患者的血清尿液采用醋酸纤维膜电泳、免疫固定电泳和免疫球蛋白定量等方法鉴定M蛋白,采用直接和间接免疫酶标技术检测瘤组织IgE及轻链的表达。结果 醋酸纤维膜电泳显示在快γ区有一单克隆小峰,占18％。免疫固定电泳结果显示一单克隆区带,与λ抗血清反应,与κ、IgG、IgA、IgM、IgD)抗血清不反应。免疫球蛋白定量结果显示IgG 21.6g/L,IgA 1.2g/L,IgM 2.64g/L,κ 7.49 g/L,λ16.0g/L,κ/λ0.47。免疫组织化学染色结果表明瘤组织IgE及λ轻链,不表达κ轻链。结论 本文所报告的病例为国内首例IgE多发性骨髓瘤。     

Antiproliferative effects of natural interferon beta alone and in combination with natural interferon gamma on human breast carcinomas in nude mice

Summary Nude mice bearing bilateral xenografts of human breast carcinoma cells (MCF-7 and BT20) were treated with 2 or 4 5-day cycles of intralesional (i.l.) injections of human natural interferon beta (nIFN-) alone or in combination with human natural interferon gamma (nIFN-). The injections were administered to only 1 of the 2 tumors in each animal, thus making it possible to assess at the same time local therapeutic effects in the injected tumors and systemic effects in the contralateral ones. When n-IFN- was used as a single agent only mild local antitumor effects and virtually no systemic effects were observed. In contrast, the combined administration of nIFN-/nIFN- produced marked antiproliferative effects, presumably as a result of the synergistic action of type I and type II IFNs. These effects ranged from complete regression documented histologically in 2 MCF-7 tumors to varying degrees of growth inhibition with persistence of residual microscopic or grossly detectable tumor. Local effects were more pronounced than systemic effects. The therapeutic efficacy of nIFN- proved to be greater than that of recombinant interferon beta (rIFN-). In MCF-7 tumors nIFN- appeared to be less effective than nIFN-, whereas the opposite was true for BT 20 tumors.     

Granulocyte colony-stimulating factor-producing malignant pleural mesothelioma with the expression of other cytokines

We report a 65-year-old man with malignant pleural mesothelioma that produced granulocyte colony-stimulating factor (G-CSF) and other cytokines. At the first presentation, the WBC count was 8600 cells/µl and C-reactive protein (CRP) was 0.6mg/dl. Seventeen months later, the WBC count had increased to 53600 cells/µl (93% neutrophils) and CRP to 27.1mg/dl. The serum concentration of G-CSF had increased to 36.0pg/dl (normal range, <5.0pg/dl), interleukin 1 (IL-1) to 46.0pg/dl (normal range, <10pg/dl), and IL-6 to 197pg/dl (normal range, <4.0pg/dl). The patient died 19 months after the first presentation, and 6 weeks after sudden leukocytosis. At autopsy, a diagnosis of malignant pleural mesothelioma was made. The tumor cells were positive for anti-human G-CSF, granulocyte-macrophage colony-stimulating factor, IL-1, and IL-6 antibodies. Malignant mesothelioma may produce G-CSF and other cytokines. Mesothelial cells may have the potential to produce G-CSF and other cytokines in the progress of malignant formation, and this may be a factor influencing the poor prognosis.     

Neuroblastoma and parental occupation

Objectives: We evaluated parental occupation and the risk of neuroblastoma using data from a large case–control study conducted by the Children's Cancer Group and the Pediatric Oncology Group.Methods: We compared the distribution of 73 paternal and 57 maternal occupational groups among 504 newly diagnosed cases of neuroblastoma and individually matched controls obtained by telephone random digit dialing in the United States and Canada.Results: An increased risk of neuroblastoma was found for fathers employed as broadcast, telephone and dispatch operators (odds ratio [OR]=6.1; 95% confidence interval [CI]=0.7–50.9), electrical power installers and power plant operators (OR=2.7; CI=0.9–8.1), landscapers and groundskeepers (OR=2.3; CI=1.0–5.2), and painters (OR=2.1; CI=0.9–4.8). Elevated odds ratios were found for mothers employed as farmers and farm workers (OR=2.2; CI=0.6–8.8), florists and garden store workers (OR=2.4; CI=0.6–9.9), hairdressers and barbers (OR=2.8; CI=1.2–6.3), electric power installers and power plant operators, and sailors, fishers, and railroad workers. No increase in risk was found for other paternal occupations previously associated, including electricians, electrical equipment assemblers and repairers (OR=1.1; CI=0.6–2.0), or welders (OR=0.5; CI=0.1–1.6).Conclusion: The study reinforced some prior evidence of increased risks in electrical, farming and gardening, and painting occupations, but failed to confirm other previously reported associations. Further analyses of exposure to electromagnetic fields, metals, solvents, and pesticides are currently under way.     

Effect of Dose and Infusion Time on the Delivery of p-boronophenylalanine for Neutron Capture Therapy

Clinical trials of boron neutron capture therapy (BNCT) for glioblastoma multiforme are currently in progress using p-boronophenylalanine (BPA) as the 10B delivery agent. Enhancement of tumor boron uptake and/or the tumor-to-blood (T:B) boron concentration ratio would have the potential of significantly improving the therapeutic gain of BNCT. The effects of total dose, infusion time, and route of administration of BPA on tumor and blood boron concentrations were studied in rats bearing the 9L gliosarcoma. Increasing the total dose of BPA from 250 to 1000mg/kg, administered intravenously over a 2-h infusion period, resulted in an increase in tumor boron concentration from 30 to 70µg 10B/g, with a constant T:B boron concentration ratio of about 3.7:1. Similarly, extension of the infusion time from 2 to 6h, at a constant dose-rate of 125mg BPA/kg/h, resulted in an increase in tumor boron concentration from 30 to 80µg 10B/g, while, again, maintaining a constant T:B ratio of about 3.7:1. In contrast, intracarotid infusion of BPA for 1h at a dose rate of 125mg BPA/kg resulted in an increase in the tumor boron concentration from 26 to 38µg 10B/g with a corresponding increase in the T:B ratio from 3.5:1 to 5.0:1. The effects of these results on the therapeutic gain potentially achievable with BNCT are discussed.     

Differential effects of chemotherapeutic agents on the Bcl‐2/Bax apoptosis pathway in human breast cancer cell line MCF‐7

The present study explored the effects of three commonly used chemotherapeutic agents on the Bcl2/Bax apoptosis pathway and the interaction of these chemotherapeutic drugs with the estradiolmediated regulation of this pathway. Our results showed that: (1) Treatment of MCF7 cells with Adriamycin resulted in time and concentrationdependent decreases in Bcl2 and increases in Bax mRNA and protein levels. (2) Camptothecin elicited similar trends on Bcl2 and Bax as Adriamycin, while etoposide, at 50–100 fold (1–5M) the effective concentration of Adriamycin and camptothecin, only resulted in an increase in Bax mRNA levels. (3) Adriamycin and camptothecin, but not etoposide, were effective in suppressing estradiolstimulated increases in Bcl2 mRNA levels. Our study provides evidence that the Bcl2/Bax apoptosis pathway may be differentially regulated by chemotherapeutic agents. In addition, interaction between these agents and estradiol on the Bcl2/Bax apoptosis pathway may also exist.     

Up-regulation of γ-glutamylcysteine synthetase activity in melphalan-resistant human multiple myeloma cells expressing increased glutathione levels

Levels of intracellular glutathione (GSH) and the GSH-related enzymes -glutamylcysteine synthetase (-GCS) and -glutamyltranspeptidase (-GT) were measured in the melphalan-resistant human multiple myeloma cell line 8226/LR-5 and were compared to those measured in the drug-sensitive 8226/S and doxorubicin-resistant 8226/Dox40 cell lines. Both GSH and -GCS activity, the rate-limiting step in the de novo synthesis of GSH, were elevated by a factor of approximately 2 in the melphalanresistant 8226/LR-5 cells relative to the other two lines. -GT activity was not elevated significantly in the /LR-5 cells. Northern analysis with a probe specific for the large subunit of human liver -GCS identified two bands (3.2 and 4.0 kb), both of which were increased by a factor of 2–3 in the 8226/LR-5 line. Levels of -GCS mRNA expression were comparable in the /S and /Dox40 cell lines. Levels of -GT mRNA were similar in the /S and /LR-5 lines but were reduced in the /Dox40 cells. These data suggest that the increased GSH levels associated with resistance to melphalan in the 8226/LR-5 myeloma cells is attributable to up-regulation of -GCS. This observation is consistent with recent demonstrations of up-regulation of -GCS in melphalan-resistant prostate carcinoma cells and cisplatinum-resistant ovarian carcinoma cells, suggesting that increased expression of -GCS may be an important mediator of GSH-associated resistance mechanisms.     

Regulation of BAX and BCL‐2 expression in breast cancer cells by chemotherapy

Optimizing chemotherapeutic drug delivery strategies relies, in part, on identification of the most clinically effective sequence, dose, and duration of drug exposure. The combination of dose intensive etoposide (VP16) followed by cyclophosphamide has clinical efficacy in the treatment of advanced breast cancer. However, molecular mechanisms that underlie the effectiveness of this combination of chemotherapeutic agents have not been investigated. In this study we investigated regulation of BAX and BCL2 expression by VP16 and cyclophosphamide as a potential mechanism for the induction of breast cancer cell death induced by this regimen.There was a dose and time dependent increase in BAX expression in the breast cancer cell lines MCF7, MDAMB435S, and MDAMBA231 following in vitro treatment with 50–100M VP16. Elevation of BAX protein expression in the presence of VP16 alone did not correlate with reduced viability or induction of apoptosis in MCF7, MDAMB435S, or MDAMBA231. VP16 did effectively block the breast cancer cell lines evaluated (MCF7 and MDAMB435S) at G₂/M phase of the cell cycle, confirming activity of the drug in vitro. MCF7 and MDAMB435S cells that were pretreated with VP16 and subsequently exposed to 1.0–12.0g/m1 4hydroperoxycyclophosphamide (4HC), an active metabolite of cyclophosphamide, had markedly reduced viability when compared to matched controls treated with either VP16 or 4HC individually. Consistent with this loss of viability, exposure of all three cell lines to the combination of VP16 and 4HC resulted in higher BAX protein levels than those observed following treatment with either single agent. This combination of chemotherapeutic agents also resulted in reduced BCL2 expression.These observations suggest that combination chemotherapy may derive its efficacy, in part, through coordinated regulation of specific gene products associated with apoptosis. Characterization of molecular events that underlie susceptibility of specific tumor cells to combination chemotherapeutic regimens may lead to additional improvements in treatment strategies for this disease.     

Deaths from hematopoietic and other cancers in relation to permanent hair dye use in a large prospective study (United States)

Objectives: To assess in a large prospective study whether women who used permanent hair dye, especially dark dye for many years, experienced increased death rates from hematopoietic and other cancers that have been associated with hair dye use in some previous reports.Methods: In 1982, 547,586 women provided information on use of permanent hair dye and other lifestyle factors when enrolled in an American Cancer Society (ACS) prospective study. We extended mortality follow-up from 7 to 12 years. Using Cox proportional hazards modeling we compared death rates from hematopoietic and other cancers among women according to their hair dye use at baseline with death rates in unexposed women.Results: The adjusted death rate from all cancers combined was marginally lower among women who ever used hair dye than nonusers (relative risk [RR]=0.9; 95% confidence interval [CI]=0.9–1.0). Mortality from all hematopoietic cancers was marginally higher among users than nonusers (RR=1.1; CI=1.0–1.2), and increased with an index that combined duration of use and darker coloration (test of trend p=0.02). Women who used black or brown dye for 10 or more years experienced somewhat higher death rates from non-Hodgkin's lymphoma and (for black dye only) multiple myeloma. The temporal increase in death rates from non-Hodgkin's lymphoma and multiple myeloma between 1982–88 and 1989–94 was similar for women in our study who never used hair dyes to the increase among all US women.Conclusions: If prolonged use of dark permanent hair dyes contributes to death rates from non-Hodgkin's lymphoma and multiple myeloma, then the increase is small and difficult to detect reliably even in large prospective studies. The use of permanent hair dye is unlikely to be a major contributor to the temporal rise in non-Hodgkin's lymphoma and multiple myeloma in the US.     

Cytokine‐regulated urokinase‐type‐plasminogen‐activator (uPA) production by human breast fibroblasts in vitro

It has been shown that, in breast stroma, urokinasetype plasminogen activator (uPA) mRNA is predominantly expressed by myofibroblasts located at the invasive areas of the tumor. To examine which factors present in a tumor environment are candidates responsible for the induction of these uPAproducing myofibroblasts, we studied in vitro the capacity of a paired panel of normal and tumorderived human breast fibroblasts to produce uPA protein and the myofibroblast marker smoothmuscleactin (SMA) in response to various cytokines implicated in the process of tissueremodeling during malignant transformation.We found that fibroblasts produced increased amounts of uPA protein after exposure to aFGF, bFGF, EGF, PDGFBB, and IFN, were unaffected in this respect by IL6, MCSF, GMCSF and Oncostatin M, and produced decreased amounts of uPA protein after exposure to IL1, TNF, IGFI, and IGFII. None of these cytokines were able to induce a striking increase in the fraction of SMApositive fibroblasts. On the other hand, 25pM TGF₁ increased the fraction of SMApositive fibroblasts 5fold in both normal and tumortissuederived fibroblasts. Nonetheless, the normalderived fibroblasts were unaffected in their uPAproducing capacity by TGF₁, and the tumorderived fibroblasts produced decreased amounts of uPA protein after exposure to this cytokine, implying that at least in vitro the myofibroblast phenotype is not a prerequisite for the production of uPA by human breast fibroblasts. In addition, we established that the basaluPAproduction of both normal and tumorderived fibroblasts was increased by autocrinely produced bFGFlike activity, and that the basaluPAproduction of at least the normalderived fibroblasts was decreased by autocrinely produced IGFlike activity.Altogether, our data suggest an active role for fibroblasts in the process of uPAdirected breast tumor proteolysis.     

Prognostic relevance of transforming growth factor alpha (TGF-α) and tumor necrosis factor alpha (TNF-α) detected in breast cancer tissues by immunohistochemistry

Summary The function of different growth factors in the development and progression of malignant tumors and the role of cytotoxic cytokines in the host response generated against neoplasms have been recently studied. Anti-TGF- and anti-TNF- monoclonal antibody families have been developed and characterized previously by our laboratory. Libraries of anti-TGF- and anti-TNF- monoclonal antibodies were selected for equal immunoreactivity both in native (frozen) and in formaldehyde fixed, paraffin embedded histological sections. No differences were found between native and fixed samples demonstrated in 10 cases in the present prospective study. Retrospective investigation was performed in 35 histopathological specimens of breast cancer patients detailed clinically and observed during 5 years after the surgical treatment. Correlation between TGF- and/or TNF- expression and clinical staging - TNM score, lymph node metastasis, tumor recurrence and survival time - was analyzed. According to our present study, the TGF- positive patients had worse clinical prognosis than the TNF- positive and double positive cases during long term observation.     

Ligand-Induced Regulation of ERα and ERβ is Indicative of Human Breast Cancer Cell Proliferation

Two estrogen receptors (ER), ER and ER, are expressed in breast cancer but their role in treatment response is unclear. The overall objective of this study was to determine if the presence of ER protein in breast cancer cell lines is an indicator of a poor prognosis based on cell proliferation. In addition, we determined the effect of estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen and genistein, on ER and ER protein regulation, to help in the understanding of the mechanism behind their role in modulating cell proliferation. Using western blot and immunofluorescence analysis, the ER positive cell lines, MCF-7 and T47D, were found to contain both ER and ER, and thus were used as model systems. E2 and genistein, which increased cell proliferation in both cell lines, induced an up regulation of ER in both cell lines. This suggests that an estrogenic response in breast cancer cells is indicated by an increase in ER expression. Tamoxifen decreased cell proliferation in both cell lines, while up regulating ER in both cell lines, suggesting that antiestrogenic response is indicated by an increase in ER expression. Although a change in the ER/ER ratio may play a role in the effect seen in cell proliferation, this study indicates that ER is a poor prognosticator of cell proliferation in breast cancer and that ER is a positive prognosticator of responsiveness to antiestrogen treatment.     

Pharmacokinetic and pharmacodynamic comparison of fluoropyrimidine derivatives, capecitabine and 5′-deoxy-5-fluorouridine (5′-DFUR)

Purpose Capecitabine is a three-step prodrug that was rationally designed to be a more effective and safer alternative to its intermediate metabolite, 5-deoxy-5-fluorouridine (5-DFUR). We compared the pharmacokinetics/pharmacodynamics of these drugs in metastatic breast cancer patients.Methods Six patients received oral capecitabine at 1657 mg/m² twice daily and 17 received 5-DFUR at 400 mg three times daily. Both drugs were administered for 21 days followed by a 7-day rest.Results Median daily 5-DFUR AUC was significantly higher for capecitabine than for 5-DFUR (81.1 vs 32.6 mmol h/l; P=0.01). Following treatment with 5-DFUR, the median AUC and C_max of 5-DFUR tended to be higher in patients with a partial response (3.83 g h/ml and 4.88 g/ml) and stable disease (6.46 g h/ml and 4.96 g/ml) than in those with disease progression (2.53 g h/ml and 1.36 g/ml). The AUC and C_max of 5-DFUR was significantly related to overall survival.Conclusions These results support the superiority of capecitabine over 5-DFUR.     

The cytotoxicity of sarcosinamide chloroethylnitrosourea (SarCNU) and BCNU in primary gliomas and glioma cell lines: analysis of data in reference to theoretical peak plasma concentrations in man

Summary The cytotoxicity of a new compound, sarcosinamide chloroethylnitrosourea (SarCNU), was compared with that of the clinically available bis-chloroethylnitrosourea (BCNU) in 13 primary human gliomas and in 3 human glioma cell lines using the Human Tumor Cloning Assay (HTCA). At concentrations 16 g/ml, SarCNU reduced the growth to 30% of control in 11 of 13 primary gliomas. At similar concentrations, BCNU produced a comparable cytotoxic effect in 6 out of 13 specimens. At concentrations 16 g/ml, BCNU reduced colony growth to 30% of control in all three glioma cell lines and SarCNU produced the same effect in only one glioma cell line. A recently described statistical model [10], which employs the LD₅₀ dose of new agents in mice, was used to estimate the achievable peak plasma concentration (PPC) of SarCNU. The calculated PPC for SarCNU was found to be 14.8 g/ml compared with 2 g/ml for BCNU. A reevaluation of the cytotoxic activities of SarCNU and BCNU at concentrations approximating their respective PPCs revealed that SarCNU reduced the growth to 30% of control in one cell line at a concentration below its PPC. In contrast, BCNU exhibited similar toxicity in each cell line only at concentrations exceeding its PPC of 2 g/ml. In the case of the primary gliomas, SarCNU was active (30% of control) in ten tumors at concentrations 14.8 g/ml, whereas BCNU was active in only one glioma at a concentration 2 g/ml. The results suggest that SarCNU should be more active than BCNU against human gliomas, provided that the statistical model used has correctly estimated the PPC of SarCNU.     

Mitotic rate,DNA distribution,and chromatinin situ sensitivity to heparin in breast cancer

Summary The purpose of this study was to characterize breast carcinomas by cell kinetic parameters. Mitotic rate (MR) and flow cytometrically (FCM) measured cell cycle distribution as well as chromatin testing in situ employing heparin for determination of activated chromatin, provided the following results:MR counted in 73 unselected carcinomas showed an increase up to a tumor size of 4.2cm (p < 0.05); beyond this diameter, the MR was found to decrease.In T1-T2 carcinomas, cell cycle stage analysis yielded higher percentages of cells in S and G₂M phase for ductal (13% and 12%, N = 22) than for lobular (8% and 7%, N = 8) node-negative carcinomas (p < 0.002). In ductal carcinomas, lymph node involvement was reflected by higher % G₂M values (15%, N = 26) compared with negative cases (12%, N = 22) (p < 0.05).Ductal node-positive T3-T4 carcinomas (N = 10) revealed a higher % S value (16%) than their T1-T2 counterparts. A correlation between MR and % G₂M was established only up to a tumor size of 4.2 cm (r = 0.39, p < 0.05).A highly sensitive (H) and a poorly sensitive (P) subgroup of carcinomas with respect to heparininduced changes in fluorescence intensity of the G_1/0 peak of the DNA aneuploid cell line were identified, as previously shown [1]. These subgroups were here updated with a larger number of carcinomas and were limited to T1-T2 cancers (N = 57). Group H included more younger patients (p < 0.005), less cases with nodal involvement in ductal carcinomas (p < 0.05), and lower % G₂M values in lobular node-negative cases (p < 0.05), than group P. DNA diploid cells always existing in DNA aneuploid carcinomas are more sensitive than their aneuploid counterparts (p < 0.01); however, they strengthen the stratification to H and P. We suggest H carcinomas to be less aggressive than P carcinomas. Small breast carcinomas are recommended to cell kinetic investigations for individualizing adjuvant therapy.     

Sex hormone-induced mammary carcinogenesis in the female Noble rats: Expression of Bcl-2 and Bax in hormonal mammary carcinogenesis

We have established a Noble rat model to explore the mechanisms of hormonal mammary carcinogenesis, in which the role of androgen in promoting mammary carcinogenesis was highlighted. We have also established that stromal-epithelial interactions may be responsible for the promotional effects of testosterone in mammary carcinogenesis. Based on these understandings, in the present study we examined the expression of Bcl-2 and Bax in pre-malignant mammary glands from rats treated with different protocols of sex hormones for 7 weeks as well as sex hormone induced mammary tumours. We observed that Bcl-2 was strongly expressed in most of mammary tumour cells, whereas weak or negative in adjacent normal or hyperplastic ductal structures. On the contrary, Bax immunoreactivity was weak in mammary tumour cells while strongly expressed in adjacent normal or hyperplastic ductal structures. More importantly, the results from comparative study of pre-malignant glands further showed that when animals were treated with 17-oestradiol, the mammary epithelial cells expressed high levels of Bcl-2. The results from rats treated with testosterone, either alone or in combination with oestrogen, give rise to high levels of Bax expression in pre-malignant mammary glands. These observations indicate that in pre-malignant mammary glands, treatment with testosterone, either alone or in combination with 17-oestradiol, may induce high apoptotic activities. However, in fully developed mammary tumours, the apoptotic activities apparently decrease in tumour cells. TUNEL assay provides further data to support this conclusion. Our study, thus, suggests that androgens may play a promoting role in mammary carcinogenesis by upregulation of Bax expression and induction of high apoptotic activities in pre-malignant stage, which would provide a selective pressure favouring the expansion of the initiated cells.     

Effects of supplemental α-tocopherol and β-carotene on colorectal cancer: results from a controlled trial (Finland)

Background:Some epidemiological investigations suggest that higher intake or biochemical status of vitamin E and -carotene might be associated with reduced risk of colorectal cancer. Methods:We tested the effects of -tocopherol and -carotene supplementation on the incidence of colorectal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a double-blind, placebo-controlled trial among 29,133 50–69-year-old male cigarette smokers. Participants were randomly assigned to receive -tocopherol (50mg), -carotene (20mg), both agents, or a placebo daily for 5–8 years. Incident colorectal cancers (n=135) were identified through the nationwide cancer registry, and 99% were histologically confirmed. Intervention effects were evaluated using survival analysis and proportional hazards models. Results:Colorectal cancer incidence was somewhat lower in the -tocopherol arm compared to the no -tocopherol arm, but this finding was not statistically significant (relative risk (RR)=0.78, 95% confidence interval (CI) 0.55–1.09; log-rank test p=0.15). -Carotene had no effect on colorectal cancer incidence (RR=1.05, 95% CI 0.75–1.47; log-rank test p=0.78). There was no interaction between the two substances. Conclusion:Our study found no evidence of a beneficial or harmful effect for -carotene in colorectal cancer in older male smokers, but does provide suggestive evidence that vitamin E supplementation may have had a modest preventive effect. The latter finding is in accord with previous research linking higher vitamin E status to reduced colorectal cancer risk.     

Alcohol consumption and risk of breast cancer: a cohort study

Objectives: To study the association between alcohol consumption and breast cancer risk. Methods: A case–cohort analysis was undertaken within the cohort of 56,837 women who were enrolled in the Canadian National Breast Screening Study (NBSS) and who completed a self-administered dietary questionnaire. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40–59 at recruitment.) The cohort was recruited between 1980 and 1985, and during follow-up to the end of 1993 a total of 1469 women in the dietary cohort were diagnosed with biopsy-confirmed incident breast cancer. For comparative purposes a subcohort consisting of a random sample of 5681 women was selected from the full dietary cohort. After exclusions for various reasons the analyses were based on 1336 cases and 5238 noncases. Results: When compared to nondrinkers the adjusted incidence rate ratios (95% confidence intervals) for those consuming>0 and 10g of alcohol/day, >10 and 20g/day, >20 and thinsp;30g/day, >30 and 40g/day, >40 and 50g/day, and >50g/day were 1.01 (0.84–1.22), 1.16 (0.91–1.47), 1.27 (0.91–1.78), 0.77 (0.51–1.16), 1.00 (0.57–1.75), and 1.70 (0.97–2.98), respectively; the associated p value for the test for trend was 0.351. Similar findings were obtained when analyses were conducted separately in the screened and control arms of the NBSS, in premenopausal and postmenopausal women, for screen-detected and interval-detected breast cancer, and by levels of other breast cancer risk factors. Conclusions: The results of this study suggest that alcohol consumption might be associated with increased risk of breast cancer at relatively high levels of intake.     

Induction of insulin‐like growth factor binding protein expression by ICI 182,780 in a tamoxifen‐resistant human breast cancer cell line

Earlier studies in our laboratory demonstrated that the steroidal antiestrogen ICI 182,780 is very effective in abolishing the tamoxifenresistant proliferation of MCF 7/523 cells [1]. In addition, preliminary binding studies showed that ICI 182,780 increased the binding of insulinlike growth factor (IGF)I to the MCF 7/523 cells, although this finding was not the result of an increase in the expression of the insulinlike growth factorI receptor (IGFIR). Hence, we reasoned that the inhibition of tamoxifenresistant cell growth by ICI 182,780 might have been due to increased expression of insulinlike growth factor binding proteins (IGFBPs).We observed the upregulation of noninsulinsuppressible IGFI binding in both the tamoxifensensitive MCF 7/521 cell line (1.5fold) and the tamoxifenresistant MCF 7/523 cell line (2.5fold) after 5 days of treatment with ICI 182,780 (10^–7 M) in serumfree medium, suggesting a role for cellassociated IGFBPs. Affinity crosslinking experiments confirmed the presence of an IGFI:IGFBP complex of approximately 38kDa in tamoxifen or ICI 182,780treated cells. Western ligand blots showed higher levels of a soluble 30kDa IGFBP in media conditioned by either of the subclones that had been treated with ICI 182,780, an effect consistently opposed by estrogen (E₂:10^–9 M). RTPCR showed higher levels of IGFBP5 mRNA than any of the other known IGFBPs, suggesting that this was the major IGFBP subtype. The protein was subsequently identified by Western immunoblotting as IGFBP5. In conclusion, we postulate that this may be a mechanism contributing to the greater potency of ICI 182,780 in the growth inhibition of the MCF 7/523, tamoxifenresistant cell line.     

Sensitivities of human glioma cell lines to interferons and double-stranded RNAs individually and in synergistic combinations

Summary The antiproliferative effects of human interferons (IFNs) and double-stranded RNAs (dsRNAs) were studied in five human glioma cell lines. Dose response curves were generated over a 72 hour treatment period. The concentration of interferon or double-stranded RNA necessary to produce a 50% antiproliferative response (GI₅₀) was calculated by linear regression analysis. Two cell lines were more sensitive to IFN- than to IFN-, one cell line was more sensitive to IFN- than to IFN- and two cell lines had approximately equal sensitivities to both interferons. All cell lines showed some sensitivity to either IFN- or IFN-. IFN- had no antiproliferative effect on any of the cell lines. In addition, only one of the cell lines displayed sensitivity to dsRNA, in which the response to poly(I) · poly(C) was greater than that to a mismatched analogue of poly(I) · poly(C), r(I)n · r(C₁₂,U)_n (Ampligen). There was no correlation between the sensitivities to type I IFNs ( and ), type II IFN () or the dsRNAs. The antiproliferative effect of combinations of IFNs, or IFNs and Ampligen, was studied in one of the cell lines. A significant synergistic antitumor effect was seen with all of the IFN/Ampligen combinations (p < 0.02), including IFN-/Ampligen, even though these cells were resistant to IFN- alone. Synergy was also seen in the IFN-/IFN- (p < 0.02) and IFN-/IFN- (p < 0.05) combinations. The IFN-/IFN- combination gave an additive antitumor effect. These results indicate that IFN- and IFN- alone or combinations of type I IFNs, type II IFNs and Ampligen can be effective in inhibiting the growth of glioma cells.