Sensitivity of short-term cultures derived from human malignant glioma to the anti-cancer drug temozolomide

Sankar, A.S. Suman; Thomas, D. G. T.; Jl, Darling

doi:10.1097/00001813-199902000-00006

Cited by 30 publications

(16 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cells inside a spheroid are facing respiratory stress, lack of nutrients and lack of growth factors. Reports describing an attenuated response of glioblastoma cells to temozolomide treatment (Sankar et al, 1999;Hirose et al, 2001) and a resistance of those cells to undergo apoptosis (Hirose et al, 2001) prompted us to investigate the drug's ability to induce programmed cell death in this cell culture model. In p53 proficient lymphoblastoid tumour cells, it has been shown that temozolomide application (D'Atri et al, 1998) leads to accumulation of p53 and, further downstream along the apoptotic pathway, to the specific DNA degradation pattern.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

et al. 2003

View full text Add to dashboard Cite

Temozolomide is an alkylating cytostatic drug that finds increasing application in the treatment of melanoma, anaplastic astrocytoma and glioblastoma multiforme. The compound is a prodrug that decomposes spontaneously, independent of an enzymatic activation step. DNA methylation induces futile mismatch repair cycles and depletion of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase should then initiate programmed cell death. We show drug-dependent inhibition of tumour growth in a threedimensional cell culture model of the glioma cell lines U87MG and GaMG. Migrational behaviour of the glioblastoma cells remained unaltered. However, coincubation of tumour spheroids with primary brain aggregates showed reduced tumour cell invasion into brain tissue in the presence of temozolomide. This was not achieved by slowing cellular migration, as temozolomide-treated cells displayed no reduced motility. By transferase-mediated dUTP nick-end labelling (TUNEL) of apoptotic nuclei, we found that the drug was able to induce apoptosis throughout the tumour cell spheroids. Apoptosis was highest in the core region of the spheroids. Repetitive application of sublethal doses of temozolomide to multicellular spheroids resulted in the development of drug resistance in GaMG cells. We suggest that temozolomide is a strong initiator of apoptosis in glioblastoma tumour cells in a spheroid cell culture system, when cells are already in a stressful environment.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Most of the studies on temozolomide and its activity against glioma cells were carried out in monolayer cultures (Sankar et al, 1999;Hirose et al, 2001). The spheroid model is a threedimensional cell culture system that more closely resembles the in vivo situation inside a tumour.…”

mentioning

confidence: 99%

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

et al. 2003

View full text Add to dashboard Cite

show abstract

“…First, we show that it is a far more potent anti-glioma agent than many other chemotherapeutic drugs including paclitaxel (Taxol) [5]. In cytotoxicity studies using a clonogenic assay, we found docetaxel to have an LD 90 of 1000 times lower than BCNU or temozolamide [28], the two most frequently used agents against malignant gliomas. We demonstrate that log cell kill occurred at concentrations 2 to 9 times lower than paclitaxel (Taxol) for the same glioma cell lines.…”

Section: Discussionmentioning

confidence: 83%

Interstitial Docetaxel (Taxotere), Carmustine and Combined Interstitial Therapy: a Novel Treatment for Experimental Malignant Glioma

et al. 2006

View full text Add to dashboard Cite

Docetaxel (Taxotere ® ) is a hemisynthetic, anti-cancer compound with good preclinical and clinical activity in a variety of systemic neoplasms. We tested its activity against malignant gliomas using local delivery methods. Antitumor activity was assessed in vitro against human and rat brain-tumor cell lines. For in vivo evaluation, we incorporated docetaxel into a biodegradable polymer matrix, determined associated toxicity in the rat brain, and measured efficacy at extending survival in a rat model of malignant glioma. Also, we examined the combined local delivery of docetaxel with carmustine (BCNU) against the experimental intracranial glioma. Rats bearing intracranial 9L gliosarcomas were treated 5 days after tumor implantation with various polymers (placebo, 5% docetaxel, 3.8% BCNU, or 5% docetaxel and 3.8% BCNU combination). Animals receiving docetaxel polymers (n = 15, median survival 39.1 days) had significantly improved survival over control animals (n = 12, median survival 22.5 days, P = 0.01). Similarly, animals receiving BCNU polymers (n = 15, median survival 39.3 days, 13.3% long-term survivors) demonstrated an increase in survival compared to the controls (P = 0.04). Animals receiving the combination polymers demonstrated a modest increase in survival compared to either chemotherapeutic agent alone (n = 14, median survival 54.9 days, 28.6% long-term survivors) with markedly improved survival over controls (P = 0.003). We conclude that locally delivered docetaxel shows promise as a novel antiglioma therapy and that the combination of drug regimens via biodegradable polymers may be a great therapeutic benefit to patients with malignant glioma.

show abstract

“…The IC 50 for 17a-AED is o20 mM for the glioblastoma and the lymphoma cells. This is particularly noteworthy when one considers that the IC 50 of temozolomide on malignant glioma cell cultures has been reported to be 100 mM or greater (Sankar et al, 1999;Kanzawa et al, 2003aKanzawa et al, , 2004. In addition, investigations by Yoshida et al (2003) on the antiproliferative action of DHEA on human cancer cell lines demonstrated that DHEA at 100 mM could inhibit B50% of Hep G2 hepatoma cell proliferation and 30% of Caco-2 colonic adenocarcinoma cell proliferation; however, there was no significant reduction in tumour cell viability when DHEA was used at this dose.…”

Section: Discussionmentioning

confidence: 99%

The neuro-steroid, 3β androstene 17α diol exhibits potent cytotoxic effects on human malignant glioma and lymphoma cells through different programmed cell death pathways

2007

View full text Add to dashboard Cite

The neuro-steroids 3b-androstene-17a-diol (17a-AED), 3b-androstene-17b-diol (17b-AED), 3b-androstene-7a,-17b-triol (7a-AET) and 3b-androstene-7b,-17b-triol (7b-AET) are metabolites of dehydroepiandrosterone and are produced in neuro-ectodermal tissue. Both epimers of androstenediols (17a-AED and 17b-AED) and androstenetriols (7a-AET and 7b-AET) have markedly different biological functions of their chemical analogue. We investigated the cytotoxic activity of these neuro-steroids on human T98G and U251MG glioblastoma and U937 lymphoma cells. Proliferation studies showed that 17a-AED is the most potent inhibitor, with an IC 50 B15 mM. For T98G glioma, 90% inhibition was achieved with 25 mM of 17a-AED. Other neuro-steroids tested only marginally suppressed cell proliferation. Reduced cell adherence and viability could be detected after 18 h of 17a-AED exposure. Treatment with 17a-AED induced a significant level of apoptosis in U937 lymphoma cells, but not in the glioma cells. Cytopathology of 17a-AED-treated T98G cells revealed the presence of multiple cytoplasmic vacuoles. Acridine orange staining demonstrated the formation of acidic vesicular organelles in 17a-AED-treated T98G and U251MG, which was inhibited by bafilomycin A1. These findings indicate that 17a-AED bears the most potent cytotoxic activity of the neuro-steroids tested, and the effectiveness may depend on the number of hydroxyls and their position on the androstene molecule. These cytotoxic effects may utilize a nonapoptotic pathway in malignant glioma cells.

show abstract

Sensitivity of short-term cultures derived from human malignant glioma to the anti-cancer drug temozolomide

Cited by 30 publications

References 0 publications

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

Interstitial Docetaxel (Taxotere), Carmustine and Combined Interstitial Therapy: a Novel Treatment for Experimental Malignant Glioma

The neuro-steroid, 3β androstene 17α diol exhibits potent cytotoxic effects on human malignant glioma and lymphoma cells through different programmed cell death pathways

Contact Info

Product

Resources

About