Apurinic/Apyrimidinic Endonuclease Activity Is Associated with Response to Radiation and Chemotherapy in Medulloblastoma and Primitive Neuroectodermal Tumors

Abstract

Purpose: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to radiation-and alkylator-induced cytotoxic abasic sites in human cells. We assayed apurinic/apyrimidinic endonuclease activity in medulloblastomas and primitive neuroectodermal tumors (PNET) to establish correlates with tumor and patient characteristics and with response to adjuvant radiation plus multiagent chemotherapy. Experimental Design: Ap endo activity was assayed in 52 medulloblastomas and 10 PNETs from patients 0.4 to 21years old. Ape1/Ref-1, the predominant human Ap endo activity, was measured in 42 medulloblastomas by immunostaining. Cox proportional hazards regression models were used to analyze the association of activity with time to tumor progression (TTP). Results: Tumor Ap endo activity varied 180-fold and was significantly associated with age and gender. Tumor Ape1/Ref-1was detected almost exclusively in nuclei. In a multivariate model, with Ap endo activity entered as a continuous variable, the hazard ratio for progression after adjuvant treatment in 46 medulloblastomas and four PNETs increased by a factor of 1.073 for every 0.01 unit increase in activity (P V 0.001) and was independent of age and gender. Suppressing Ap endo activity in a human medulloblastoma cell line significantly increased sensitivity to 1,3-bis(2-chlororethyl)-1-nitrosourea and temozolomide, suggesting that the association of tumor activity withTTP reflected, at least in part, abasic site repair. Conclusions: Our data (a) suggest that Ap endo activity promotes resistance to radiation plus chemotherapy in medulloblastomas/PNETs, (b) provide a potential marker of treatment outcome, and (c) suggest clinical use of Ap endo inhibitors to overcome resistance.

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

“…Our results are supported by those of others in that the suppression of APE1 results in hypersensitivity to chemotherapeutic agents (10,26,27). Additionally, targeted reduction of Ape1/Ref-1 protein by specific anti-sense oligonucleotides renders mammalian cells hypersensitive to methylmethane sulfonate (MMS), H 2 O 2 , bleomycin, temozolomide (TMZ) and gemcitabine (22,28,29). Moreover, Robertson and colleagues found that elevated expression of APE1 in testicular cancer cell lines results in resistance to certain therapeutic agents, such as bleomycin and radiation (21).…”

“…Recent evidence indicated that APE1/Ref-1, the key enzyme in BER pathway, may be a crucial determinant of chemotherapy sensitivity (16)(17)(18)(19)(20)(21)(22). In several tumors, APE1/ Ref-1 subcelluar localization has been demonstrated to have a prognostic value or to correlate with aggressiveness (16,23,24).…”

A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents

“…43), and a central BER component such as APE1, would elicit a more pronounced cytotoxic response to BCNU than single protein -targeted paradigms. Notably, the results of others support the notion that the APE1 repair nuclease capacity is a determinant in BCNU resistance, particularly in brain tumors (21,44).…”

“…[17][18][19][20][21][22][23][24]. These findings reveal a prominent role for APE1 in the repair of specific oxidative, alkylation, and enzymatic DNA intermediates, and identify this protein as a potential target for certain therapeutic paradigms.…”

Human Apurinic/Apyrimidinic Endonuclease 1

“…Some of the earliest work, published by Kelley and colleagues, revealed that APE1 provides resistance against not only MMS and hydrogen peroxide, but also the anti-cancer agents thiotepa, etoposide, and ionizing radiation (221). Through the efforts of many labs since, there is a general consensus emerging that indicates a role for APE1 in dictating cellular responsiveness to clinically relevant alkylators, most notably temozolomide (7,14,137,142,193), and a subset of chain-terminating nucleoside analogs, most prominently troxacitabine (114,137,180). Such a role is consistent with the biochemical activities of APE1, as alkylating agents, particularly mono-functional versions, induce a high number of abasic sites through both direct and indirect mechanisms, and certain anti-metabolites generate exonuclease 3¢-end substrates.…”