Personalized Cancer Medicine: DNA Repair Alterations Are Promising Predictive Biomarkers in Cancer - DNA Repair in Cancer Therapy - page 254

TABLE 12.1 Base Excision and Single-Strand Break Repair as a Predictive Marker in Human Cancers

Cancer type Treatment Repair enzyme Results Reference

Head and neck Cx APE1 Nuclear expression associated with resistance to

CRT and poor outcome

82

Cervix RT APE1 Inverse relationship between intrinsic

radiosensitivity and APE1 level

83

Seminoma, yolk sac, and
malignant teratoma

Bleomycin APE1 Expression level correlated with DNA repair ability

and confers proportional level protection from
bleomycin treatment

77

NSCLC Cisplatin APE1 Levels correlated with cisplatin resistance 84

Lung cancer RT APE1 Asp148Glu variant associated with sensitivity to

ionizing radiation

97

Lung cancer CRT APE1 Asp148Gln polymorphism associated with 98

[

complete or partial RR but not to Cx alone

NSCLC Platinum-based XRCC1 Response with 339 Arg/Arg genotype than Arg/

Gln or Gln/Gln

102

[

NSCLC Cx XRCC1 194Arg/Trp or Trp/Trp genotype RR than Arg/ 102

[

Arg

NSCLC Platinum-based XRCC1 [ Variant (Gln) alleles at Arg399Gln associated with 103

Y survival

NSCLC Platinum-based XRCC1 Arg194Trp, Arg280His, Arg399Gln polymorphisms

e no association with survival

104

NSCLC Platinum-based XRCC1 T-77C polymorphism e no association with survival 105

Arg genotype at codon 399 e [ Gastric Platinum-based XRCC1 median OS 107

Esophagus Various Cx þ / RT XRCC1 Arg399Gln associated with pathological CR 106

CRC Irinotecan-based XRCC1 Gln399Gln highest mortality 109

CRC Oxaliplatin/5FU XRCC1 Arg399Gln e No association with prognosis 111

Breast Dox/Cyc or Cyc/

MTT/5-FU

XRCC1 AA genotype at locus 1196 association with risk 113

[

recurrence and death

Breast High dose Cx and

autologous SCT

XRCC1 Arg399Gln polymorphism associated with DFS & 116

[

PFS

DLBCL R-CHOP XRCC1 Variant genotypes of XRCC1 194 e no association

with treatment outcome

114

Prostate RT XRCC1 Highest median survival with R399Q AG/R194W

CC haplotype

117

Abbreviations: NSCLC, non-small-cell lung cancer; DLBCL, diffuse large B cell lymphoma; CRC, colorectal cancer; CRT, chemoradiotherapy; RT, radiotherapy;
Cx, chemotherapy; Dox, doxorubicin; cyc, cyclophosphamide; MTT, methotrexate; RR, response rate; DFS, disease-free survival; PFS, progression free survival; OS,
overall survival; CR, complete response; increased; decreased.

[ Y

mice are viable but hypersensitive to oxidative stress. 64
Using either antisense oligonucleotides or siRNA
approaches, several groups reported that depletion of
intracellular APE1 sensitized mammalian cells to
a variety of DNA-damaging agents. 68 e 72 An alternative
approach demonstrated that dominant negative APE1
mutation enhances cellular sensitivity to antimetabolites
(5-fluorouracil and 5-fluorodeoxyuridine) and alkylat-
ing agents (including streptozocin and temozolomide). 73
Heterologous expression studies showed that APE1
restored protection to E. coli AP endonuclease-deficient

domain of APE1 performs a redox regulatory function
that can maintain certain transcription factors, such as
c-Jun and several others, in a reduced and therefore acti-
vated state for DNA binding. 33,53 e 55 Recent evidence also
suggests that APE1 may have a role in transcriptional
regulation, 56 e 59 ribosomal function and RNA

processing. 60,61
Several preclinical studies confirm that APE1 is essen-
tial for cell viability. 62 e 67 Although homozygous dele-
tion of the APE1 homolog in the mouse (APEX) leads
to embryonic APEX / þ

lethality, 62,63

heterozygous