ANTICANCER RESEARCH 28: 2437-2442 (2008)
Influence of Valproic Acid on Outcome of
High-grade Gliomas in Children
AMIRHADI MASOUDI, MARILY ELOPRE, ELHAM AMINI, MARGARET E NAGEL,
JOANN L. ATER, VIDYA GOPALAKRISHNAN and JOHANNES E.A. WOLFF
Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center,
1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
Abstract. Background: Chemotherapy has limited effects in
the treatment of high-grade gliomas (HGGs). Valproic acid
(VPA), a histone deacetylase (HDAC) inhibitor, may
sensitize HGGs to radiochemotherapy. As the drug has been
given frequently as an antiepileptic drug, a retrospective
analysis was conducted to ensure relevant information was
not missed before a prospective study was launched.
Materials and Methods: An analysis of 66 pediatric patients
(range, 1-19 years of age) with glioblastoma multiforme
(GBM) (n=40) or anaplastic astrocytoma (AA) (n=26) was
retrospectively conducted for predictors of survival and
response and for effects of VPA on outcome or toxicity.
Results: The overall survival (OS) was better for AA
(p=0.0114) and complete resection (p<0.00005) and event-
free survival (EFS) was better for complete resection
(p=0.0049). Nine patients received VPA (for seizure) plus
further oncological treatment. The most severe adverse effect
was a pulmonary embolism (n=1); no other severe side-
effects were noted. The response to nonsurgical treatment
after 8 weeks was: complete response (CR): 0, partial
response (PR): 3, stable disease (SD): 4, progressive disease
(PD): 2. Some of the patients with SD responded later
resulting in best response: CR:0, PR:5, SD:2, PD:2.
Conclusion: Treatment with VPA plus radiochemotherapy is
well tolerated with an encouraging response rate.
High-grade gliomas (HGGs), such as anaplastic astrocytomas
(AA) and glioblastoma multiforme (GBM), are relatively rare
in children (1, 2). HGGs in children are typically treated
Correspondence to: Dr. Johannes E.A. Wolff, Division of Pediatrics,
Section of Pediatric Neuro-Oncology, The University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Blvd, Unit 87, Houston,
TX 77030, U.S.A. Tel: +1 713 794 4963, Fax: +1 713 794 5042,
e-mail: jwolff@mdanderson.org
Key Words: Anaplastic astrocytoma, glioblastoma multiforme, high
grade glioma, histone deacetylase inhibitor, pediatric, valproic acid.
0250-7005/2008 $2.00+.40
with a combination of surgery, radiotherapy (RT) and/or
chemotherapy (3, 4). Grossly total resection of HGG has
been shown to improve survival and this improvement is
particularly striking in pediatric patients ( 5, 6) . RT is
also known to improve survival ( 4) . Treatment with
prednisone, lomustine, and vincristine has also been
shown to improve survival in children with HGG (7) and
temozolomide improves survival in adults with HGG (8,
9). However, the best choice of agents remains an area of
debate ( 10) . Furthermore, despite all therapeutic
approaches, the prognosis for patients with HGG is
generally dismal (2, 6), emphasizing the need for novel
approaches such as epigenetic modulation of gene
expression, a powerful therapeutic option for various
other malignancies (11, 12).
Valproic acid (VPA) has traditionally been used to treat
epilepsy and migraines and for mood stabilization (13). Now
it has also been shown to be a histone deacetylase (HDAC)
inhibitor (14, 15). HDACs are enzymes involved in the
remodeling of chromatin and they have a key role in the
epigenetic regulation of gene expression (16). Inhibition of
HDAC induces tumor cell differentiation, apoptosis and
growth arrest (12, 14). In preclinical studies, VPA inhibited
human and rodent glial tumor cell growth and induced a
distinct mature glial phenotype (12, 17). Evidence has also
been presented that HDAC inhibitors can sensitize malignant
cells to RT (18, 19) and chemotherapy (14, 20). Clinical
evidence of cellular differentiations and tumor control is rare,
however, epileptic patients receiving VPA have significantly
enhanced hemoglobin F levels, supporting the hypothesis
that nontoxic levels of VPA can induce cellular
differentiation (21). Tumor response to valproate sodium has
also been described (11).
Prospective studies will be necessary to clarify the
possible role of VPA as an adjuvant to chemotherapy in
HGG. However, because VPA is given for antiepileptic
treatment in brain tumor patients, a retrospective study of
HGG patients could offer important insights into VPA
effects and help guide prospective study design. Therefore,
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 ANTICANCER RESEARCH 28: 2437-2442 (2008)
before launching a prospective study, pediatric patients
(children and adolescents <19 years of age) with HGGs
were retrospectively analyzed to determine whether VPA
influenced survival and response rates or adverse events in
these patients.
Patients and Methods
This retrospective chart analysis was reviewed and approved by the
Institutional Review Board of The University of Texas M.D.
Anderson Cancer Center. The institutional database was used to
locate pediatric patients with HGG from 1997 to 2007. The
eligibility criteria for the first data extraction included age <19 years
and histologically confirmed HGG. These eligibility criteria were
validated by clinical records as primary data sources resulting in a
smaller, improved database encompassing sex, age at diagnosis,
tumor location, histology, surgery type, radiation dose,
chemotherapy protocol, adverse events, VPA use, response, follow-
up time and status at last follow-up.
Patients’ disease response to either radiation, or chemotherapy or
both was classified as continuing complete remission (CCR;
continuing absence of radiographically identifiable tumor after
resection), complete response (CR; complete disappearance of all
detectable disease), partial response (PR; a reduction in tumor
volume of ≥50% ), stable disease (SD; a decrease in tumor volume
of <50% or an increase of ≤25% ), and progressive disease (PD; an
increase in tumor volume of >25% ).
The Common Terminology Criteria for Adverse Events Version
3.0 (from the U.S. National Cancer Institute (22)) was used to
assess side-effects. These criteria do not include lactic acid
dehydrogenase (LDH) level among the defined toxic effects.
Therefore, a total LDH level of <270 U/l was defined as normal
and a total LDH level of 270-675 U/l, 676-1350 U/l, 1351-5500
U/l and >5500 U/l as grade I, II, III and IV toxic effects,
respectively.
In order to determine if the relevant parameters differed in the
VPA group from the other patients, the total group of pediatric HGG
patients was described and potential predictive factors were
analyzed for their effect on event-free survival (EFS) and overall
survival (OS) times using the log-rank test, subgroup analyses and
Cox regression analyses. To analyze response, the patients who
achieved a CCR after complete resection were excluded.
The relevant parameters were then compared between the
patients who received VPA and those who did not receive VPA
using Chi-square analysis for the qualitative parameters of the
database and analysis of variance for the quantitative parameters.
A matched-pair analysis of the effect of receiving VPA versus not
receiving VPA was conducted using the predicatively relevant factors
(tumor grade and resection type) and follow-up time. If two or more
patients who did not receive VPA were eligible to match with one
patient who did receive VPA, the most recently treated patient was
selected. The initial response (8 weeks after the initiation of
treatment), the best response, which included both early and late
response, as well as EFS and OS were compared between patients
who received VPA and those who did not.
Descriptive tools were used to assess the side-effects. For all the
analyses, SPSS software, version 12.0 (SPSS Inc., Chicago, Illinois,
USA) was used. Because the analyses were descriptive, no level of
statistical significance was set. However, p<0.05 was considered
relevant enough to merit further attention.
2438
Results
Sixty-six patients with histologically proven grade III or IV
glioma who were treated at M.D. Anderson Cancer Center
between 1997 and 2007 were found. There were 34 males
and 32 females, with a median age at diagnosis of 12.5 years
(range, 1-19 years). The median follow-up time was 53
weeks. Twenty percent of the patients had undergone a
complete resection, 59% had undergone a subtotal or partial
resection and 21% had undergone a biopsy without
resection. Thirty-nine patients received antiepileptic drugs
(AEDs) either because of known epilepsy or to prevent
seizure after surgery and 9 of these received VPA. The
median RT dose was 56 Gy. The initial response to RT
and/or chemotherapy reported 8 weeks after initiation of
treatment was evaluated, 17 patients had PD, 16 had SD, 13
achieved a PR and 7 achieved a CCR. No response
information was available in 13 patients. The best response
achieved was PD in 10 patients, SD in 17, PR in 18 and CCR
in 8. No best response information was available in 13
patients. The median OS time of all patients was 1.5 years.
A significant difference in OS (p<0.00005) and EFS
(p=0.0049) was detected between patients who had
undergone total resection or less than total resection. The
patients who had undergone a complete tumor resection
achieved the best survival, and those who had undergone
biopsy without resection had the worst survival (Figure 1).
The patients with AA achieved significantly better OS than
patients with GBM (p=0.0114, Figure 2). On Cox regression
analysis, both resection type and tumor grade were
statistically relevant predictors of survival. There were no
significant differences in EFS between the groups categorized
by sex (p=0.8912), age at diagnosis (p=0.5681), tumor
location (p=0.1611) and tumor grade (p=0.0567). There were
also no significant differences in OS between groups
categorized by sex (p=0.5130), age at diagnosis (p=0.4797)
and tumor location (p=0.2062). Subgroup analyses did not
reveal any relevant differences either. The patients who
achieved at least a PR had better survival times than those
with SD or PD regardless of whether their initial response
after 8 weeks of treatment (OS p=0.0016 and EFS
p<0.00005; Figure 3) or their best response (OS p=0.0209
and EFS p<0.00005) was used for analysis. These
comparisons remained significant on Cox regression analysis.
Nine out of the 66 patients received VPA as an AED in
addition to further oncological treatment (Table I). The
median age at diagnosis was 11 years. The median duration
of VPA administration was 18 weeks and the median follow-
up time was 55 weeks. The location of the tumor was
supratentorial in seven patients and infratentorial in two. Five
patients came to M.D. Anderson at the time of primary
diagnosis and four came upon relapse. In eight patients, VPA
was prescribed as a monotherapy to control seizures.
 Masoudi et al: VPA in Pediatric Patients with HGG

Figure 1. Overall survival related to type of resection in 66 patients with Figure 2. Overall survival related to histology in 66 patients with HGG
HGG (p<0.00005). Total resection n=13, subtotal resection (n=28), (p=0.0114). AA: Anaplastic astrocytoma (n=26), GBM: glioblastoma
partial resection (n=11), biopsy (n=14). multiforme (n=40).

However, one patient continued to have seizures, and

clonazepam was added to VPA. Valproate plasma levels were
between 50 and 173 mg/l, with a median of 62 mg/l. One
patient had one episode of VPA toxicity reported, with a
valproate blood level of 173 mg/l.
Table II summarizes the adverse events experienced by the
nine patients who received VPA. In five of the patients, no
grade III/IV hematological events were documented. One
patient had grade IV leukopenia, two had grade III
thrombocytopenia, and one had both grade III
thrombocytopenia and grade III leukopenia. All the patients
with grade III or IV thrombocytopenia were treated with
platelet transfusions. The incidence of fever and neutropenia
was experienced by two patients. The most severe side-effect
documented was in a patient who developed deep venous
Figure 3. Overall survival related to response 8 weeks after starting
thrombosis with a pulmonary embolism (grade IV radiochemotherapy (p=0.0016). PD: progressive disease (n=10), PR:
cardiovascular toxicity). The patient developed aspiration partial response (n=18), SD: stable disease (n=17).
pneumonia and was intubated and hospitalized for a total of
14 days. No severe hemorrhages were reported, but one
patient developed mild gastrointestinal bleeding, and one Treatment with VPA was discontinued in seven patients
patient had grade I epistaxis that was controlled with because of death resulting from PD. In the remaining two
pressure. There were no documented cardiac or endocrine patients, VPA treatment was stopped owing to lack of
side-effects. Gastrointestinal events were observed in all the epileptic activity based on electroencephalography and
patients, including mild (grade I or II) nausea (n=6) and clinical findings.
grade II colitis with bloody stools (n=1). However, no severe All nine patients received further oncological treatment
gastrointestinal events, such as pancreatitis, were reported. during their treatment with VPA (Table I). The initial (after
Although hepatic reactions were the main concern 8 weeks) response was PD in two, SD in four and PR in
monitored, none of the patients experienced hepatic failure three. No CCRs or CRs were observed. Some of the tumors
or a severe change in hepatic enzyme levels. Dermatological responded later, and the best responses were PD in two
and skin adverse effects were common (n=6), but not severe. patients, SD in two and PR in five.
The patients complained of mild dry skin, alopecia, and The patients in the matched-pair analysis who did not
grade I rash, and one patient experienced a grade I injection receive VPA had the same initial responses and best responses
site reaction that resolved with topical treatments. (Table III). There were no significant differences in response

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 ANTICANCER RESEARCH 28: 2437-2442 (2008)

Table I. Characteristics of patients who received VPA during HGG treatment.

Patient Gender Age at diagnosis Histology Treatment received: Duration of Duration of Follow-up
(years) with VPA treatment with VPA treatment with VPA duration
(weeks) plus additional (weeks)
treatment (weeks)

1 M 15 AA RT (54 Gy), then TPCH 41 41 62

2 M 8 GBM Etoposide 182 56 380
3 F 11 GBM Azacitidine 15 15 26
4 F 15 GBM Azacitidine 18 18 55
5 F 7 AA Etoposide 18 18 88
6 F 11 GBM RT (58 Gy) 15 15 33
7 M 17 GBM TMZ + CCNU + IRI 25 25 50
8 M 7 GBM MTX, then EPV, then RT (50 Gy) 18 18 33
9 M 16 GBM RT (50 Gy) + TMZ then ITC 76 76 88

AA, anaplastic astrocytoma; CCNU, lomustine; EPV, etoposide, cisplatin, vincristine; F, female; GBM, glioblastoma multiform; IRI, irinotecan;
ITC, isotretinoin, temozolomide, and celecoxib; M, male; MTX, methotrexate; RT, radiotherapy; TMZ, temozolomide; TPCH, 6-thioguanine,
procarbazine, lomustine, and hydroxyurea; VPA, valproic acid.

Table II. Adverse events associated with VPA plus radiotherapy and/or chemotherapy.

Patient Adverse event (Grade*)

Blood/bone Cardio- Dermatological/ Gastrointestinal Hemorrhage Hepatic/ Infection Metabolic/

marrow vascular skin pancreatic laboratory

1 Leu (IV), Thr (II), Thrombosis/ Alopecia (I) Om (I), Nau (II) None None FeN (III), IwnN (II), LDH (II)
HbD (II) embolism (IV) IwN (III) AST (I)
2 Leu (III), Thr (III), None None Nau (II), Vom (I) Epis (I) None IwnN (II) None
HbD (I)
3 Leu (I), Thr (II) None Injection site Nau (I), Ano (I) None None None AST (I)
HbD (I) reaction (I)
4 Leu (II), Thr (III), None Alopecia (I) Nau (I), Con (I) None None FeN (III) LDH (I)
HbD (II) Rash (I)
5 Leu (I), Thr (III) None None Om (II), Ano (I) None None None LDH (I)
HbD (I) Alkp (I)
AST (I)
6 None None Dry skin (I) Con (I), Ano (II) None None None LDH (I)
7 Leu (II), Thr (II) None Alopecia (I) Nau (I), Vom (II) None None None None
8 Leu (II), HbD (II) HTN (II) None Om (II) None None IwnN (II) ALT (I)
9 Leu (I), Thr (I) None Alopecia (I) Nau (II), Con (II), None None None AST (I)
Dry skin (I) Om (I), Ano (II),
Colit (II)

Alkp, alkaline phosphatase; ALT, alanine aminotransferase; Ano, anorexia; AST, aspartate aminotransferase; Colit, colitis; Con, constipation; Epis,
epistaxis; FeN, febrile neutropenia; HbD, hemoglobin decrease; HTN, hypertension; IwN, infection with grade III or VI neutropenia; IwnN, infection
with normal absolute neutrophil count or with grade I or II neutropenia; LDH, lactate dehydrogenase; Leu, leukopenia; Nau, nausea; Om, oral cavity
mucositis; Thr, thrombocytopenia; Vom, vomiting. *According to Common Toxicity Criteria Version 3.0 from the U.S. National Cancer Institute (22).

(p=0.288), EFS (p=0.0937), or OS (p=0.2254) between the
patients who received VPA and those who did not.
Discussion
Nine patients had been treated with VPA for epilepsy or
other reasons during treatment for HGG, but it did not seem
to have an effect on adverse events or outcomes in these
patients. HDAC inhibitors are to be tested in clinical trials
because of promising preclinical data and the clinical data
presented here provide assurance that such a trial would be
safe to start in this patient population.
Recently, HDAC inhibition has emerged as a potential
strategy to reverse aberrant epigenetic changes associated
with cancer (16). The clinical experience with new HDAC
inhibitors, such as suberoylanilide hydroxamic acid and

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 Masoudi et al: VPA in Pediatric Patients with HGG
Table III. Matched-pair analysis of initial response (8 weeks after
starting radiotherapy and/or chemotherapy) and best response in
patients who received VPA and those who did not.
Response No. of patients No. of patients
with VPA (% ) without VPA (% )
Initial Best Initial Best
response response response response
Progressive disease 2 (22.2% ) 2 (22.2% ) 5 (55.6% ) 5 (55.6% )
Stable disease 4 (44.5% ) 2 (22.2% ) 3 (33.3% ) 3 (33.3% )
Partial response 3 (33.3% ) 5 (55.6% ) 1 (11.1% ) 1 (11.1% )
depsipeptide, is limited (16). VPA, in contrast, has been in
clinical use since 1967. In addition to its known
pharmacokinetics, VPA possesses an impressive safety
profile. The most frequent adverse effects are mild to
moderate in intensity, and hypersensitivity reactions are rare.
The most severe adverse effect of VPA is hepatotoxicity (13,
23), which was seen in a fetal case at a median drug level of
only 78 mg/l (24). Although no hepatic failure was observed
in our study, this risk should not be discounted when treating
children with VPA. Other potential, but serious side-effects
are pancreatitis, hypothyroidism, and polycystic ovarian
syndrome. None of the patients in our study had these side-
effects. This retrospective study found that adding VPA to
radiochemotherapy did not increase toxicity compared to
what is widely known for the chemotherapy protocols given
here and it is likely that the adverse effects observed in our
patients came from the radiochemotherapy. A prospective
study is needed to confirm these findings.
The effects of VPA on brain tumors have been studied in
vitro (17) and in vivo (11, 19, 25) since 1998, and VPA has
been shown to have a potentially relevant therapeutic
benefit. However, the combination of chemotherapeutic
agents and AEDs has not been investigated sufficiently (26).
In particular, little is known about the combination of VPA
and chemotherapy in pediatric patients with HGG. More is
known from adult patients, but the data appear
contradictory. Grossman et al. (27) evaluated reactions
between 9-aminocamptothecin and AEDs and did not find
any grade III or IV myelosuppression, suggesting that VPA
did not add to the toxicity of the chemotherapy. In contrast,
Bourg et al. (28) found that chemotherapy plus VPA in
patients with brain tumors resulted in a three-fold higher
incidence of reversible thrombocytopenia, neutropenia, or
both in comparison with chemotherapy combined with other
AEDs. Those hematological side-effects decreased after the
dose of VPA was modified while continuing chemotherapy.
No additional toxicity was reported by Raymond et al. (29)
when VPA given in a study that investigated the effects of
irinotecan on GBM. Witt et al. (11) reported drowsiness as
the main side-effect in a patient with GBM who received
VPA (145 mg/l) plus chemotherapy. Finally, Oberndorfer et
al. (26) compared the effects of P450 enzyme-inducing
AEDs (EI-AED such as carbamazepine) and non-EI-AEDs
in GBM patients treated with standard chemotherapeutic
agents. VPA was the most common non-EI-AED and more
hematotoxicity (grade I-III) was found in the patients treated
with VPA than in the other patients. To our knowledge, there
have been no reports of severe adverse effects of VPA when
it is added to chemotherapy for HGG. This adds evidence to
our conclusion that it is safe to start combination treatment
studies giving VPA with other oncological treatments.
Among the 66 patients with HGG in the present study,
complete resection of HGG led to better survival outcomes
than subtotal/partial resection or biopsy only, patients with
AA had a longer survival than patients with GBM and
response to nonsurgical treatment was prognostic of survival
in children with HGG. These findings may appear intuitively
obvious, yet are frequently debated and not necessarily true
for all pediatric brain tumors. Our findings support a
maximal surgical resection approach and the value of
continuing to search for effective nonsurgical treatments,
such as the addition of HDAC inhibitors to chemotherapy or
radiotherapy in this patient population.
Tumor response to VPA treatment has been described in
vitro (12, 20, 30) and in patients (11, 25, 26). Driever et al.
(25) reported on a child with a relapsed supratentorial
primitive neuroectodermal tumor who received VPA for
epilepsy. In contrast to the initial tumor, the recurrent tumor
showed glial differentiation and a low proliferation index. Witt
et al. (11) reported a CR in a 10-year-old boy with GBM who
received VPA. The tumor had not responded to
radiochemotherapy (54 Gy; vincristine, cisplatin, etoposide,
and ifosfamide for 20 weeks; and then topotecan for 10
weeks) and the patient developed seizures. Magnetic
resonance imaging showed a CR after 10 months of VPA.
Among the nine patients in this study, no CRs were reported.
This might be because the VPA doses received were lower
(median 62 mg/l) than that received in the patient in Witt et
al.’s study (142 mg/l). However, the responses presented here
were still quite good for this patient population and might
suggest that VPA increased the efficacy of chemotherapy. This
hypothesis is supported by the findings of Oberndorfer et al.
(26), who reported significantly better responses in patients
with GBM who received VPA plus lomustine than in patients
who received other AEDs and lomustine. These data, though
encouraging, are limited; a prospective study is warranted.
In summary, this study confirmed that complete resection
of HGG resulted in better EFS and OS and patients with AA
achieved better survival than patients with GBM. Furthermore,
the relevance of treatment response to overall survival was also
shown. In addition, adding VPA to radiochemotherapy did not
appear to increase toxicity. These results laid the groundwork
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 ANTICANCER RESEARCH 28: 2437-2442 (2008)
for a now ongoing clinical trial combining VPA and etoposide
in pediatric patients with recurrent brain tumors and may
encourage future studies of VPA as an adjunct to postoperative
radiochemotherapy in children with HGG.
Acknowledgements
We thank members of the Department of Biostatistics at The
University of Texas M.D. Anderson Cancer Center for their helpful
suggestions. Parts of this paper were presented at the 12th Annual
Meeting of the Society for Neuro-Oncology on November 15, 2007,
in Dallas, TX.
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Received January 14, 2008
Revised March 31, 2008
Accepted April 1, 2008