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Showing papers in "International Journal of Cancer in 2001"


Journal ArticleDOI
TL;DR: GLOBOCAN 2000 updates the previous data-based global estimates of incidence, mortality and prevalence to the year 2000 and uses a “databased” approach, rather different from themodeling method used in other estimates.
Abstract: Describing the distribution of disease between different populations and over time has been ahighly successfu l way of devising hypothese s about causation and for quantifying the potential for preventive activities.1 Statistical data are also essentia l componentsof diseasesurveillanceprograms. Theseplay acritical role in the developmen t and implementation of health policy, through identification of health problems, decisions on priorities for preventive and curative programs and evaluation of outcomes of programs of prevention, early detection/screenin g and treatment in relation to resource inputs. Over the last 12 years, aseries of estimates of the global burden of cancer have been published in the International Journal of Cancer. 2–6 The methods have evolved and been refined, but basically they rely upon the best availabl e data on cancer incidence and/or mortality at country level to build up theglobal picture. The results are more or less accurat e for different countries, depending on the extent and accuracy of locally availabl e data. This “databased” approach is rather different from themodeling method used in other estimates. 7–10 Essentially, these use sets of regression models, which predict cause-specifi c mortality rates of different populations from the correspondin g all-cause mortality.11 The constant s of the regression equations derive from dataset s with different overal mortality rates (often including historic data from wester n countries) . Cancer deaths are then subdivided into the different cancer types, according to the best availabl e information on relative frequencies. GLOBOCAN 2000 updates thepreviousl y published data-based global estimates of incidence, mortality and prevalence to the year 2000.12

3,748 citations


Journal ArticleDOI
TL;DR: Data demonstrate that p16INK4a is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears and that Dysplastic cells could also be identified in cervicalsmears using a specific p16ink4a monoclonal antibody.
Abstract: Cytological screening for cervical cancer or its precursors using Papanicolaou's smear test (Pap test) has been highly efficient to reduce the morbidity and mortality of cervical cancer. However, evaluation of the Pap test relies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parameters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for many patients and the high screening costs associated with repeated testing. Cervical dysplasia is induced by persistent infections through high-risk types of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is triggered by increasing expression of two viral oncogenes, E6 and E7, which both interact with various cell cycle-regulating proteins. Among these is the retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin-dependent kinase inhibitor gene p16INK4a. Increasing expression of the viral oncogenes in dysplastic cervical cells might thus be reflected by increased expression of p16INK4a. In line with this hypothesis, we observed marked overexpression of p16INK4a in all cervical intraepithelial neoplasm (CIN) I lesions (n = 47) except those associated with low-risk HPV types (n = 7), all CIN II lesions (n = 32), all CIN III lesions (n = 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16INK4a was observed in normal cervical epithelium (n = 42), inflammatory lesions (n = 48) and low-grade cervical lesions (CIN I) associated with low-risk HPV types (n = 7). Dysplastic cells could also be identified in cervical smears using a specific p16INK4a monoclonal antibody. These data demonstrate that p16INK4a is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears. © 2001 Wiley-Liss, Inc.

1,012 citations


Journal ArticleDOI
TL;DR: Excess body mass accounts for 5% of all cancers in the European Union, 3% in men and 6% in women, corresponding to 27,000 male and 45,000 female cancer cases yearly, and can be avoided by halving the prevalence of overweight and obese people in Europe.
Abstract: There is growing evidence that excess body weight increases the risk of cancer at several sites, including kidney, endometrium, colon, prostate, gallbladder and breast in post-menopausal women. The proportion of all cancers attributable to overweight has, however, never been systematically estimated. We reviewed the epidemiological literature and quantitatively summarised, by meta-analysis, the relationship between excess weight and the risk of developing cancer at the 6 sites listed above. Estimates were then combined with sex-specific estimates of the prevalence of overweight [body mass index (BMI) 25-29 kg/m(2)] and obesity (BMI > or = 30 kg/m(2)) in each country in the European Union to obtain the proportion of cancers attributable to excess weight. Overall, excess body mass accounts for 5% of all cancers in the European Union, 3% in men and 6% in women, corresponding to 27,000 male and 45,000 female cancer cases yearly. The attributable proportion varied, in men, between 2.1% for Greece and 4.9% for Germany and, in women, between 3.9% for Denmark and 8.8% for Spain. The highest attributable proportions were obtained for cancers of the endometrium (39%), kidney (25% in both sexes) and gallbladder (25% in men and 24% in women). The largest number of attributable cases was for colon cancer (21,500 annual cases), followed by endometrium (14,000 cases) and breast (12,800 cases). Some 36,000 cases could be avoided by halving the prevalence of overweight and obese people in Europe.

783 citations


Journal ArticleDOI
TL;DR: A method for the immunochemical detection of NY‐ESO‐1 in paraffin‐embedded tissues has been developed and used to define the expression pattern of NY-ESO-1 in normal tissues and in a panel of human tumors.
Abstract: NY-ESO-1, a member of the CT (cancer/testis) family of antigens, is expressed in normal testis and in a range of human tumor types. Knowledge of NY-ESO-1 expression has depended on RT-PCR detection of mRNA and there is a need for detecting NY-ESO-1 at the protein level. In the present study, a method for the immunochemical detection of NY-ESO-1 in paraffin-embedded tissues has been developed and used to define the expression pattern of NY-ESO-1 in normal tissues and in a panel of human tumors. No normal tissue other than testis showed NY-ESO-1 reactivity, and expression in testis was restricted to germ cells particularly spermatogonia. In human tumors, the frequency of NY-ESO-1 antigen expression corresponds with past analysis of NY-ESO-1 mRNA expression e.g., 20-30% of lung cancers, bladder cancers and melanoma, and no expression in colon and renal cancer. Co-typing of NY-ESO-1 antigen and mRNA expression in a large panel of lung cancers showed a good correlation. There is great variability in NY-ESO-1 expression in individual tumors, ranging from an infrequent homogeneous pattern of staining to highly heterogeneous antigen expression.

425 citations


Journal ArticleDOI
TL;DR: FCS‐free cultured mature DCs are defined as superior inducers of T‐cell responses in melanoma patients and demonstrate that this novel vaccination protocol is an efficient approach to compare different immunization strategies within the same patient.
Abstract: Dendritic cells (DCs) elicit potent anti-tumoral T-cell responses in vitro and in vivo. However, different types of DC have yet to be compared for their capacity to induce anti-tumor responses in vivo at different developmental stages. Herein, we correlated the efficiencies of different types of monocyte-derived DC as vaccines on the resulting anti-tumor immune responses in vivo. Immature and mature DCs were separately pulsed with a peptide derived from tyrosinase, MelanA/MART-1 or MAGE-1 and a recall antigen. Both DC populations were injected every 2 weeks in different lymph nodes of the same patient. Immune responses were monitored before, during and after vaccination. Mature DCs induced increased recall antigen-specific CD4(+) T-cell responses in 7/8 patients, while immature DCs did so in only 3/8. Expansion of peptide-specific IFN-gamma-producing CD8(+) T cells was observed in 5/7 patients vaccinated with mature DCs but in only 1/7 using immature DCs. However, these functional data did not correlate with the tetramer staining. Herein, immature DCs also showed expansion of peptide-specific T cells. In 2/4 patients vaccinated with mature DCs, we observed induction of peptide-specific cytotoxic T cells, as monitored by chromium-release assays, whereas immature DCs failed to induce peptide-specific cytotoxic T cells in the same patients. Instead, FCS-cultured immature DCs induced FCS-specific IgE responses in 1 patient. Our data demonstrate that this novel vaccination protocol is an efficient approach to compare different immunization strategies within the same patient. Thus, our data define FCS-free cultured mature DCs as superior inducers of T-cell responses in melanoma patients.

386 citations


Journal ArticleDOI
TL;DR: Previous findings of a second peak of high‐risk HPV infections in postmenopausal women are confirmed, in this case with a clear predominance of cancer‐associated HPV types.
Abstract: Cervical cancer is caused by human papillomavirus (HPV) and is the most common cancer among Mexican women, but no population-based studies have reported the prevalence and determinants of HPV infection in Mexico. A population-based study was carried out between 1996 and 1999, based on an age-stratified random sample of 1,340 women with normal cytologic diagnoses from 33 municipalities of Morelos State, Mexico. The prevalence of cervical HPV DNA was determined by reverse line blot strip assay to detect 17 cancer-associated and 10 non-cancer-associated HPV types. Two peaks of HPV DNA prevalence were observed. A first peak of 16.7% was observed in the age group under 25 years. HPV DNA prevalence declined to 3.7% in the age group 35-44 years, then increased progressively to 23% among women 65 years and older. Cancer-associated HPV types were the most common in all age groups; non-cancer-associated HPV types were rare in the young and became more common linearly with age. Twenty-four types of HPV were detected; HPV 16, HPV 53, HPV 31 and HPV 18 were the most common, but none was present in more than 1.7% of subjects. The main determinant of infection with both cancer-associated and non-cancer-associated HPV types was the number of sexual partners in all age groups. Less-educated women were at an increased risk of infection with cancer-associated but not with non-cancer-associated HPV types; low socioeconomic status was associated with detection of non-cancer-associated HPV types. Among young women an increasing number of pregnancies was associated with lower HPV detection and among older women low socioeconomic status was related to increased HPV detection, particularly for the age group 35-54 years. Among women with cancer-associated HPV types, there was a higher intensity of polymerase chain reaction signal in younger than in older age groups (p < 0.001). We present additional evidence for the sexually transmitted nature of HPV infection, regardless of age group and HPV type. We confirm previous findings of a second peak of high-risk HPV infections in postmenopausal women, in this case with a clear predominance of cancer-associated HPV types. In populations with this pattern, which can be related to reactivation of latent HPV infections or high previous exposure in older women, screening with HPV testing can have a reduced specificity among older women if proper cut-off points for HPV positivity are not used. Longitudinal studies of immune responses to HPV infection in different age groups are warranted.

357 citations


Journal ArticleDOI
TL;DR: Although the reasons for the trends are not entirely clear, the increased seroprevalence of HCV in the developed world and the elimination of HBV‐cofactors in the developing world are likely to have contributed to the patterns.
Abstract: Primary liver cancer (PLC) is common in many areas of the developing world, but uncommon in most of the developed world. Some evidence suggests, however, that the global pattern of PLC may be changing. To clarify this issue, we examined incidence rates for PLC over the 15-year time period, 1978-92, in selected cancer registries around the world. With some exceptions, developed countries have experienced PLC increases in incidence whereas developing countries have experienced declines. Although the reasons for the trends are not entirely clear, the increased seroprevalence of HCV in the developed world and the elimination of HBV-cofactors in the developing world are likely to have contributed to the patterns. Further progress against PLC may be seen in the developing world once the HBV-vaccinated segment of the population reaches adulthood. Published 2001 Wiley-Liss, Inc.

346 citations


Journal ArticleDOI
TL;DR: The results suggest that survivin expression may provide prognostic information in patients with esophageal cancer.
Abstract: Survivin, a new member of the inhibitor-of-apoptosis (IAP) family, has been reported to be expressed in many cancers but not in differentiated normal tissue. Its expression in esophageal cancer, however, has not been reported. We investigated 51 esophageal cancers and their adjacent normal epithelial tissues for mRNA expression of survivin by RT-PCR. The survivin expression in esophageal cancer tissue was significantly higher than that in normal esophageal tissue (0.211 ± 0.226 vs. 0.057 ± 0.135, p < 0.0001). pN4 tumors had significantly higher survivin expression than the pN0-3 tumors (p = 0.0093). Fourteen patients with advanced esophageal cancer had received chemotherapy prior to surgery. The survivin expression in the cancer tissue in patients who achieved a partial response (PR) was significantly lower than that in patients with no change (NC) and in patients with progressive disease (PD; 0.099 ± 0.134 vs. 0.320 ± 0.222, p = 0.0434). The median survival for patients with high survivin expression (9.0 months) was less than that for patients with low survivin group expression (30.0 months, p = 0.0023). Survivin expression was one of the significant predictors of survival on univariate analysis (hazard ratio 2.471; 95% confidence interval 1.104-5.533). The results suggest that survivin expression may provide prognostic information in patients with esophageal cancer. © 2001 Wiley-Liss, Inc.

328 citations


Journal ArticleDOI
Samuel T. Chao1, John H. Suh1, Shanker Raja1, Shih Yuan Lee1, Gene H. Barnett1 
TL;DR: MRI co‐registration appears to improve the sensitivity of FDG PET, making it a useful modality to distinguish between radiation necrosis and recurrent brain metastasis.
Abstract: Radiation necrosis and recurrent brain tumor have similar symptoms and are indistinguishable on both magnetic resonance imaging (MRI) and computed tomograph scans. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been proposed as a diagnostic alternative, particularly when co-registered with MRI. We studied 47 patients with brain tumors treated with stereotactic radiosurgery and followed with FDG PET. For all tumor types, the sensitivity of FDG PET for diagnosing tumor was 75% and the specificity was 81%. For brain metastasis without MRI co-registration, FDG PET had a sensitivity of 65% and a specificity of 80%. For brain metastasis with MRI co-registration, FDG PET had a sensitivity of 86% and specificity of 80%. MRI co-registration appears to improve the sensitivity of FDG PET, making it a useful modality to distinguish between radiation necrosis and recurrent brain metastasis.

323 citations


Journal ArticleDOI
TL;DR: Clinical studies have begun in which DCs are generated ex vivo, charged with tumor antigens, exposed to maturation stimuli and reinfused to immunize patients, finding DC-based active immunization does not resul t in major shortterm toxicity in healthy subject sor cancer patients.
Abstract: DCs1 are antigen-presentin g cells that regulat e several components of the immune system. The mature or terminal stage of DC developmen t induces specific T-cell immunity and resistanc e to experimenta l tumors in vivo. However, DC maturation is induced by inflammator y and microbial stimuli, so it isunlikely that mature DCsnormally present antigens from tumor cells in cancer patients. Accordingly, clinical studies have begun in which DCs are generated ex vivo, charged with tumor antigens, exposed to maturation stimuli and reinfused to immunize patients. This approach has the potential to control response s to cancer antigens in a specific and nontoxic manner , in both vaccination and therapeuti c settings. DCs can mobilize several immune resistanc e mechanisms. These include CD8 CTLs, CD4 helper T cells, NK and NKT cells. Each of these lymphocytes recognizes target s through a distinct mechanis m and has the capacit y to kil l tumor cells and release valuabl e protective cytokines like IFN-g. CD4 T cells also provide essentia l help for the expansion and maintenanc e of CD8 cytolytic cells, while NK and NKT cells can eliminate target s that dampen presentatio n on MHC class I to escape CTL recognition. The stimulation and concerted action of these classes of lymphocytes can now be studied directly in patients, using ex vivo–derived DCs. Several findings have emerged from studies of healthy volunteers who have been immunized with DCs charged with model antigens, KLH protein and influenza virus matrix peptide. Mature DCs elicit a polarized Th1 type of CD4 T-cell response , only a single injection being required. Vaccination with antigen-bearing DCs also markedl y improves the functional affinity of CD8 T cells. These findings are important in the context of immunotherapy becaus e Th1 cells are more efficient helper cells in experimental model s of viral infection and tumors, while high-affinity CTLs shoul d improve recognition of tumor-derived peptides. An important caution also has surfaced when DCs are not adequately differentiated. Immature DCs can silence adaptive T-cell responses , e.g., by inducing IL-10–producing, T-reg cells. DC-based active immunization does not resul t in major shortterm toxicity in healthy subject sor cancer patients. Tumor-specific T-cell response s have been induced and detected in fresh blood specimens without the need for restimulation in vitro. However, the immune response s observed in the first protocol s are still smaller than those seen naturall y in acute viral infections. Occasional clinical regression s have been noted in these initial feasibility studies, particularl y in melanomas , pediatri c tumors, lymphomas, prostat e cancer s and renal cell cancers . This information, coupled with progres in DC biology, suggest s many ways to improve the efficacy of this new therapy. Some relevant topics include antigen loading and DC maturation procedures , frequency and route of DC injection, efficiency of DC homing to lymphoid tissues and their longevity once there and the role of distinct DC subsets . A valuabl e positive control in active immunization protocols is to include an aliquot of DCs pulsed with a viral peptide to verify that the DCs and the patient’s immune system are measurabl y competent. Most of the first vaccination protocol s have used DCs charged with synthetic, HLA-binding tumor peptides. Many methodsare in place to allow DCs to proces abroader array of peptides appropriate for the patient’s MHC haplotype. These include transfection (RNA, DNA and viral vectors) , select pathways of adsorptive endocytosis , exosomes and tumor cell fusion. An intriguing new approach involves the processing of whole tumor cells. Immature DCs are able to internalize tumor cells, including melanoma, EBV lymphoma and prostat e carcinoma cell lines. Following maturation, theprocessing of tumor cells leads to presentatio n of multiple epitopes on both MHC class I and II product s of DCs. Basic issues in human cancer immunology can be investigated with ex vivo–based DC immunization. Some topics for the near future are the extent to which tumor-specific tolerance is an obstacl e to immunetherapy and theneed to mobilizeseveral adaptive and innate mechanisms in tandem, including Th1 type CD4 helper T, NK and NKT cells. Progres is also being made in manipulating DCsdirectly in vivo. Thiswil l help to design vaccine adjuvant s that improve presentatio n of tumor cells in patients. Although tumorschallengetheimmunesystem in formidableways relative to infectious diseases , it is now feasibl e to use active immunotherap y and DC biology to manipulat e and study the human respons e to cancer.

315 citations


Journal ArticleDOI
TL;DR: In this paper, the presence of high-risk human papillomavirus (HPVs) was associated with a subset of head and neck cancers (HNSCCs), and the inactivation of p53 by the HPV E6 oncoprotein was linked to the development of HNSCC.
Abstract: High-risk human papillomaviruses (HPVs) have been proposed to be associated with a subset of head and neck cancers (HNSCCs). However, clear biological evidence linking HPV-mediated oncogenesis to the development of HNSCC is hardly available. An important biological mechanism underlying HPV-mediated carcinogenesis is the inactivation of p53 by the HPV E6 oncoprotein. In the present study we investigated this biological relationship between HPV and HNSCC. In total 84 HNSCC tumors were analyzed for the presence of high-risk HPV nucleic acids by DNA polymerase chain reaction-enzyme immunoassay (PCR-EIA) and E6 reverse transcriptase (RT)-PCR as well as for the presence of mutations in the p53 gene. We found 20/84 HPV16 DNA-positive cases with one or more DNA assays, 10 of which were consistently positive with all assays. Only 9/20 cases showed E6 mRNA expression, indicative for viral activity. Only these nine E6 mRNA-positive cases all lacked a p53 mutation, whereas both the other HPV DNA-positive and HPV-DNA negative tumors showed p53 mutations in 36% and 63% of the cases, respectively. Moreover, only in lymph node metastases of HPV E6 mRNA-positive tumors both viral DNA and E6 mRNA were present. Our study provides strong biological evidence for a plausible etiological role of high-risk HPV in a subgroup of HNSCC. Analysis of E6 mRNA expression by RT-PCR or alternatively, semiquantitative analyses of the viral load, seem more reliable assays to assess HPV involvement in HNSCC than the very sensitive DNA PCR analyses used routinely.

Journal ArticleDOI
TL;DR: It is suggested that bladder‐cancer risk can be genetically modulated by XRCC3, which may repair DNA cross‐link lesions produced by aromatic amines and other environmental chemicals.
Abstract: Individuals differ widely in their ability to repair DNA damage, and DNA-repair deficiency may be involved in modulating cancer risk. In a case-control study of 124 bladder-cancer patients and 85 hospital controls (urological and non-urological), 3 DNA polymorphisms localized in 3 genes of different repair pathways (XRCC1-Arg399Gln, exon 10; XRCC3-Thr241Met, exon 7; XPD-Lys751Gln, exon 23) have been analyzed. Results were correlated with DNA damage measured as 32P-post-labeling bulky DNA adducts in white blood cells from peripheral blood. Genotyping was performed by PCR-RFLP analysis, and allele frequencies in cases/controls were as follows: XRCC1-399Gln = 0.34/0.39, XRCC3-241Met = 0.48/0.35 and XPD-751Gln = 0.42/0.42. Odds ratios (ORs) were significantly greater than 1 only for the XRCC3 (exon 7) variant, and they were consistent across the 2 control groups. XPD and XRCC1 appear to have no impact on the risk of bladder cancer. Indeed, the effect of XRCC3 was more evident in non-smokers [OR = 4.8, 95% confidence interval (CI) 1.1–21.2]. XRCC3 apparently interacted with the N-acetyltransferase type 2 (NAT-2) genotype. The effect of XRCC3 was limited to the NAT-2 slow genotype (OR = 3.4, 95% CI 1.5–7.9), suggesting that XRCC3 might be involved in a common repair pathway of bulky DNA adducts. In addition, the risk of having DNA adduct levels above the median was higher in NAT-2 slow acetylators, homozygotes for the XRCC3-241Met variant allele (OR = 14.6, 95% CI 1.5–138). However, any discussion of interactions should be considered preliminary because of the small numbers involved. Our results suggest that bladder-cancer risk can be genetically modulated by XRCC3, which may repair DNA cross-link lesions produced by aromatic amines and other environmental chemicals. © 2001 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: Data are suggestive of only a weak positive association with substitution of saturated fat for carbohydrate consumption; none of the other types of fat examined was significantly associated with breast cancer risk relative to an equivalent reduction in carbohydrate consumption.
Abstract: Recently, there has been interest in whether intakes of specific types of fat are associated with breast cancer risk independently of other types of fat, but results have been inconsistent. We identified 8 prospective studies that met predefined criteria and analyzed their primary data using a standardized approach. Holding total energy intake constant, we calculated relative risks for increments of 5% of energy for each type of fat compared with an equivalent amount of energy from carbohydrates or from other types of fat. We combined study-specific relative risks using a random effects model. In the pooled database, 7,329 incident invasive breast cancer cases occurred among 351,821 women. The pooled relative risks (95% confidence intervals [CI]) for an increment of 5% of energy were 1.09 (1.00-1.19) for saturated, 0.93 (0.84-1.03) for monounsaturated and 1.05 (0.96-1.16) for polyunsaturated fat compared with equivalent energy intake from carbohydrates. For a 5% of energy increment, the relative risks were 1.18 (95% CI 0.99-1.42) for substituting saturated for monounsaturated fat, 0.98 (95% CI 0.85-1.12) for substituting saturated for polyunsaturated fat and 0.87 (95% CI 0.73-1.02) for substituting monounsaturated for polyunsaturated fat. No associations were observed for animal or vegetable fat intakes. These associations were not modified by menopausal status. These data are suggestive of only a weak positive association with substitution of saturated fat for carbohydrate consumption; none of the other types of fat examined was significantly associated with breast cancer risk relative to an equivalent reduction in carbohydrate consumption. © 2001 Wiley-Liss, Inc. Chemicals/CAS: Dietary Fats

Journal ArticleDOI
TL;DR: It is found that PTEN promoter methylation is relatively frequent in endometrial carcinoma and its association with metastatic disease and microsatellite instability implicates its importance in the development of this tumor type.
Abstract: Loss of heterozygosity and mutations in the PTEN (MMAC1) tumor suppressor gene are frequent in endometrial carcinoma. Promoter hypermethylation has recently been identified as an alternative mechanism of tumor suppressor gene inactivation in cancer, but its importance in the PTEN gene in endometrial carcinoma is unknown. The purpose of our study was to assess the frequency of promoter methylation of the PTEN gene and to determine its correlation with clinicopathologic variables in a prospective and population-based series of endometrial carcinomas with complete follow-up. Presence of PTEN promoter methylation was seen in 26 of 138 patients (19%). Methylation was significantly associated with metastatic disease (p = 0.01) and a microsatellite unstable phenotype (p = 0.006). In conclusion, we find that PTEN promoter methylation is relatively frequent in endometrial carcinoma. Its association with metastatic disease and microsatellite instability implicates its importance in the development of this tumor type.

Journal ArticleDOI
TL;DR: The results indicate that an expected up‐regulation of dietary intake in response to elevated energy expenditure is frequently lost in cancer patients, which may be the explanation behind cancer cachexia rather than a primary decrease in appetite.
Abstract: Weight loss and anorexia are frequent findings in advanced cancer. The progressive wasting could be attributed to changes in dietary intake and/or energy expenditure mediated by metabolic alterations. In this study, we analyzed dietary intake in generalized malignant disease of solid tumor type in relation to resting energy expenditure (REE) and reported weight loss. In a group of 297 unselected cancer patients from a university hospital outpatient clinic, dietary intake of energy and macronutrients from a 4-day food record, REE by indirect calorimetry, height, weight and weight loss were recorded. Protein intake was validated against 24 hr urine nitrogen in a subgroup (n = 53), and no indication of systematic misreporting was found. Mean daily dietary intake was below maintenance requirements, 26 ± 10 kcal/kg. Weight loss of more than 10% was present in 43% of patients and elevated REE (>110% of predicted) in 48%. Dietary intake did not differ between normo- and hypermetabolic patients, nor was tumour type or gender related to energy and protein intake. Weight loss could not be accounted for by diminished dietary intake since energy intake in absolute amounts was not different and intake per kilogram body weight was higher in weight-losing patients compared to weight-stable patients. Dietary macronutrient composition did not differ from the general population. Dietary intake of energy and protein was decreased, but dietary macronutrient composition did not appear to be changed. Weight loss and hypermetabolism were frequent and not compensated for by an increase in spontaneous food intake. Our results indicate that an expected up-regulation of dietary intake in response to elevated energy expenditure is frequently lost in cancer patients. This may be the explanation behind cancer cachexia rather than a primary decrease in appetite. © 2001 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: Although a limited number of patients were included in this study, the association between prolonged survival and an immune response against the vaccine suggests that a clinical benefit of ras peptide vaccination may be obtained for this group of patients.
Abstract: K-RAS mutations are frequently found in adenocarcinomas of the pancreas, and induction of immunity against mutant ras can therefore be of possible clinical benefit in patients with pancreatic cancer. We present data from a clinical phase I/II trial involving patients with adenocarcinoma of the pancreas vaccinated by i.d. injection of synthetic mutant ras peptides in combination with granulocyte-macrophage colony-stimulating factor. Forty-eight patients (10 surgically resected and 38 with advanced disease) were treated on an outpatient basis. Peptide-specific immunity was induced in 25 of 43 (58%) evaluable patients, indicating that the protocol used is very potent and capable of eliciting immune responses even in patients with end-stage disease. Patients followed-up for longer periods showed evidence of induction of long-lived immunological memory against the ras mutations. CD4(+) T cells reactive with an Arg12 mutation also present in the tumor could be isolated from a tumor biopsy, demonstrating that activated, ras-specific T cells were able to selectively accumulate in the tumor. Vaccination was well tolerated in all patients. Patients with advanced cancer demonstrating an immune response to the peptide vaccine showed prolonged survival from the start of treatment compared to non-responders (median survival 148 days vs. 61 days, respectively; p = 0.0002). Although a limited number of patients were included in our study, the association between prolonged survival and an immune response against the vaccine suggests that a clinical benefit of ras peptide vaccination may be obtained for this group of patients.

Journal ArticleDOI
TL;DR: It is demonstrated that STK15/BTAK mRNA is over‐expressed in the majority of breast cancers and its over‐expression is significantly associated with CIN, implicating STK 15/ BTAK in carcinogenesis through induction of CIN.
Abstract: Over-expression of a centrosomal serine/threonine kinase, STK15/BTAK, induces centrosome amplification, which results in chromosomal instability (CIN) in cell culture. In the present study, we investigated the correlation of STK15/BTAK mRNA expression with CIN and various clinicopathological factors in human breast cancer. STK15/BTAK mRNA levels were quantified by real-time PCR, and CIN values were determined by FISH analysis of chromosomes 1, 11 and 17 using centromeric probes. STK15/BTAK mRNA levels (0.310 ± 0.413, mean ± SD, n = 47) in breast cancers were significantly (p < 0.01) higher than those in normal breast tissues (0.044 ± 0.029, n = 9). Furthermore, breast cancers were divided into 3 groups (low, intermediate and high) according to STK15/BTAK mRNA expression levels. CIN values of the low-expression group (27.9 ± 12.6%, n = 18) were significantly (p < 0.01) higher than those of normal breast tissues (9.2 ± 2.6%, n = 6), and those of the high-expression group (38.0 ± 12.7%, n = 14) were significantly (p < 0.05) higher than those of the low-expression group. STK15/BTAK mRNA expression showed a significant (p < 0.05) correlation with high histological grade and negativity of estrogen and progesterone receptors. Our results demonstrate that STK15/BTAK mRNA is over-expressed in the majority of breast cancers and its over-expression is significantly associated with CIN, implicating STK15/BTAK in carcinogenesis through induction of CIN. STK15/BTAK mRNA levels might be useful as an indicator of poor prognosis and resistance to endocrine therapy. © 2001 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: The present study is the first to address the relationship between ERK1/2 MAPK phosphorylation (p‐MAPK) and response to anti‐hormonal agents in clinical breast cancer, providing further evidence that ERK 1/2MAP kinase plays a role in circumvention of anti-hormonal response in breast cancer.
Abstract: It is believed that growth factor phosphorylation cascades interact closely with oestrogen receptor (ER) signaling to regulate breast cancer growth, and that alterations in these pathways may underlie resistance to anti-hormones such as tamoxifen. There is an increasing body of experimental evidence implicating the mitogen-activated protein kinase extracellular signal-regulated-kinases ERK1 and ERK2 (ERK1/2 MAPK) in these events. The present study is the first to address the relationship between ERK1/2 MAPK phosphorylation (p-MAPK) and response to anti-hormonal agents in clinical breast cancer (n = 90). Immunocytochemical analysis using a phosphorylation state-specific ERK1/2 MAPK antibody revealed 72% of breast tumors to have considerable nuclear p-MAPK immunostaining (designated p-MAPK positive), whereas staining was barely detectable or absent in the remaining 28% (designated p-MAPK negative). Comparison with staining in normal breast material obtained from reduction mammoplasty patients (n = 10) demonstrated an increased frequency of higher intensity p-MAPK immunostaining cells within carcinomas (p = 0.002). Significant relationships were revealed between p-MAPK positivity and poorer quality (p = 0.001) and shortened duration (p = 0.006) of anti-hormonal response, as well as with decreased survival time from the initiation of therapy (p = 0.022). These associations were retained in ER positive disease (p = 0.013, p = 0.037 and p = 0.048 respectively), where multivariate analysis demonstrated p-MAPK status to be a significantly independent predictor for response duration (p = 0.034) and patient survival (p = 0.029). Phosphorylated ERK1/2 MAP kinase is thus potentially prognostic for prediction of response to anti-hormonal agents and survival, data providing further evidence that ERK1/2 MAP kinase plays a role in circumvention of anti-hormonal response in breast cancer.

Journal ArticleDOI
TL;DR: It is anticipated that the use of TMAs will greatly accelerate the transition of basic research findings to clinical applications and allow a high throughput molecular analysis of thousands of tumors within a few hours.
Abstract: A rapidly increasing number of genes are being suspected to play a role in cancer biology. To evaluate the clinical significance of newly detected potential cancer genes, it is usually required to examine a high number of well-characterized primary tumors. Using traditional methods of molecular pathology, this is a time consuming endeavor rapidly exhausting precious tissue resources. To allow for a high throughput tissue analysis we have developed a “tissue chip” approach (Kononen et al., Nat. Med. 1998;4:844–7). Using this tissue microarray (TMA) technology, samples from up to 1,000 different tumors are arrayed in one recipient paraffin block, sections of which can be used for all kind of in situ analyses. Section from TMA blocks can then be utilized for the simultaneous analysis of up to 1,000 different tumors on the DNA, RNA or protein level. TMAs allow a high throughput molecular analysis of thousands of tumors within a few hours. All currently available data have suggested that minute arrayed tissue specimens are highly representative of their donor tissues. There are multiple different types of TMAs that can be utilized in cancer research including multi tumor arrays (containing different tumor types), tumor progression arrays (tumors of different stages) and prognostic arrays (tumors with clinical endpoints). The combination of multiple different TMAs allows a very quick but comprehensive characterization of biomarkers of interest. We anticipate that the use of TMAs will greatly accelerate the transition of basic research findings to clinical applications. © 2001 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: This is the first time that green tea drinking was found to be protective against chronic gastritis, which may be of importance when designing intervention strategies for stomach cancer and its pre‐malignant lesions in the high‐risk population.
Abstract: Despite the declining trend, stomach cancer remains the second most common cancer worldwide. We examined the role of green tea consumption on chronic gastritis and stomach cancer risks. A population-based case-control study was conducted in Yangzhong, China, with 133 stomach cancer cases, 166 chronic gastritis cases, and 433 healthy controls. Epidemiologic data were collected by standard questionnaire and odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models in SAS. Inverse association was observed between green tea drinking and chronic gastritis and stomach cancer risks. After adjusting for age, gender, education, body mass index, pack-years of smoking and alcohol drinking, ORs of green tea drinking were 0.52 (95% CI: 0.29-0.94) and 0.49 (95% CI: 0.31-0.77) for stomach cancer and chronic gastritis, respectively. In addition, dose-response relationships were observed with years of green tea drinking in both diseases. The results provide further support on the protective effect of green tea against stomach cancer. This is the first time that green tea drinking was found to be protective against chronic gastritis, which may be of importance when designing intervention strategies for stomach cancer and its pre-malignant lesions in the high-risk population.

Journal ArticleDOI
TL;DR: It is found that nasosinal tumors were more likely to display higher stage at presentation, and were more often associated with perineural invasion, which concur with previous reports on ACC in terms of survival and recurrence statistics.
Abstract: Adenoid cystic carcinoma (ACC) are uncommon tumors, representing about 10% to 15% of head and neck tumors. We compare the survival and control rates at our institution with those reported in the literature, and examine putative predictors of outcome. All patients registered with the tumor registry as having had ACC were identified. Demographic and survival variables were retrieved from the database. Additionally, a chart review of all patients was done to obtain specific information. Minor gland tumors were staged using the American Joint Committee on Cancer's criteria for squamous cell carcinomas in identical sites. Histopathologic variables retrieved included grade of the tumor, margins, and perineural invasion. Treatment modalities, field sizes, and radiation doses were recorded in applicable cases. An effort to retrieve archival tumor specimens for immunohistochemical analysis was undertaken. A total of 69 patients were treated for ACC from 1955 to 1999. One patient, who presented with fatal brain metastasis, was excluded from further analysis. Of the remaining 68 patients, 30 were men and 38 were women. The average age at diagnosis was 52 years, and mean follow-up was 13.2 years. Mean survival was 7.7 years. Overall survival (OS) rates at 5, 10, and 15 years were 72%, 44%, and 34%, and cause-specific survival was 83%, 71%, and 55%, respectively. Recurrence-free survival rates were 65%, 52%, and 30% at 5, 10, and 15 years, with a total of 29 of 68 (43%) eventually suffering a recurrence. Overall survival was adversely affected by advancing T and AJCC stage. Higher tumor grades were also associated with decreased OS, although the numbers compared were small. Primaries of the nasosinal region fared poorly when compared with other locations. Total recurrence-free survival, local and distant recurrence rates were distinctly better in primaries of the oral cavity/oropharynx when compared with those in other locations. Reduced distant recurrence-free survival was significantly associated with increasing stage. No other variables were predictive for recurrence. Additionally, we found that nasosinal tumors were more likely to display higher stage at presentation, and were more often associated with perineural invasion. Also of interest was the association of perineural invasion with margin status, with 15 of 20 patients with positive margins displaying perineural invasion, while only 5 of 17 with negative margins showed nerve invasion (P = 0.02). On immunohistochemistry, 2 cases of the 29 (7%) tumor specimens found displayed HER-2/neu positivity. No correlation between clinical behavior and positive staining could be demonstrated. Our data concur with previous reports on ACC in terms of survival and recurrence statistics. Stage and site of primary were important determinants of outcome. Grade may still serve a role in decision making. We could not demonstrate any differences attributable to primary modality of therapy, perhaps due to the nonrandomization of patients into the various treatment tracks and the inclusion of palliative cases. Similarly, perineural invasion, radiation dose and field size, and HER-2/neu positivity did not prove to be important factors in our experience.

Journal ArticleDOI
TL;DR: This study provides the first evidence that DNA hypermethylation is used by human neoplastic cells to switch off HLA class I genes, thus providing a new route of escape from immune recognition, in a tumor line derived from a melanoma patient.
Abstract: Cell surface expression of HLA class I/peptide complexes on tumor cells is a key step in the generation of T-cell-based immune responses. Several genetic defects underlying the lack of HLA class I expression have been characterized. Here we describe another molecular mechanism that accounts for the complete absence of HLA class I molecule expression in a tumor line (MSR3-mel) derived from a melanoma patient. Hypermethylation of the MSR3-mel DNA, specifically of HLA-A and -B genes, was identified, which resulted in loss of HLA class I heavy chain transcription. Treatment of MSR3-mel cells with the demethylating agent 5'-aza-2'-deoxycytidine (DAC) allowed HLA-A and -B transcription, restoring cell surface expression of HLA class I antigens and tumor cell recognition by MAGE-specific cytotoxic T lymphocytes. The MSR3-mel line was obtained from a metastatic lesion of a nonresponding patient undergoing MAGE-3.A1 T-cell-based peptide immunotherapy. It is tempting to speculate that the hypermethylation-induced lack of HLA class I expression is the cause of the impaired response to vaccination. This study provides the first evidence that DNA hypermethylation is used by human neoplastic cells to switch off HLA class I genes, thus providing a new route of escape from immune recognition.

Journal ArticleDOI
TL;DR: These studies show that selective and nonselective COX‐2 inhibitors retarded tumor progression in this COX-2‐expressing murine mammary tumor model by inhibiting tumor cell migration, invasiveness and tumor‐induced angiogenesis.
Abstract: Tumor-derived prostaglandins (PGs) have been implicated in the progression of murine and human breast cancer. Chronic treatment with a non-selective PG inhibitor indomethacin was shown in this laboratory to retard the development and metastasis of spontaneous mammary tumors in C3H/HeJ female retired breeder mice. The present study examined the role of endogenous prostaglandins in the proliferation/survival, the migratory and invasive behavior and angiogenic ability of a highly metastatic murine mammary tumor cell line, C3L5, originally derived from a C3H/HeJ spontaneous mammary tumor. This cell line was shown to express high levels of cyclooxygenase (COX) –2 mRNA and protein as detected by Northern and Western blotting as well as immunostaining. PGE2 production by C3L5 cells was primarily owing to COX-2, since this was blocked similarly with non-selective COX inhibitor indomethacin and selective COX-2 inhibitor NS-398, but unaffected with the selective COX-1 inhibitor valeryl salicylate. C3L5 cell proliferation/survival in vitro was not influenced by PGs, since their cellularity remained unaffected in the presence of PGE2 or NS-398 or PG-receptor (EP1/EP2) antagonist AH6809; a marginal decline was noted only at high doses of indomethacin, which was not abrogated by addition of exogenous PGE2. Migratory and invasive abilities of C3L5 cells, as quantitated with in vitro transwell migration/invasion assays, were inhibited with indomethacin or NS-398 or AH6809 in a dose-dependent manner; the indomethacin and NS-398-mediated inhibition was partially reversed upon addition of exogenous PGE2. An in vivo angiogenesis assay that used subcutaneous implants of growth factor-reduced matrigel inclusive of tumor cells showed a significant inhibition of blood vessel formation in these implants in animals treated with indomethacin compared with animals receiving vehicle alone. These studies show that selective and nonselective COX-2 inhibitors retarded tumor progression in this COX-2-expressing murine mammary tumor model by inhibiting tumor cell migration, invasiveness and tumor-induced angiogenesis. The inhibitory effects were not entirely PG dependent; some PG-independent effects were also noted. © 2001 Wiley-Liss, Inc.

PatentDOI
TL;DR: Evaluation of patient liver biopsies for galectin‐3 expression resulted in the finding that hepatocellular carcinoma (HCC) frequently expressed significant levels of this lectin, and co‐transfection studies demonstrated that galECTin‐ 3 expression can occur through transactivation of the lectin promoter by HBV‐X.
Abstract: The present invention relates to the discovery of a marker for liver disease. Novel diagnostics, prognostics, therapeutics and methods of use of the foregoing for the treatment and prevention of hepatocellular carcinoma are also disclosed.

Journal ArticleDOI
TL;DR: It is suggested that low‐penetrance polygenic dominant effects or dominant genes of high penetrance but low mutant allele frequency in the population may be involved in the observed familial cancers at many sites, particularly to gastric, renal, non‐thyroid endocrine, bladder, colon, testicular and prostate cancers and leukemia.
Abstract: Comparisons of cancer risks in persons by sibling cancers and those by parental cancers are informative of elucidating the potential genetic modes in the etiology of the cancers. The Swedish Family-Cancer Database was used to systematically estimate the effects of parental and sibling cancers on the cancer risks in the individuals born after 1934 (offspring). The study population included 5,520,756 offspring and their parents from 2,112,616 nuclear families. Standardized incidence ratios (SIRs) were calculated to analyze the risks for cancers in offspring by parental cancers (offspring risk) and by sibling cancers (sibling risk). For 20 concordant sites, all offspring and sibling risks were significantly increased except for sibling risks for squamous cell carcinoma of the skin and myeloma. Apart from breast cancer, the SIRs were more than 10 when offspring had both an affected parent and an affected sib at the concordant site. The ratio for the sibling to offspring risk was around 2.0 or more for gastric, renal, non-thyroid endocrine, urinary bladder, colon, testicular and prostate cancers and leukemia. For discordant sites, many reported across-site associations were confirmed and several consistent novel associations (rectum-skin, breast-endocrine and lung-endocrine) were found only among sibs. Our findings suggested that low-penetrance polygenic dominant effects or dominant genes of high penetrance but low mutant allele frequency in the population may be involved in the observed familial cancers at many sites. Recessive or X-linked effects may contribute particularly to gastric, renal, non-thyroid endocrine, bladder, colon, testicular and prostate cancers and leukemia. The search for pleiotropic recessive/X-linked susceptibility genes should be well motivated based on our results.

Journal ArticleDOI
TL;DR: The role of frameshift peptide‐directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benefit asymptomatic at‐risk individuals in HNPCC families by a prophylactic vaccination strategy.
Abstract: Microsatellite instability (MSI) caused by defective DNA mismatch repair (MMR) is a hallmark of hereditary nonpolyposis colorectal cancers (HNPCC) but also occurs in about 15% of sporadic tumors. If instability affects microsatellites in coding regions, translational frameshifts lead to truncated proteins often marked by unique frameshift peptide sequences at their C-terminus. Since MSI tumors show enhanced lymphocytic infiltration and our previous analysis identified numerous coding mono- and dinucleotide repeat-bearing candidate genes as targets of genetic instability, we examined the role of frameshift peptides in triggering cellular immune responses. Using peptide pulsed autologous CD40-activated B cells, we have generated cytotoxic T lymphocytes (CTL) that specifically recognize HLA-A2.1-restricted peptides derived from frameshift sequences. Among 16 frameshift peptides predicted from mutations in 8 different genes, 3 peptides conferred specific lysis of target cells exogenously loaded with cognate peptide. One peptide derived from a (-1) frameshift mutation in the TGFbetaIIR gene gave rise to a CTL bulk culture capable of lysing the MSI colorectal cancer cell line HCT116 carrying this frameshift mutation. Given the huge number of human coding microsatellites and assuming only a fraction being mutated and encoding immunologically relevant peptides in MSI tumors, frameshift protein sequences represent a novel subclass of tumor-specific antigens. It is tempting to speculate that a frameshift peptide-directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benefit asymptomatic at-risk individuals in HNPCC families by a prophylactic vaccination strategy.

Journal ArticleDOI
TL;DR: Evidence is provided that mam, PIP, CK19, mamB, muc1 and CEA can be applied as a panel for detection of metastatic and occult micrometastatic disease.
Abstract: Real-time RT-PCR is a relatively new technology that uses an online fluorescence detection system to determine gene expression levels. It has the potential to significantly improve detection of breast cancer metastasis by virtue of its exquisite sensitivity, high throughput capacity and quantitative readout system. To assess the utility of this technology in breast cancer staging, we determined the relative expression levels of 12 cancer-associated genes (mam, PIP, mamB, CEA, CK19, VEGF, erbB2, muc1, c-myc, p97, vim and Ki67) in 51 negative-control normal lymph nodes and in 17 histopathology-positive ALNs. We then performed a receiver operating characteristic (ROC) curve analysis to determine the sensitivity and specificity levels of each gene. Areas under the ROC curve indicated that the most accurate diagnostic markers were mam (99.6%), PIP (93.3%), CK19 (91.0%), mamB (87.9%), muc1 (81.5%) and CEA (79.4.0%). mam was overexpressed in 16 of 17 lymph nodes known to contain metastatic breast cancer at levels ranging from 22- to 2.8 x 10(5)-fold above normal mean expression, whereas PIP was overexpressed from 30- to 2.2 x 10(6)-fold above normal in 13 lymph nodes. Real-time RT-PCR analysis of pathology-negative LN from breast cancer patients revealed evidence of overexpression of PIP (6 nodes), mam (3 nodes) and CEA (1 node) in 8 of 21 nodes (38%). Our results provide evidence that mam, PIP, CK19, mamB, muc1 and CEA can be applied as a panel for detection of metastatic and occult micrometastatic disease.

Journal ArticleDOI
TL;DR: It is concluded that most ILCs show genetic or epigenetic changes affecting the E‐cadherin gene and that many of these tumours lack E‐ cadher in expression, consistent with biallelic inactivation of CDH1 by promoter methylation, mutation or allelic loss in any combination.
Abstract: The cell-cell adhesion receptor gene E-cadherin (CDH1) is expressed by epithelial cells, in which it mediates adhesion and morphogenesis. Invasive lobular carcinoma (ILC) characteristically infiltrates diffusely as single cells; by immunohistochemistry, many of these tumours lack E-cadherin expression. In the present study we investigated various ways in which loss of function of the E-cadherin gene could occur in ILCs, namely, promoter methylation, mutation and allelic loss. We analysed 22 ILCs and found 12 (55%) E-cadherin-negative samples by immunohistochemical analysis. Methylation-specific polymerase chain reaction (PCR) showed that 17/22 (77%) of these tumours had methylation of the CDH1 promoter, including 11/12 (91%) of the E-cadherin-negative tumours. All 16 exons of E-cadherin (including intron-exon boundaries) were amplified from chromosomal DNA and screened for mutations by conformation-sensitive gel electrophoresis (CSGE). Bands with altered mobility were analysed by direct sequencing. We identified five frameshift mutations, which resulted in downstream stop codons and one splice site mutation in six different tumours (29%). Loss of heterozygosity (LOH) was assessed using microsatellite markers, and 9/18 (50%) informative tumours showed LOH. We conclude that most ILCs show genetic or epigenetic changes affecting the E-cadherin gene and that many of these tumours lack E-cadherin expression. In all cases in which there was loss of expression, this was consistent with biallelic inactivation of CDH1 by promoter methylation, mutation or allelic loss in any combination.

Journal ArticleDOI
TL;DR: Both over‐expression of the maintenance DNA methyltransferase DNMT1 and over-expression of a newly identified de novo DNA methyl transferase, DNMT3b, are involved in human carcinogenesis, probably at different stages and through different mechanisms.
Abstract: We evaluated the significance of aberrant DNA methyltransferase expression in human carcinogenesis by examining 32 colorectal and 34 stomach cancers. Levels of mRNAs encoding DNA methyltransferases were measured by reverse transcription, followed by real-time quantitative detection of PCR products. The DNA methylation state of CpG islands and peri-centromeric satellite regions was examined by bisulfite modification and Southern blotting, respectively. The average level of mRNA for DNMT1 and DNMT3b in colorectal and stomach cancers was significantly higher than in corresponding non-cancerous mucosae, whereas the average level of mRNA for DNMT2 was significantly lower in colorectal and stomach cancers than in non-cancerous tissue. Over-expression of DNMT3b in stomach cancer was significantly higher in cases with lymph node metastasis than in cases without. DNA hypermethylation on the p16, human Mut L homologue-1 and thrombospondin-1 genes and the methylated in tumor (MINT) 1, 2, 12, 25 and 31 clones was found in 23%, 27%, 9%, 23%, 20%, 23%, 20% and 10% of the colon cancers and in 9%, 19%, 30%, 25%, 34%, 19%, 81% and 3% of the stomach cancers, respectively. Criteria for identification of the CpG island methylator phenotype (CIMP) were met in 23% of colorectal cancers and 31% of stomach cancers. DNA hypomethylation on satellites 2 and 3 was detected in 0% and 8% of colorectal and stomach cancers, respectively. Over-expression of DNMT1 mRNA was significantly associated with CIMP, whereas the level of DNMT3b mRNA was not associated with CIMP or DNA hypomethylation of peri-centromeric satellite regions. These data suggest that both over-expression of the maintenance DNA methyltransferase DNMT1 and over-expression of a newly identified de novo DNA methyltransferase, DNMT3b, are involved in human carcinogenesis, probably at different stages and through different mechanisms.

Journal ArticleDOI
TL;DR: Overexpression of the growth factor receptors EGFR and erbB2 occurs frequently in several human cancers and is associated with aggressive tumour behaviour and poor patient prognosis, and ZD1839, at the doses studied, is a potent inhibitor of proliferation.
Abstract: Overexpression of the growth factor receptors EGFR and erbB2 occurs frequently in several human cancers and is associated with aggressive tumour behaviour and poor patient prognosis. We have investigated the effects of ZD1839 (Iressa), a novel EGFR tyrosine kinase inhibitor, on the growth, in vitro and in vivo, of human cancer cell lines expressing various levels of EGFR and erbB2. Proliferation of EGFR-overexpressing A431 and MDA-MB-231 cells in vitro was potently inhibited (50%-70%) by ZD1839 with half-maximally effective doses in the low nanomolar range. In parallel, ZD1839 blocked autophosphorylation of EGFR and prevented activation of PLC-gamma 1, ERK MAP kinases and PKB/Akt by EGF. It also inhibited proliferation in EGFR(+) cancer cell lines overexpressing erbB2 (SKBr3, SKOV3, BT474) by between 20% and 80%, effects which correlated with inhibition of EGF-dependent erbB2 phosphorylation and activation of ERK MAP kinase and PKB/Akt in SKOV3 cells. Oral administration of ZD1839 inhibited the growth of MDA-MB-231 and SKOV3 tumours, established as xenografts in athymic mice, by 71% and 32%, respectively. Growth inhibition coincided with reduced proliferation but no change in apoptotic index. Collectively, these results show that ZD1839, at the doses studied, is a potent inhibitor of proliferation not only in cells overexpressing EGFR but also in EGFR(+) cells that overexpress erbB2.