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Multifaceted resistance of gliomas to temozolomide
Dora B Bocangel1, Sydney Finkelstein, S Clifford Schold
1Department of Pathology, The University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15261, USA.
Purpose And Experimental Design:
The contributions of O6-methylguanine-DNA-methyltransferase(MGMT), p53 status, mismatch repair, and apoptotic response to the resistance of glial tumors to temozolomide (TMZ) were tested using seven established human glial tumor cell lines in culture and xenografts in athymic mice.
Results:
Resistance to TMZ was only marginally dependent on MGMT activity, because subtoxic doses of TMZ easily eliminated MGMT reserves for at least 18 h after treatment. Resistance to TMZ varied most notably with the p53 status of the tumor. Tumors with wild-type (wt) p53 and a functional p53 response to DNA damage (SWB40 and SWB61) were most sensitive. The p21-related cell cycle arrest was intimately linked to TMZ toxicity because tumors with wt p53 but lacking a robust increase in p21 protein level (D-54) were resistant to TMZ. In contrast, tumors with a dysfunctional p53 cycle and a weak cell cycle response to DNA damage (SWB39 and SWB77) were extremely unresponsive to treatment even with the aid of MGMT inactivators. Notable exceptions to the above were observed with the p53 mutated tumors SWB33 and SWB95, which were arrested by TMZ in G1-S and consequently underwent apoptosis despite their failure to express p21.
Conclusions:
By testing a limited number of glial tumors in cell culture and also as xenografts, we have shown that mobilization of the p53 in response to TMZ damage is likely to induce a cell cycle arrest and apoptosis in glial tumors. Additional pathways linking cell cycle arrest and apoptosis contribute to the efficacy of TMZ against p53 mutated glial tumors. The unusual resistance of tumors, of which the cell cycle was not arrested in response to TMZ treatment, was associated with allelic losses during regrowth of treated tumors. Nevertheless such resistance was not related to dysfunctional mismatch repair.
Insights
Glial tumor resistance to temozolomide (TMZ) primarily depends on p53 status and its DNA damage response, not MGMT activity. A functional p53 response induces cell cycle arrest and apoptosis, enhancing TMZ efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Temozolomide (TMZ) is a key chemotherapeutic agent for glial tumors.
- Understanding resistance mechanisms is crucial for improving treatment outcomes.
- Key molecular factors influencing TMZ response include MGMT, p53, mismatch repair, and apoptosis.
Purpose of the Study:
- To investigate the roles of O6-methylguanine-DNA-methyltransferase (MGMT), p53 status, mismatch repair, and apoptotic response in mediating glial tumor resistance to TMZ.
- To evaluate these factors in both cell culture and in vivo xenograft models.
Main Methods:
- Utilized seven established human glial tumor cell lines.
- Employed athymic mouse xenograft models for in vivo studies.
- Assessed MGMT activity, p53 status, p21 expression, cell cycle arrest, and apoptosis following TMZ treatment.
Main Results:
- TMZ resistance was only marginally linked to MGMT activity.
- Tumor sensitivity to TMZ was strongly correlated with p53 status and a functional p53-mediated DNA damage response.
- Wild-type p53 with robust p21 expression led to cell cycle arrest and sensitivity; dysfunctional p53 or lack of p21 resulted in resistance.
- p53-mutated tumors showed TMZ-induced G1-S arrest and apoptosis, even without p21 expression.
- Resistance in non-arrested tumors was linked to allelic losses during regrowth, not mismatch repair deficiency.
Conclusions:
- p53 mobilization in response to TMZ damage is a critical driver of cell cycle arrest and apoptosis in glial tumors.
- Additional pathways contribute to TMZ efficacy in p53-mutated glial tumors.
- Tumor resistance can arise from allelic losses during regrowth, independent of mismatch repair status.