PARENT SESSION
1:30 PM to 3:30 PM
Sunday, April 21, 2002
Poster Session 8 Radiosensitizers and Bioreductive Drugs
Room: Nevada Exhibition Center

(P13-128) Role of p53 in the resistance of gliomas to BCNU and TMZ.

Bocangel, Dora^*,1, Bhakat, Kishor¹, Kokkinakis, Demetrius², Mitra, Sankar¹, ¹ Sealy Center for Molecular Sciences, Galveston, TX² University of Pittsburg, Pittsburg, Pennsylvania

ABSTRACT-
Tumor suppressor p53 regulates apoptosis, cell-cycle arrest, and DNA repair. Mutations of p53 are linked with poor prognosis for advanced, metastatic and hormone-refractory cancers. In vitro, loss of p53 function increases post irradiation clonogenic cell survival, and the radiobiological response of glioblastoma cells is p53-dependent. The presence of mutant p53 has also been shown to decrease resistance to therapy in some tumor types. In spite of the different findings, the majority of the literature supports a role for p53 in resistance to anticancer therapy. Therapy for most cancers involves a combination of surgery, ionizing radiation (IR), and chemotherapy. The toxic effect of IR occurs primarily through induction of DNA strand breaks. Chemotherapeutic agent BCNU induces base adducts that cause interstrand crosslinks, and subsequently DNA strand breaks. Temozolomide (TMZ), another agent currently used, induces Guanine adducts, which are subject to repair by MGMT. TMZ does not cause DNA crosslinks, but induces apoptosis when the Guanine mispairs, and triggers abortive mismatch repair (MMR), and DNA strand breaks. Here we examine the response of glioma cells to cytotoxic agents BCNU and TMZ, in relation to p53 status and other mechanisms of resistance (MMR and MGMT). Above a threshold of MGMT (45 fmol/mg protein), resistance to BCNU in the glioblastoma cells correlated with MGMT level, but resistance to TMZ did not. Overall, cell lines with functional p53 were markedly more sensitive to TMZ than those with mutated p53. Ectopic expression of wt-p53 downregulates MGMT promoter activity, yet the mechanism for this effect is not known. p53-dependent transactivation requires its interaction with p300/CBP as a coactivator. Here we show that a mutant form of p53 (unable to bind p300/CBP) did not downregulate MGMT promoter activity. Moreover, wt-p53-mediated repression of MGMT promoter activity is partially relieved by p300 overexpression. (NIH Grants CA57725, CA78561 and CA84461).

KEYWORDS: p53, glioma, MGMT, resistance