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C M Bender

Publications and source records attributed to C M Bender.

18 recordsLinked to original sources
PubMed2001

Cognitive function and reproductive hormones in adjuvant therapy for breast cancer: a critical review.

Deterioration in cognitive function-particularly learning, memory, and attention-has been reported by women with breast cancer who receive adjuvant chemotherapy. Deficits in cognitive function reported by women with breast cancer are similar to those experienced by women as a consequence of natural or surgical menopause. The basis of these deteriorations may include reductions in reproductive hormone levels, particularly estrogens and progesterones, that occur as a result of adjuvant chemotherapy. This paper critically examines the literature related to the impact of adjuvant chemotherapy and reproductive hormone changes on cognitive function in women with breast cancer and suggests direction for future research in this area. The paper proposes a framework for investigation of the problem and discusses the challenges associated with the conduct of this research.

Antineoplastic Agents↗
PubMed2001

Mismatch repair deficiency and CpG island hypermethylation in sporadic colon adenocarcinomas.

Many studies have documented CpG island hypermethylation in human colon adenocarcinomas. Several of these reports have additionally found such CpG island hypermethylation to be more extensive in tumors with a mismatch-repair deficiency, as revealed by microsatellite instability (MSI+). Because the source of samples used in these prior studies may not have been representative of the general population, we have reinvestigated this issue using samples from a population-based study. A total of 15 MSI+ tumors were identified, and they were compared with 47 MSI- tumors that were similar in distribution by age, sex, and race. Microdissected tumor and normal adjacent mucosal DNA samples from each patient were subjected to a quantitative DNA methylation analysis at 13 separate CpG dinucleotides located in five CpG islands in four different genes [APC, ESR1 (ER), CDKN2A (p16; promoter and exon 2), and MLH1]. Four of five CpG islands showed a statistically significantly increased level of methylation in tumor tissue compared with adjacent normal mucosa. In contrast to previous studies, we did not find any statistically significant correlations between MSI status and methylation levels of any of the CpG islands other than MLH1. Furthermore, we observed a positive correlation between MLH1 methylation and CDKN2A methylation (P = 0.03), whereas no association was noted between MSI positivity and CDKN2A methylation (P = 0.95). The latter results suggest a possible defect in the protection against CpG island hypermethylation shared between CDKN2A and MLH1 and do not support the notion of a functional association between CDKN2A methylation and the phenotype of mismatch repair deficiency.

Adenocarcinoma↗
PubMed2000

PAX6 methylation and ectopic expression in human tumor cells.

The mechanisms underlying the de novo methylation of CpG islands in human cancer remain almost completely unknown. We used a methylation-sensitive arbitrarily primed polymerase chain reaction (Ms AP-PCR) technique to scan genomic DNA for differential methylation patterns and identified a 550 bp band that was hypermethylated in a majority of colon and bladder cancer cells. This band corresponded to a CpG-rich region in exon 5 of PAX6, which is a highly conserved transcription regulatory factor involved in embryogenesis. Interestingly, exon 5 was very frequently methylated in solid tumors compared with adjacent normal tissues, 17 out of 27 (63%) in bladder, and colon, but the promoter remained unmethylated in all these cases. This methylation was not effective in blocking transcription since ectopic expression of PAX6 was seen in several tumors and cell lines with extensive exon 5 methylation. De novo methylation of the promoter was only seen in tumor cell lines and was associated with gene silencing since treatment with 5-aza-2'-deoxycytidine restored expression to the cells and resulted in a less methylated promoter. Thus, ectopic expression and hypermethylation of exon 5 of PAX6 demonstrate that methylation within a transcribed region, as opposed to promoter methylation, does not block gene expression.

Antimetabolites, Antineoplastic↗
PubMed2000

Cognitive function and quality of life in interferon therapy for melanoma.

The purpose of this pilot study was to describe short- and long-term changes in cognitive function and quality of life in patients with melanoma receiving interferon (IFN) alpha-2b. This study used a three-group, repeated measures design in which cognitive function and quality of life were evaluated prior to initiation of treatment at 3-month intervals during treatment and 3 months following the completion of treatment. The sample consisted of 16 adults with Stage II or III melanoma, randomized to one of three treatment groups. Participants in Arm A received high-dose IFN alpha-2b, those in Arm B received low-dose IFN alpha-2b, and those in Arm C received no therapy (control). No significant changes in cognitive function were detected. In participants in Arm A, there was a significant deterioration in the physical well-being dimension of quality of life from baseline to 3 months after beginning therapy.

Antineoplastic Agents↗
PubMed1999

Roles of cell division and gene transcription in the methylation of CpG islands.

De novo methylation of CpG islands within the promoters of eukaryotic genes is often associated with their transcriptional repression, yet the methylation of CpG islands located downstream of promoters does not block transcription. We investigated the kinetics of mRNA induction, demethylation, and remethylation of the p16 promoter and second-exon CpG islands in T24 cells after 5-aza-2'-deoxycytidine (5-Aza-CdR) treatment to explore the relationship between CpG island methylation and gene transcription. The rates of remethylation of both CpG islands were associated with time but not with the rate of cell division, and remethylation of the p16 exon 2 CpG island occurred at a higher rate than that of the p16 promoter. We also examined the relationship between the remethylation of coding sequence CpG islands and gene transcription. The kinetics of remethylation of the p16 exon 2, PAX-6 exon 5, c-ABL exon 11, and MYF-3 exon 3 loci were examined following 5-Aza-CdR treatment because these genes contain exonic CpG islands which are hypermethylated in T24 cells. Remethylation occurred most rapidly in the p16, PAX-6, and c-ABL genes, shown to be transcribed prior to drug treatment. These regions also exhibited higher levels of remethylation in single-cell clones and subclones derived from 5-Aza-CdR-treated T24 cells. Our data suggest that de novo methylation is not restricted to the S phase of the cell cycle and that transcription through CpG islands does not inhibit their remethylation.

Azacitidine↗
PubMed1998

The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines.

Methylation of CpG sites in the control regions of tumor suppressor genes may be an important mechanism for their heritable, yet reversible, transcriptional inactivation. These changes in methylation may impair the proper expression and/or function of cell cycle regulatory genes and confer a selective growth advantage to affected cells. Detailed methylation analysis using genomic bisulfite sequencing was performed on a series of subclones of a bladder cancer cell line in which a hypermethylated p16 gene had been reactivated by transient treatment with 5-aza-2'-deoxycytidine. Methylation of the CpG island in the promoter of the p16 gene in human bladder cancer cells did not stop the formation of a transcript initiated 20 kb upstream by the p19 promoter but did prevent the expression of a p16 transcript. Furthermore, we show that reactivant clones that expressed p16 at varying levels contained heterogeneous methylation patterns, suggesting that p16 expression can occur even in the presence of a relatively heavily methylated coding region. We also present the first functional evidence that methylation of only a small number of CpG sites can significantly down-regulate p16 promoter activity, thus providing support for the model of progressive inactivation of this tumor suppressor gene by DNA methylation.

Azacitidine↗
PubMed1998

Inhibition of DNA methylation by 5-aza-2'-deoxycytidine suppresses the growth of human tumor cell lines.

Alterations in DNA methylation patterns accompany the establishment of immortal cell lines. De novo methylation of CpG islands within the control regions of growth-regulatory genes may inactivate their transcription, giving cells selective growth advantages in culture. We exposed seven human tumor cell lines and two human fibroblast cell strains to the demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-CdR), to determine whether the silencing of growth-regulatory genes by de novo methylation in immortalized cell lines could be reversed, possibly restoring growth control. After recovery from the immediate cytotoxic effects of 5-Aza-CdR, this agent suppressed cellular growth in all seven tumor lines but not in either fibroblast strain. Because alterations in the p16 (CDKN2/MTS1) cell cycle regulatory gene are associated with numerous cancers, we analyzed expression of this gene before and after 5-Aza-CdR treatment. The gene was reactivated by 5-Aza-CdR treatment in three of four tumor cell lines not expressing p16, whereas the fourth tumor line contained a p16 homozygous deletion. p16 was shown to be hypermethylated only in the cell lines and its up-regulation by 5-Aza-CdR was associated with demethylation of the p16 promoter. The remaining tumor lines expressed p16 at constant levels before and after 5-Aza-CdR treatment and showed minimal p16 promoter methylation, suggesting that other growth-regulatory genes may have been silenced by de novo methylation in these cells. p16 expression, cell growth inhibition, and G1 cell cycle arrest by 5-Aza-CdR in the T24 bladder tumor cell line were also heritable after prolonged passage in culture. Furthermore, a dormant p16 gene was reactivated in T24 cells growing in nu/nu rats, and 5-Aza-CdR treatment of T24 cells before inoculation into nu/nu mice decreased the rate of tumor growth. These results suggest that 5-Aza-CdR may slow the growth of tumor cells by reactivating growth-regulatory genes silenced by de novo methylation.

Animals↗
PubMed1998

DNA methylation as a target for drug design.

DNA methylation is essential for normal embryonic development. Distinctive genomic methylation patterns must be formed and maintained with high fidelity to ensure the inactivities of specific promoters during development. The mutagenic and epigenetic aspects of DNA methylation are especially interesting because they may lead to the inactivation of genes which are involved in human carcinogenesis. The mutagenicity of 5-Methylcytosine (5mC) and the role of promoter hypermethylation in gene silencing, particularly in cancer, suggest a clinical significance for the design of novel DNA methylation inhibitors which may be utilized to reverse the effects of DNA methylation.

Animals↗
PubMed1997

Low frequency of p16/CDKN2A methylation in sporadic melanoma: comparative approaches for methylation analysis of primary tumors.

Methylation of the 5' CpG island of the p16 tumor suppressor gene represents one possible mechanism for inactivation of this cell cycle regulatory gene that is also a melanoma predisposition locus. We have investigated the potential contribution of somatic silencing of the p16 gene by DNA methylation in 30 cases of sporadic cutaneous melanoma. The methylation status of the 5' CpG island of p16 was initially determined by Southern analysis and then reevaluated (in a blinded manner) using methylation-specific PCR, methylation-sensitive single nucleotide primer extension, and bisulfite genomic sequencing. All methodologies yielded concordant results, and significant levels of methylation were observed in 3 of the 30 (10%) melanoma DNAs analyzed. Of the three tumors found to be methylated, two were also positive for LOH on 9p21 (where the p16 gene resides), implying that both p16 alleles were inactivated, one via deletion and the other via methylation-associated transcriptional silencing. The association between methylation and transcriptional silencing of p16 was also further supported by inducing p16 expression with a DNA demethylating agent (5-aza-2'-deoxycytidine) in a melanoma cell line known to harbor a methylated p16 allele. Although methylation-associated gene silencing does not represent a common mechanism for p16 inactivation in sporadic melanoma, our findings provide support that PCR-based techniques, such as methylation-specific PCR and methylation-sensitive single nucleotide primer extension, can be reliably used for the accurate detection and quantitation of aberrant levels of DNA methylation in tumor specimens.

Chromosome Deletion↗
PubMed1995

Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing.

Loss of heterozygosity on 9p21, where the p16/CDKN2 tumor suppressor and the p15INK4B cell cycle regulator genes are located, is a common genetic alteration in bladder cancer. However, it has been difficult to demonstrate homozygous deletions and intragenic mutations in either of these two genes in primary transitional cell carcinomas (TCC) of the bladder. Similarly, colon cancer-derived cell lines have shown no homozygous deletions of the p16/CDKN2 locus in contrast to a wide variety of tumor-derived cell lines. We have investigated abnormal methylation of the 5' CpG islands of the p16/CDKN2 and p15INK4B genes as an alternative mechanism of inactivation of these genes in bladder and colon cancers. De novo methylation of the 5' CpG island of p16/CDKN2 was observed in 12 of 18 (67%) uncultured bladder TCCs and in 2 of 3 (67%) bladder cell lines. In contrast, only 1 of 10 (10%) colon carcinomas showed methylation of the 5' CpG island of p16/CDKN2. It was striking to find that this region was extensively methylated and the gene not expressed in the normal colonic mucosa of 6 of 10 (60%) patients with colon cancer, whereas 5 of the corresponding colon tumors showed no methylation and high levels of p16/CDKN2 expression. Our data show a significant correlation (P = 0.00001, two-sided) between the absence of p16/CDKN2 expression and methylation of its 5' CpG island in bladder tumors, cell lines, and normal colon mucosa. In contrast, no association was observed between expression and methylation status of the 5' CpG island of p15INK4B. Our results suggest that the p16/CDKN2 tumor suppressor gene may be inactivated by methylation of its 5' CpG island in TCCs of the bladder. We also present evidence of methylation of the 5' CpG island in this autosomal gene in normal colonic tissue.

Base Sequence↗
PubMed1995

Ifosfamide-induced neurotoxicity: associated symptoms and nursing implications.

PURPOSE/OBJECTIVES: To review current understanding of the neurotoxicity associated with ifosfamide administration. DATA SOURCES: Published studies of ifosfamide-induced neurotoxicity, published literature on other causes of neurotoxicity associated with cancer, and a case study. DATA SYNTHESIS: Ifosfamide-induced neurotoxicity has not been well-described in the nursing literature. To correctly identify ifosfamide-induced neurotoxicity, nurses need to assess the patient's history and neurologic, affective, and cognitive status and implement appropriate nursing interventions. CONCLUSIONS: Research aimed at accurate identification of ifosfamide-induced neurotoxicity and the most effective nursing interventions is needed. IMPLICATIONS FOR NURSING PRACTICE: Judicious nursing assessment will facilitate differentiation of ifosfamide-induced neurotoxicity from other neurotoxicities associated with cancer and its treatment.

Brain Diseases↗
PubMed1994

Cognitive dysfunction associated with biological response modifier therapy.

PURPOSE/OBJECTIVES: To review current knowledge regarding the cognitive dysfunction related to administration of biological response modifiers (BRMs), including assessment and nursing intervention. DATA SOURCES: Published studies of cognitive dysfunction in people receiving BRMs, including research based on clinical observation and using pre- and post-treatment measures of cognitive and neurologic function. DATA SYNTHESIS: BRM-associated cognitive dysfunction is a significant clinical problem; however, its mechanisms of action are poorly understood. Clinical observation of patients cognitive and neurologic assessment, and interventions based on presence of premonitory symptomatology are warranted. CONCLUSIONS: Continued research into the causes of this problem and the definition of intervention protocols is needed. IMPLICATIONS FOR NURSING PRACTICE: Anticipatory care including assessing for early identification and family involvement in monitoring for changes, performing structured assessment of cognitive function, ensuring patient safety and reorientation, if necessary, and minimizing sleep disturbances.

Clinical Trials as Topic↗
PubMed1992

Management of chemotherapy-related nausea and vomiting using a serotonin antagonist.

Patients receiving chemotherapy continue to experience nausea and vomiting despite recent strides to understand the physiology of these symptoms and despite current antiemetic therapies. Ondansetron, a serotonin antagonist, has shown to be a safe and effective drug in alleviating nausea and vomiting. This research-synthesis article provides summaries of eight clinical trials completed between 1988 and 1991. It includes a discussion of the pharmacodynamics and pharmacokinetics of ondansetron, suggestions for adverse events, and implications for nursing practice and future research.

Antiemetics↗
PubMedDate not supplied

An introduction to oxygen free radicals.

Oxygen free radicals are byproducts from the fundamental metabolic activities within the body. Normally, radicals are neutralized by enzymatic activity or natural antioxidants. Thus the generation of free radicals poses no problem so long as the balance between oxygen radical production and eradication remains in balance. There are multiple medical conditions, such as myocardial infarction, carcinogenesis, and neurologic trauma, to name a few, that may be aggravated by the presence of oxygen free radicals. This article will present an overview of oxygen free radicals: their normal formation and control and how they might further injure tissue in particular diseases. The implications for health care professionals are highlighted.

Antioxidants↗
PubMedDate not supplied

Potential mechanisms of interferon neurotoxicity.

This article examines potential mechanisms underlying the neurologic toxicities associated with interferon therapy in patients with cancer. The following mechanisms for interferon-related toxicities have been proposed: changes in certain neuroendocrine hormone levels; structural similarities and common pathways between interferon and specific neuroendocrine hormones; and the immunoregulatory effects of interferon. Strategies for the assessment and management of interferon-related neurologic toxicities are discussed. A reduction in dose or discontinuation of interferon may be recommended if interferon neurotoxicity develops. Additional interventions may include reorientation strategies, provision of uninterrupted periods of rest, and safety precautions. Directions for future research are recommended.

Antineoplastic Agents↗