Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors.
OBJECTIVE
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.


METHODS
Ap endo activity was assayed in 52 medulloblastomas and 10 PNETs from patients 0.4 to 21 years 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-1 was 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 < or = 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 with TTP 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.
Bobola
Michael S
MS
Division of Neurosurgery, Department of Surgery, Children's Hospital and Regional Medical Center, Seattle, WA 98105, USA. michael.bobola@seattleschildren.org
Finn
Laura S
LS
Ellenbogen
Richard G
RG
Geyer
J Russell
JR
Berger
Mitchel S
MS
Braga
Justin M
JM
Meade
Elizabeth H
EH
Gross
Mary E
ME
Silber
John R
JR
D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008527:Medulloblastoma / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D015999:Multivariate Analysis; D018242:Neuroectodermal Tumors, Primitive / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013997:Time Factors; D014162:Transfection
D018906:Antineoplastic Agents, Alkylating; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D002330:Carmustine