Biomedical subjects

J M Bruner

Publications and source records attributed to J M Bruner.

At least 19 recordsLinked to original sources

PubMed2005

TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation.

Patients with malignant gliomas have a poor prognosis and new treatment paradigms are needed against this disease. TRAIL/Apo2L selectively induces apoptosis in malignant cells sparing normal cells and is hence of interest as a potential therapeutic agent against gliomas. To determine the factors that modulate sensitivity to TRAIL, we examined the differences in TRAIL-activated signaling pathways in glioma cells with variable sensitivities to the agent. Apoptosis in response to TRAIL was unrelated to DR5 expression or endogenous p53 status in a panel of 8 glioma cell lines. TRAIL activated the extrinsic (cleavage of caspase-8, caspase-3 and PARP) and mitochondrial apoptotic pathways and reduced FLIP levels. It also induced caspase-dependent JNK activation, which did not influence TRAIL-induced apoptosis. Because the pro-survival PI3K/Akt pathway is highly relevant to gliomas, we assessed whether Akt could protect against TRAIL-induced apoptosis. Pretreatment with SH-6, a novel Akt inhibitor, enhanced TRAIL-induced apoptosis, suggesting a protective role for Akt. Conversely, TRAIL induced caspase-dependent cleavage of Akt neutralizing its anti-apoptotic effects. These results demonstrate that TRAIL-induced apoptosis in gliomas involves both activation of death pathways and downregulation of survival pathways. Additional studies are warranted to determine the therapeutic potential of TRAIL against gliomas.

Apoptosis↗

PubMed2001

Gamma-radiation sensitivity and risk of glioma.

BACKGROUND: About 9% of human cancers are brain tumors, of which 90% are gliomas. gamma-Radiation has been identified as a risk factor for brain tumors. In a previous pilot study, we found that lymphocytes from patients with glioma were more sensitive to gamma-radiation than were lymphocytes from matched control subjects. In this larger case-control study, we compared the gamma-radiation sensitivity of lymphocytes from glioma patients with those from control subjects and investigated the association between mutagen sensitivity and the risk for developing glioma. METHODS: We used a mutagen sensitivity assay (an indirect measure of DNA repair activity) to assess chromosomal damage. We gamma-irradiated (1.5 Gy) short-term lymphocyte cultures from 219 case patients with glioma and from 238 healthy control subjects frequency matched by age and sex. After irradiation, cells were cultured for 4 hours, and then Colcemid was added for 1 hour to arrest cells in mitosis. Fifty metaphases were randomly selected for each sample and scored for chromatid breaks. All statistical tests were two-sided. RESULTS: We observed a statistically significantly higher frequency of chromatid breaks per cell from case patients with glioma (mean = 0.55; 95% confidence interval [CI] = 0.50 to 0.59) than from control subjects (mean = 0.44; 95% CI = 0.41 to 0.48) (P<.001). Using 0.40 (the median number of chromatid breaks per cell in control subjects) as the cut point for defining mutagen sensitivity and adjusting for age, sex, and smoking status, we found that mutagen sensitivity was statistically significantly associated with an increased risk for glioma (odds ratio = 2.09; 95% CI = 1.43 to 3.06). When the data were divided into tertiles, the relative risk for glioma increased from the lowest tertile to the highest tertile (trend test, P<.001). CONCLUSION: gamma-Radiation-induced mutagen sensitivity of lymphocytes may be associated with an increased risk for glioma, a result that supports our earlier preliminary findings.

Adult↗

PubMed2001

Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations.

Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin H synthase, has been implicated in the growth and progression of a variety of human cancers. Although COX-2 overexpression has been observed in human gliomas, the prognostic or clinical relevance of this overexpression has not been investigated to date. In addition, no study has analyzed the relationship between COX-2 expression and other molecular alterations in gliomas. Consequently, we examined COX-2 expression by immunohistochemistry in tumor specimens from 66 patients with low- and high-grade astrocytomas and correlated the percentage of COX-2 expression with patient survival. We also analyzed the relative importance of COX-2 expression in comparison with other clinicopathological features (age and tumor grade) and other molecular alterations commonly found in gliomas (high MIB-1 level, p53 alteration, loss of retinoblastoma (Rb) protein or p16, and high bcl-2 level). Kaplan-Meier analyses demonstrated that high COX-2 expression (>50% of cells stained positive) correlated with poor survival for the study group as a whole (P < 0.0001) and for those with glioblastoma multiforme in particular (P < 0.03). Cox regression analyses demonstrated that COX-2 expression was the strongest predictor of outcome, independent of all other variables. In addition, high COX-2 expression correlated with increasing histological grade but did not correlate with positive p53 immunostaining, bcl-2 expression, loss of p16 or retinoblastoma protein expression, or high MIB-1 expression. These findings indicate that high COX-2 expression in tumor cells is associated with clinically more aggressive gliomas and is a strong predictor of poor survival.

Adolescent↗

PubMed2001

Risk assessment for developing gliomas: a comparison of two cytogenetic approaches.

Chromosome instability (CIN) measured as chromosome aberrations has long been suggested as a cancer susceptibility biomarker. Conventional cytogenetic end-points are now being improved by combining molecular methods, which increases the sensitivity, specificity, and precision of the assay. In this study we examined both spontaneous and gamma-ray induced CIN in lymphocyte cultures from 51 previously untreated glioma patients and 51 age-, sex- and ethnicity-matched controls. CIN was assessed using two parallel methods: (1) the mutagen sensitivity (MS) assay and (2) the multicolor fluorescence in situ hybridization (FISH) assay. The frequency of spontaneous breaks was significantly higher in glioma patients (mean+/-S.D., 2.12+/-1.07) than in controls (1.24+/-0.86, P<0.001) when using the FISH assay but not the MS assay (0.019+/-0.02 and 0.019+/-0.01, respectively; P=0.915). Similarly, the frequency of induced chromatid breaks was significantly higher using the FISH assay (3.39+/-1.72) but not the MS assay (0.42+/-0.16) in the patients versus controls (2.08+/-1.18 and 0.37+/-0.15, respectively; P<0.001 and P=0.10, respectively). By using the median number of breaks in the controls as the cutoff value, we observed an odds ratio (ORs) of 5.13 (95% CI=2.23-12.1) for spontaneous and 4.86 (95% CI=2.08-11.4) for induced CIN using the FISH assay, whereas the ORs were 1.32 (95% CI=0.49-3.58) and 1.28 (95% CI=0.59-2.80) for spontaneous and induced CIN using the MS assay. There was also a significant increase in the frequency of hyperdiploid cells in the glioma cases which could only be detected using the FISH assay (OR=4.0, 95% CL=0.9-17.0). By combining both methods an estimated risk of 7.0 (95% CI=1.7-25.6) was observed. There was no correlation between the breaks detected by the two methods suggesting that each method is a measure of a different event. The results indicate that using the multicolor FISH assay for detection of CIN in peripheral blood lymphocytes in glioma patients is a more useful marker for risk assessment.

Adult↗

PubMed2001

Genetic abnormalities in oligodendroglial and ependymal tumours.

Oligodendroglial and ependymal tumours are not the most common glial neoplasms; however, they are important subtypes of gliomas with different tumour biologies. Cytogenetic information has suggested that losses of chromosomes 1 p and 19 q are the most frequent genetic alterations in oligodendroglial tumours. Combined loss of these chromosomes has been associated with better chemotherapeutic response and prolonged overall survival. Loss of chromosome 22 is a well defined abnormality in ependymomas. In addition, deletion of chromosome 6 q may be another frequent chromosomic aberration in paediatric ependymomas.

Brain Neoplasms↗

PubMed2001

Adenocarcinoma of the salivary gland metastatic to the pituitary gland: case report.

OBJECTIVE AND IMPORTANCE: A case of metastasis to the pituitary gland from a ductal adenocarcinoma of the salivary gland is presented. Metastasis to this site is rare, and a salivary gland source has never previously been described. CLINICAL PRESENTATION: This patient presented with hypopituitarism, including diabetes insipidus. INTERVENTION: A craniotomy was performed to alleviate visual loss. The histological features of the sellar tumor were identical to those of a tumor removed from the parotid gland 18 months earlier. CONCLUSION: Although intrasellar tumors originating from embryonic rests of salivary gland tissue have been reported, metastasis from a malignant neoplasm arising within a true salivary gland is also possible and should not be excluded from consideration for patients in whom a salivary gland-like tumor is discovered in the sella turcica.

Carcinoma, Ductal, Breast↗

PubMed2000

Toward a molecular classification of the gliomas: histopathology, molecular genetics, and gene expression profiling.

As many as 100,000 new cases of brain tumor are diagnosed each year in the United States. About half of these are primary gliomas and the remaining half are metastatic tumors and non-glial primary tumors. Currently, gliomas are classified based on phenotypic characteristics. Recent progress in the elucidation of genetic alterations found in gliomas have raised the exciting possibility of using genetic and molecular analyses to resolve some of the problematic issues currently associated with the histological approach to glioma classification. Recently, immunohistochemical studies using novel proliferation markers have significantly advanced the assessment of tumor growth potential and the grading criteria of some tumor subtypes. Preliminary studies using cDNA array technologies suggest that the profiling of gene expression patterns may provide a novel and meaningful approach to glioma classification and subclassification. Furthermore, cDNA array technologies may also be used to identify candidate genes involved in glioma tumor development, invasion, and progression. This review summarizes current glioma classification schemes that are based on histopathological characteristics and discusses the potential for using cDNA array technology in the molecular classification of gliomas.

Brain Neoplasms↗

PubMed2000

Patterns of expression of Rb and p16 in astrocytic gliomas, and correlation with survival.

The retinoblastoma pathway is a key cell cycle regulatory complex that controls the passage of cells through the G1 checkpoint and is a frequent target of genetic alterations in gliomas. In this study, we examined the expression of Rb and p16 in 170 primary astrocytic gliomas by immunohistochemical techniques, and correlated the expression with overall survival to determine their prognostic value as immunomarkers. There were 130 patients with glioblastoma multiforme (GBM) and 40 with anaplastic astrocytoma (AA). Alterations in the levels of Rb or p16 expression were seen in the majority (>90%) of the gliomas studied. The expression of Rb was completely absent or low in 47.5% of the GBM and 67.5% of the AA. The remainder of the tumors was immunopositive for Rb to varying degrees. Immunoreactivity for p16 was absent in 56% of the GBM and 77.5% of the AA. Kaplan-Meier survival plots (log-rank test) and Cox proportional hazards regression analysis, adjusted for age and histology, showed that neither Rb nor p16 expression independently predicted survival. The results of our study suggest that although genetic alterations of Rb and p16 are common in gliomas, immunohistochemical analysis of these markers correlates poorly with prognosis.

Adolescent↗

PubMed2000

Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme.

Although the efficacy of the nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematologic and other adverse effects were at 2 week intervals. There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested. The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.

Adolescent↗

PubMed1999

Reactivation of insulin-like growth factor binding protein 2 expression in glioblastoma multiforme: a revelation by parallel gene expression profiling.

We carried out a gene expression profiling study using cDNA array technology with 24 primary glioma tissues of low-grade (oligodendroglioma), intermediate-grade (anaplastic oligodendroglioma and anaplastic astrocytoma), and high-grade (glioblastomas multiforme) tumors and found that insulin-like growth factor binding protein 2 (IGFBP2) was consistently overexpressed only in glioblastoma multiforme. The cDNA array results were confirmed by Northern and Western blotting. The fact that the IGFBP2 gene, which is normally expressed in fetal cells and turned off in adult cells, becomes reactivated in the most advanced stage of glioma suggests that glioma progression is a result of dedifferentiation or results from a block of differentiation. Identification of IGFBP2 as a gene associated with glioma progression demonstrates the power and utility of high-throughput gene expression profiling in cancer gene discovery.

Gene Expression Regulation, Enzymologic↗

PubMed1999

A phase II trial of high-dose bromodeoxyuridine with accelerated fractionation radiotherapy followed by procarbazine, lomustine, and vincristine for glioblastoma multiforme.

PURPOSE: To conduct a Phase II study to evaluate the long-term efficacy and safety of high-dose 5'-bromodeoxyuridine (BrdU) and accelerated radiotherapy followed by procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy in patients with glioblastoma multiforme. METHODS AND MATERIALS: Between 1994 and 1996, 88 patients were enrolled to receive 1.9 Gy of radiation three times a day for two 5-day cycles separated by 2 weeks; each 5-day cycle was preceded by a continuous 96-hour infusion of BrdU at a dose of 2.1 g/m2/day. After radiotherapy, patients received PCV chemotherapy. RESULTS: Median survival for all 88 patients was 50 weeks. Seventy (79.5 %) received one or more courses of PCV; their median survival was 57 weeks. Covariates predictive of improved survival were gross total versus subtotal resection or biopsy (p = 0.0048) and radiation dose > or = 56 Gy (p = 0.019). While receiving BrdU, 47 patients (53%) suffered grade 3 or 4 thrombocytopenia or leukopenia; 22 patients (25%) suffered grade 3 or 4 dermatologic toxicity. CONCLUSION: Survival was not extended in patients with glioblastoma or gliosarcoma who received BrdU at the dose and administration schedule used in this study. The BrdU dose used in this study resulted in substantial myelosuppressive and dermatologic toxicity.

Adult↗

PubMed1999

Increased chromosomal instability in peripheral lymphocytes and risk of human gliomas.

Brain tumors exhibit considerable chromosome instability (CIN), suggesting that genetic susceptibility may contribute to brain tumorigenesis. To test this hypothesis, in this pilot study, we examined for CIN in short-term lymphocyte cultures from 25 adult glioma patients and 28 age-, sex- and ethnicity-matched healthy controls (all Caucasian). We evaluated CIN by a multicolor fluorescence in situ hybridization assay using two probes: a classic satellite probe for a large heterochromatin breakage-prone region of chromosome 1 and an alpha satellite probe for a smaller region adjacent to the heterochromatin probe. Our results showed a significant increase in the mean number of spontaneous breaks per 1000 cells in glioma patients (mean +/- SD, 2.4+/-0.8) compared with controls (1.4+/-0.9; P < 0.001). By using the median number of breaks per 1000 cells in the controls as the cutoff value, we observed a crude odds ratio (OR) of 8.5 [95% confidence interval (CI) = 2.05-34.9, P < 0.001] for spontaneous breaks and brain tumor risk. After adjustment for age, sex and smoking status, the adjusted OR was 15.3 (95% CI, 2.71-87.8). A significant increase in cells with chromosome 1 aneuploidy (in the form of hyperdiploidy) (P < 0.001) was also observed in the glioma cases, with an adjusted OR of 6.6 (95% CI = 1.5-30, P < 0.05). These findings suggest that CIN can be detected in the peripheral blood lymphocytes of brain tumor patients and may be a marker for identifying individuals at risk.

Aneuploidy↗

PubMed1999

Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990-1994.

The Central Brain Tumor Registry of the United States (CBTRUS) obtained 5 years of incidence data (1990-1994)--including reports on all primary brain and CNS tumors--from 11 collaborating state cancer registries. Data were available for 20,765 tumors located in the brain, meninges, and other CNS sites, including the pituitary and pineal glands. The average annual incidence was estimated at 11.5 cases per 100,000 person-years. The higher incidence of tumors in male patients (12.1 per 100,000 person-years) than in female patients (11.0 per 100,000 person-years) was statistically significant (P < 0.05); the higher incidence in whites (11.6 per 100,000 person-years) compared with blacks (7.8 per 100,000 person-years) was statistically significant (P < 0.05). The most frequently reported histologies were meningiomas (24.0%) and glioblastomas (22.6%). Higher rates for glioblastomas, anaplastic astrocytomas, oligodendrogliomas, anaplastic oligodendrogliomas, ependymomas, mixed gliomas, astrocytomas not otherwise specified, medulloblastomas, lymphomas, and germ cell tumors in male than in female patients were statistically significant (P < 0.05), with relative risks (RR) ranging from 1.3 to 3.4. Meningiomas were the only tumors with a significant excess in females (RR = 0.5). We noted higher occurrence rates in whites than in blacks for the following histologies: diffuse astrocytomas, anaplastic astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, mixed gliomas, astrocytomas NOS, medulloblastomas, nerve sheath tumors, hemangioblastomas, and germ cell tumors, with RRs ranging from 1.5 to 3.4. Racial differences in occurrence rates were not observed for predominately benign meningiomas or pituitary tumors. This study represents the largest compilation of data on primary brain and CNS tumors in the United States. Standard reporting definitions and practices must be universally adopted to improve the quality and use of cancer registry data.

Adolescent↗

PubMed1998

Effect of time of sample collection on serum thyroid-stimulating hormone concentrations in euthyroid and hypothyroid dogs.

OBJECTIVE: To determine effect of time of sample collection on serum thyrotropin (canine thyroid-stimulating hormone [cTSH]) concentrations in euthyroid and hypothyroid dogs. DESIGN: Prospective study. ANIMALS: 6 healthy adult euthyroid dogs, 6 adult Beagles with 131iodine-induced hypothyroidism before and during administration of levothyroxine sodium, and 6 adult dogs with naturally developing hypothyroidism. PROCEDURE: Healthy euthyroid dogs were identified. Hypothyroidism was induced by administration of 131sodium iodide and confirmed by thyroid-stimulating hormone testing. These dogs then received levothyroxine for 30 days. Naturally developing hypothyroidism was diagnosed on the basis of clinical signs, low serum thyroxine (T4) concentrations, and high cTSH concentrations or abnormal results on a thyrotropin-releasing hormone response test. Samples for measurement of cTSH and T4 concentrations were obtained at 2-hour intervals from 8 AM to 8 PM. RESULTS: Mean (+/- SD) serum cTSH concentrations for healthy dogs, dogs with induced hypothyroidism before and during treatment, and dogs with naturally developing hypothyroidism were 0.11 +/- 0.08, 3.31 +/- 1.30, 0.08 +/- 0.07, and 0.55 +/- 0.27 ng/ml, respectively. Diurnal variation in cTSH concentrations was not detected. Clinically important random fluctuations in cTSH concentrations were detected for dogs with naturally developing hypothyroidism. CLINICAL IMPLICATIONS: Sample collection time does not appear to predictably influence cTSH concentrations; however, dogs with naturally developing hypothyroidism may have random fluctuations in cTSH concentrations.

Animals↗

PubMed1998

Comparison of serum concentrations of thyroid-stimulating hormone in healthy dogs, hypothyroid dogs, and euthyroid dogs with concurrent disease.

OBJECTIVE: To evaluate use of an assay for measuring serum concentration of canine thyroid-stimulating hormone (cTSH) as an aid for diagnosing thyroid disease in a population of dogs suspected of having hypothyroidism. DESIGN: Case-cohort study. ANIMALS: 62 healthy dogs and 49 dogs with clinical signs consistent with hypothyroidism (16 were hypothyroid and 33 were euthyroid with concurrent disease). PROCEDURE: Samples from healthy dogs were used to establish a reference range for serum cTSH concentration. The 49 dogs were categorized as hypothyroid or euthyroid with concurrent disease on the basis of clinical signs, results of additional diagnostic and thyroid-stimulating hormone (TSH) response tests, and response to administration of levothyroxine sodium. Function of the thyroid gland was considered normal when serum total thyroxine (T4) concentration 6 hours after TSH administration was > 2.5 micrograms/dl. Hypothyroidism was diagnosed when serum T4 concentration after TSH administration was < or = 1.5 microgram/dl. RESULTS: Serum cTSH concentration differed significantly among all 3 groups. Four of 33 (12%) euthyroid dogs had cTSH concentrations that were greater than the reference range, whereas 6 of 16 (38%) hypothyroid dogs had cTSH concentrations within the reference range. Specificity for serum cTSH concentration was 0.88 and sensitivity was 0.63. When interpreted in combination with serum T4 concentration, specificity increased to 1.0. CLINICAL IMPLICATIONS: cTSH assay had good specificity for use in the diagnosis of hypothyroidism in dogs. Because this assay had low sensitivity, a diagnosis of hypothyroidism could not be excluded on the basis of a serum cTSH concentration that was within the reference range.

Animals↗

PubMed1998

Identification of allelic loss on chromosome arm 6p in human astrocytomas by arbitrarily primed polymerase chain reaction.

We employed the arbitrarily primed polymerase chain reaction (AP-PCR), which is a PCR-based genomic fingerprinting technique, to detect novel genetic alterations in human astrocytomas. DNA fingerprints generated by arbitrary primers were compared in normal lymphocytes and tumor tissues from the same individuals. We cloned and sequenced an AP-PCR band showing a greatly decreased intensity in tumor tissue DNA, relative to normal. Southern blot showed that this sequence was homozygously deleted in the tumor cell genome. Semiquantitative PCR analysis further showed significant decreases of signals in seven of 24 tumors, consistent with homozygous deletion of this sequence. The deleted sequence was localized to chromosome region 6p21.1 by the fluorescence in situ hybridization method. Microsatellite analysis also showed frequent allelic loss of this locus compared to neighboring loci in astrocytoma tissues. These results suggest the presence of a novel tumor suppressor gene at the 6p21.1 locus.

Alleles↗

PubMed1998

Detection of p21WAF1/Cip1 in brain metastases.

The p21WAF1/Cip1 (p21) protein, a negative regulator of G1 checkpoint control, was overexpressed in the majority of human gliomas. To investigate whether p21 expression in brain metastases from various systemic origins is similar to that in gliomas and whether p21 expression is regulated differently in brain metastases and in corresponding primary tumors, we used immunohistochemical staining to examine the expression of p21 in paraffin-embedded sections prepared from primary colon and breast carcinomas and from metastatic brain tumors that originated from colon, breast, lung, and kidney cancers and from melanoma. Our results showed that 56% (28 of 50) of the brain metastases samples have more than 1% p21-positive staining cells compared with 87% of primary gliomas reported previously. Among the samples analyzed, p21 expression in brain metastases from breast carcinomas was much higher than in primary breast carcinomas. In contrast, p21 expression in brain metastases from colon carcinomas was less than primary colon carcinomas. The results from this pilot study suggest that p21 expression is regulated differently in metastatic and primary tumors.

Brain Neoplasms↗

PubMed1998

Suppression of human glioma growth by adenovirus-mediated Rb gene transfer.

OBJECTIVE: This study was conducted to obtain evidence that restoration of the retinoblastoma protein function may have therapeutic application for gliomas. BACKGROUND: The development of glioblastoma multiforme involves progressive inactivation of several tumor suppressor genes. Abnormalities of the retinoblastoma tumor suppressor gene are found in the majority of cancers, including at least 30% of malignant gliomas. No final evidence has been produced about the role of Rb in suppressing glioma growth. METHODS: To address this question, the Ad5CMV-Rb adenovirus carrying a 3.2-kb cDNA of the Rb gene was constructed. Expression of the exogenous protein was assessed by immunoblot and immunohistochemistry analyses. Growth curve assays were used to evaluate the effect of the Rb protein on glioma cell growth. Flow-cytometry analyses were used to analyze the phenotype of the cell cycle after the transfer of Rb. Human glioma xenografts implanted subcutaneously in nude mice were used for the tumorigenicity assay. RESULTS: After the transfer of Rb, 80% of the treated cells expressed high levels of the retinoblastoma protein for at least 7 days. Within 5 days of treatment, the cells lost the neoplastic morphology and showed marked growth suppression. The majority of the Rb-expressing cells were arrested in the G1 phase of the cell cycle. In addition, the restoration of the retinoblastoma activity rendered the human glioma cells unable to form tumors in nude mice. CONCLUSIONS: These findings provide direct evidence that inactivation of the retinoblastoma protein is a critical event in gliomas, and suggest that the restoration of wild-type retinoblastoma activity in these tumors may have therapeutic utility.

Adenoviridae↗