Drug-target interactions: only the first step in the commitment to a programmed cell death?

Dive, Caroline; Hickman, John A.

doi:10.1038/bjc.1991.269

Cited by 366 publications

(166 citation statements)

References 55 publications

(49 reference statements)

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“…It has been suggested that defects in the apoptotic pathway can result in chemotherapy resistance (Dive and Hickman, 1991). Many genes that either positively or negatively influence apoptosis have been identified among which are the p53 tumour suppressor gene product and members of the BCL-2 gene family of apoptosis regulators.…”

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confidence: 99%

Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2

Schuyer¹,

Burg²,

Henzen‐Logmans

et al. 2001

Br J Cancer

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Summary Traditional clinicopathological features do not predict which patients will develop chemotherapy resistance. The TP53 gene is frequently altered in ovarian cancer but its prognostic implications are controversial. Little is known on the impact of TP53-downstream genes on prognosis. Using molecular and immunohistochemical analyses we examined TP53 and its downstream genes p21, BAX and BCL-2 in ovarian tumour tissues and have evaluated the results in relation to clinico-pathological parameters, clinical outcome and response to platinum-based chemotherapy. Associations of tested factors and patient and tumour characteristics were studied by Spearman rank correlation and Pearsons χ 2 test. The Cox proportional hazard model was used for univariate and multivariate analysis. The associations of tested factors with response was tested using logistic regression analysis. TP53 mutation, p21 and BCL-2 expression were not associated with increased rates of progression and death. Expression of TP53 was associated with a shorter overall survival only (relative hazard rate [RHR] 2.01, P = 0.03). Interestingly, when combining TP53 mutation and expression data, this resulted in an increased association with overall survival (P = 0.008). BAX expression was found to be associated with both progression-free (RHR 0.44, P = 0.05) and overall survival (RHR 0.42, P = 0.03). Those patients who simultaneously expressed BAX and BCL-2 had a longer progression-free and overall survival compared to patients whose tumours did not express BCL-2 (P = 0.05 and 0.015 respectively). No relations were observed between tested factors and response to platinum-based chemotherapy. We conclude that BAX expression may represent a prognostic indicator for patients with ovarian cancer and that the combined evaluation of BAX and BCL-2 may provide additional prognostic significance.

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confidence: 99%

Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2

Schuyer¹,

Burg²,

Henzen‐Logmans

et al. 2001

Br J Cancer

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“…In addition, defects in the apoptotic pathway may represent a critical element in the progression of neoplastic disease and may also concur to determine treatment efficacy at the cellular level. In fact, many of the effects of the chemical and physical agents that are commonly used in the treatment of human malignancies are mediated by induction of apoptosis (Eastman, 1990;Dive and Hickman, 1991;Schmitt and Lowe, 1999) and thus rely at least in part on the same biochemical mechanisms involved in physiological cell death control. As a consequence, genetic alterations that prevent or delay normal cell turnover may also be responsible for treatment inefficacy in tumour cells.…”

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Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Paradiso¹,

Simone²,

Lena³

et al. 2001

Br J Cancer

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SummaryThe clinical relevance of bax and bcl-2 protein expression has been investigated in 84 patients with recurrent or metastatic colorectal cancer submitted to a chemotherapy regimen including methotrexate and fluorouracil/leucovorin. Cytoplasmic immunostaining of bax and bcl-2 was present in 65.5% and 38%, respectively, of the tumours. No association was found between bax and bcl-2 or between p53 and bax or bcl-2 protein expression. Moreover, the biomarkers were unrelated to patient and tumour characteristics known to affect the clinical outcome of colorectal cancer patients. In general, the apoptosis-related markers did not appear indicative of short-and long-term clinical response nor of prognosis. Bcl-2-negative lesions were more frequent among patients who reached an objective clinical response, which is in agreement with previously reported data regarding other tumour types. When the interrelationship between p53 and bax expression was examined, a better response rate (40%) was found for patients whose tumours did not express p53 and bax, and a better prognosis (2-year probability of overall survival 75%) for patients with p53-positive and bax-negative tumours. In the present series of patients with advanced colorectal cancer submitted to systemic chemotherapy we did not find a clear association between expression of apoptosis-related markers and clinical outcome, even in the subset of patients in which the apoptotic index as determined by the TUNEL approach was investigated.

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“…Other observations indicate that chemotherapeutic agents, y radiation, and hyperthermia, both in vitro (5, 19,21,29,32,) and in vivo (251, exert their cytotoxic effects by induction of apoptosis. Since the cell's propensity to undergo apoptosis appears to be associated with expression of several oncogenes (4,6, 24,47) and can be modulated by a variety of intrinsic and extrinsic factors, knowledge of the mechanism of apoptosis can prove to be of special value in developing therapeutic strategies (23,37). Assessment of apoptosis, either occurring spontaneously in tumors or induced by treatment, can also be of prognostic value in the clinic.…”

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confidence: 99%

Flow cytometric detection of apoptosis: Comparison of the assays of in situ DNA degradation and chromatin changes

et al. 1994

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The aim of this study was to compare three methods of detection of apoptotic cells: (1) the method based on elution of low molecular weight DNA from the ethanol fixed cells followed by cell staining with DAPI (diamidino‐2–phenylindole) or propidium iodide as the DNA fluorochromes, (2) the method of in situ labeling of DNA strand breaks with biotinylated dUTP, utilizing exogenous terminal deoxyribonucleotide transferase, and (3) the method of analysis of DNA denaturation in situ using acridine orange to differentially stain denatured and doublestranded DNA sections following cell exposure to 0.1 M HCl. Cells of the human promyelocytic HL‐60 line, treated in vitro with the DNA topoisomerase I inhibitor camptothecin, which selectively triggers apoptosis of S‐phase cells, were chosen as a model. The method based on analysis of changes in DNA denaturability was the most sensitive in terms of detection of the earliest changes in chromatin of cells undergoing apoptosis; the increased sensitivity of DNA to denaturation in Sphase cells was measured as early as 100 min after addition of camptothecin. DNA cleavage, assayed either by the univariate measurement of DNA content following extraction of low molecular weight DNA, or by labeling DNA strand breaks with biotinylated dUTP, was detected in S‐phase cells after 120 min incubation with camptothecin. The percentage of apoptotic cells at the late stage of apoptosis, the kinetics of cell transition to apoptosis, and kinetics of the loss of S phase cells were all essentially similar when measured by any method. All three methods can be used to estimate the cell cycle phase specificity of apoptosis, although the method based on DNA strand labeling with biotinylated dUTP by terminal deoxynucleotidyl transferase has the advantage of making it possible to estimate the cell cycle distribution of both the apoptotic and unaffected cell populations. The latter method also appears to be the most specific in terms of detection of apoptosis. © 1994 Wiley‐Liss, Inc.

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Drug-target interactions: only the first step in the commitment to a programmed cell death?

Cited by 366 publications

References 55 publications

Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2

Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Flow cytometric detection of apoptosis: Comparison of the assays of in situ DNA degradation and chromatin changes

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