Apoptosis and the response to anticancer therapy

Mow, Benjamin; Blajeski, April L.; Chandra, Joya; Kaufmann, Scott H.

doi:10.1097/00001622-200111000-00007

Cited by 87 publications

(72 citation statements)

References 124 publications

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“…Survivin was originally reported to be overexpressed in a variety of neoplasms (Ambrosini et al, 1997). A growing number of studies have also indicated a correlation between elevated survivin levels and a poor prognosis, for example, in acute myelogenous leukemia, neuroblastoma and malignant glioma as well as cancers of the colon, prostate, ovary, breast, pancreas, and esophagus (reviewed in Mow et al, 2001;Kamihira et al, 2001;Chakravarti et al, 2002). Several additional observations, however, have suggested that survivin might not be an inhibitor of apoptosis.…”

Section: How To Study the Role Of Apoptosis In Drug Resistancementioning

confidence: 99%

Alterations in the apoptotic machinery and their potential role in anticancer drug resistance

2003

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Section: How To Study the Role Of Apoptosis In Drug Resistancementioning

confidence: 99%

Alterations in the apoptotic machinery and their potential role in anticancer drug resistance

2003

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“…Caspases are an important family of proteases responsible for effecting programmed cell death. They are activated in response to excessive cell stress such as radiotherapy induced DNA damage (Mow et al, 2001). The Bcl-2 family also controls the release of apoptosis inducing factor (AIF) and EndoG nuclease from the mitochondria (Susin et al, 1999).…”

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Bcl-2 expression predicts radiotherapy failure in laryngeal cancer

et al. 2005

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Early stage laryngeal cancer can be effectively cured by radiotherapy or conservative laryngeal surgery. In the UK, radiotherapy is the preferred first line treatment. However, up to 25% of patients with T2 tumours will demonstrate locally persistent or recurrent disease at the original site, requiring salvage surgery to achieve a definitive cure. Patients experiencing treatment failure have a relatively poor prognosis. A retrospective analysis was conducted consisting of 124 patients with early stage (T1 -T2, N0) laryngeal squamous cell carcinoma. In total, 62 patients who failed radiotherapy were matched for T stage, laryngeal subsite and smoking history to a group of 62 patients successfully cured by radiotherapy. Using immunohistochemistry the groups were compared for expression of apoptotic proteins: bcl-2, bcl-X L , bax, bak and survivin. Radioresistant laryngeal cancer was associated with bcl-2 (Po0.001) and bcl-X L (P ¼ 0.005) expression and loss of bax expression (P ¼ 0.012) in pretreatment biopsies. Bcl-2 has an accuracy of 71% in predicting radiotherapy outcome. The association between expression of bcl-2, bcl-X L and bax with radioresistant cancer suggests a potential mechanism by which cancer cells avoid the destructive effects of radiotherapy. Predicting radioresistance, using bcl-2, would allow the clinician to recommend conservative laryngeal surgery as an alternative first line treatment to radiotherapy.

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“…Most anticancer agents exert their action by triggering apoptosis (Mow et al, 2001). The product of the tumour-suppressor gene p53 is a key mediator in this process (Soussi, 2000).…”

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Micronuclei to detect in vivo chemotherapy damage in a p53 mutated solid tumour

et al. 2003

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Apoptosis induction and micronuclei formation were compared following cytotoxic treatments in two rat glioma differing in p53 integrity. In vitro, micronuclei emergence but not apoptosis was linked to the p53 mutated status. In vivo, micronuclei assays were more sensitive to evaluate DNA damage induced by chemotherapy in a p53-mutated solid tumour. (Mow et al, 2001). The product of the tumour-suppressor gene p53 is a key mediator in this process (Soussi, 2000). In normal cells, wild-type p53 either arrests cell proliferation until the genetic damage is repaired or forces the cell to commit apoptosis (Cadwell and Zambetti, 2001). In cancer cells, where p53 alleles are often mutated, decrease in apoptosis can be compensated by the process of mitotic catastrophe, a form of cell death resulting from abnormal mitosis and leading to the formation of cells with multiple micronuclei (MN) (Roninson et al, 2001). This study aimed to compare induction of apoptosis and MN formation after chemo-or radiotherapy, in vitro in two rat glioma cell lines differing in p53 integrity, the 9L expressing a mutated p53 gene and the C6 the wild-type gene, and in vivo on established 9L solid tumours. MATERIALS AND METHODS Animals and cell linesAll experiments on Fischer 344 rats have been carried out with local ethical committee approval and met the standards required by the UKCCCR guidelines (Workman et al, 1998). The 9L gliosarcoma cell line and the C6 glioblastoma cell line were maintained in complete medium, RPMI 1640 supplemented with 10% foetal calf serum, 1% L-glutamine, 1% sodium pyruvate, 1% nonessential amino acids, 100 IU ml À1 penicillin and 100 mg ml À1 streptomycin. In vitro and in vivo radio-or chemotherapyFor in vitro treatments, 9L and C6 cells were g-irradiated (80 Gy, 137 Cs irradiator) or treated for 2 h with chemotherapeutic drugs and recultured during 24 or 72 h for apoptosis tests or 4 h for MN assays. For in vivo treatments, tumour-bearing rats (10 5 9L s.c. at day 0) received i.p. injections of cisplatin (1 mg kg À1 ), or were irradiated locally at the tumour site (20 Gy) at days 4, 11 and 18 and were killed the day after. The tumours were then dissected and prepared distinctly for apoptosis or MN assays. Apoptosis assaysAnalysis of caspase 3 activity Caspase-3 activation was measured in vitro by the cleavage of a specific fluorogenic substrate (Ac-DEVD-AMC, BD Biosciences, Erembodegem, Belgium). Briefly, 24 or 72 h after treatment, cells were lysed and incubated first in protease buffer and then for 2 h at 371C with Ac-DEVD-AMC substrate (1 mg ml À1 ). The enzyme-catalysed release of fluorescent AMC was measured, by referring to a standard curve, with a fluorimeter, at 380 nm excitation and 440 nm emission wavelengths.Measurement of phosphatidylserine translocation using AnnexinV -FITC Phosphatidylserine outer translocation on treated cells was detected by flow cytometry (BD FACScan and CellQuest software) using AnnexinV -FITC binding (1 mg ml À1 ) (BD Biosciences) and PI (2 mg ml À1 ) counterstaining.TUNEL a...

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Apoptosis and the response to anticancer therapy

Cited by 87 publications

References 124 publications

Alterations in the apoptotic machinery and their potential role in anticancer drug resistance

Alterations in the apoptotic machinery and their potential role in anticancer drug resistance

Bcl-2 expression predicts radiotherapy failure in laryngeal cancer

Micronuclei to detect in vivo chemotherapy damage in a p53 mutated solid tumour

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