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Journal of Clinical Oncology, Vol 25, No 15 (May 20), 2007: pp. 1979-1985 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.6165 Phase I Trial of Histone Deacetylase Inhibition by Valproic Acid Followed by the Topoisomerase II Inhibitor Epirubicin in Advanced Solid Tumors: A Clinical and Translational Study
From the Experimental Therapeutics, Breast Medical Oncology, and Cutaneous Oncology Programs, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL Address reprint requests to Pamela Münster, MD, Division of Experimental Therapeutics, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr, SRB-2, Tampa, FL 33612; e-mail: pamela.munster{at}moffitt.org
Purpose: To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi. Patients and Methods: Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response. Results: Forty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patients patients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells. Conclusion: The maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m2. Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.
Histone acetylases and histone deacetylases (HDAC) control the acetylation state of histones and are involved in regulation of biologic functions including cell growth, differentiation, and oncogenesis.1,2 Several HDAC inhibitors (HDACi) are currently in clinical development as anticancer agents; these compounds may be active when used alone, particularly in hematologic malignancies,3-11 and are perhaps even more active in combination with other chemotherapy agents.12-21 The anticonvulsant valproic acid (VPA) has HDAC inhibitory activity.20,22-24 In cell culture models, exposure to VPA results in dose-dependent reversible cell cycle arrest as well as chromatin decondensation and cellular differentiation.16,25-27 Several reports have suggested that HDACi synergize with cytotoxic or biologic anticancer agents.13-17,19 In particular, we found that treatment with an HDACi followed by a topoisomerase II (topo II) inhibitor resulted in synergistic cell death; 48-hour exposure to an HDACi seemed optimal for synergy, whereas synergy was abrogated with a concomitant administration or with the topo II inhibitor administered first.15 Mechanistic studies suggested that the HDACi-induced chromatin decondensation facilitated topo II inhibitor interaction with the DNA substrate, resulting in increased DNA strand breaks and recruitment of topo IIß as an alternate target.28 Cell culture studies suggested a dose-response association between VPA dose and epirubicin-induced apoptosis.28 In xenograft models, a sequence-specific administration of VPA potentiated epirubicin-induced cell death without exacerbating toxicity.29 Here, we describe the first human study translating these in vitro and xenograft observations. In a phase I dose-escalation trial, the safety, toxicity, and maximum-tolerated doses of a sequence-specific administration of VPA and epirubicin were evaluated in patients with advanced solid tumors. Pharmacokinetic (PK) and pharmacodynamic studies determined the clinical utility of VPA as an HDACi and its effects on epirubicin-induced antitumor activity and toxicity.
Eligibility Patients were required to have advanced solid tumor malignancies, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function (hemoglobin > 9 g/dL, absolute neutrophil count > 1,500 cells/µL, platelets > 100,000 cells/µL, normal creatinine and bilirubin levels, and liver enzymes within 1.5x the upper level of normal). Patients with an ejection fraction less than 50% or long QT syndrome, ventricular tachycardia, or fibrillation were excluded. Prior anthracyclines were permitted (doxorubicin  300 mg/m2 and epirubicin 600 mg/m2). Informed consents were obtained in accordance with good clinical practice and institutional guidelines.
Study Treatment
Treatment Assessment
PK Studies
H4 Acetylation
Statistical Analyses
Patient Characteristics Forty-eight patients were enrolled; 44 patients received at least one cycle of therapy and were assessable for toxicity, and 41 patients were assessable for response. Patient demographics and tumor characteristics are listed in Table 1.
Treatment Administration and Drug Delivery In the absence of DLTs, cohorts were limited to three patients. Doses were escalated according to a prespecified dose-escalation scheme (Table 2). At 75 mg/kg of VPA, epirubicin was escalated to 100 mg/m2. Undesirable vestibular symptoms (mainly tinnitus and dizziness) as a result of rapid VPA infusion prompted a change from the intravenous loading to oral VPA loading (Table 2). VPA doses were subsequently escalated to 160 mg/kg/d, which defined the maximum-administered dose (MAD). A total of 174 cycles were administered to 44 patients, with a median number of four cycles (range, one to 10 cycles). At the 100 mg/m2 dose of epirubicin, patients were limited to a maximum of seven cycles or to a total epirubicin dose of less than 750 mg/m2. In patients previously exposed to doxorubicin, an epirubicin equivalent for doxorubicin was calculated at 1.8 times the doxorubicin dose. Dose adjustments for epirubicin and VPA occurred in 9% and 10% of all administered cycles, respectively, including the two patients at the MAD. Because progression-free survival was not an end point of this phase I trial, 13 (32%) of 41 patients assessable for response were taken off study, despite the absence of progression, once the maximal dosing was reached.
DLTs At the 60-mg/kg VPA dose, one patient experienced febrile neutropenia in cycle 1 (Table 2) after having received radiation therapy to a large portion of her spine immediately before enrollment. No further episodes of febrile neutropenia were observed as DLTs. At the 75-mg/kg VPA dose, one patient experienced grade 3 somnolence, confusion, and dizziness (Table 2). The patient had received concomitant narcotic analgesics for pain control. Because drug relatedness could not be entirely ruled out, this cohort was expanded to six patients without further toxicities. Although no other DLTs were observed in any other cohorts, multiple DLTs were seen in both patients receiving VPA 160 mg/kg. DLTs included neurovestibular symptoms such as somnolence, confusion, hallucinations, hearing loss, and dizziness. Grade 3 diarrhea and hyponatremia were also observed (Table 2). These symptoms were rapidly reversible and followed the kinetics of VPA (terminal half-life: 8 to 11 hours).31 The 140-mg/kg VPA dose level was expanded to six patients without further DLTs. However, because grade 2 neurovestibular toxicities were observed in all three patients who received more than two cycles, further dose escalations to 150 mg/kg were not pursued, rendering 140 mg/kg/d the recommended phase II dose when administered on days 1 through 3 before epirubicin 100 mg/m2 and repeated every 3 weeks.
Hematologic Toxicities
Nonhematologic Toxicities VPA DLTs were predominantly neurovestibular, including dizziness, confusion, and hearing loss. No grade 3 or 4 liver function abnormalities were observed (Table 3). Grade 3 confusion and somnolence were seen in four patients (9%), including two at the MAD (Tables 2 and 3). Grade 2 somnolence was reported in 15 patients (34%). Other grade 3 or 4 toxicities included five patients (11%) with hyponatremia and five patients (11%) with hypocalcaemia. Three patients (7%) reported grade 3 fatigue (Table 3). One patient (2%) each experienced grade 3 headaches or dehydration, and two patients (5%) experienced hypoalbuminemia; it is not likely that these toxicities were drug related. On the basis of reports of QTc prolongations with other HDACi, pre-VPA ECGs were obtained on day 1. In patients who presented with QTc prolongation on day 1, a repeat ECG was performed on day 3 (after VPA exposure). Grade 2 QTc prolongations were seen in eight patients (18%), and grade 3 QTc prolongations were seen in two patients (5%); these events occurred predominantly on day 1, not day 3, of the cycle (Table 3). QTc prolongations were associated with serum potassium levels less than 4.0 mmol/L and were resolved in all patients with appropriate potassium and magnesium supplementation.
Response
Pharmacokinetic Studies
Pharmacodynamic Studies There was no significant interaction between VPA dose and the epirubicin-induced effects on platelets, WBCs, or hemoglobin in cycle 1 (Fig 1). The changes in left ventricle ejection fractions (LVEFs) before and at the end of study for patients who received at least two cycles of epirubicin showed no association with VPA dose (Fig 1). One patient had an asymptomatic decrease in LVEF to 45%. The median change in LVEF was –2.0% (range, –4.4% to 0.4%). Histone H4 acetylation was evaluated as a relative change in protein expression levels on day 3 compared with day 0 and was related to the house keeping gene, lamin. This study suggested a significant correlation between histone H4 acetylation and VPA dose as well as VPA concentration, despite the notable interpatient variability (Fig 3). All patients with a documented partial response had at least a two-fold increase in histone acetylation (Fig 3); however, the significance of this observation will require further evaluation in the ongoing phase II study.
This study describes the first use of an HDACi to sensitize cancer cells to a topo II inhibitor in patients with solid tumor malignancies. The HDACi used in this study was VPA, which has several interesting properties that emerge from this study and from preclinical studies. In cell culture models, HDACi-induced histone hyperacetylation and chromatin decondensation were associated with increased binding of topo II inhibitors to the DNA substrate. Increased DNA–topo II inhibitor binding resulted in increased DNA strand breaks and subsequent apoptosis. Cell culture and xenograft studies showed that histone hyperacetylation occurred within minutes of administration. However, although histone acetylation was a necessary step, the synergistic interaction between HDACi and topo II inhibitors required at least a 48-hour pre-exposure and a concentration sufficient to induce chromatin decondensation.28,29 Furthermore, for synergy, the molecular effects of HDACi had to be maintained until the time of topo II exposure.28,29 These preclinical observations were not restricted to VPA or to a certain class of HDACi but were also seen with vorinostat, sodium butyrate, and trichostatin A.15,16,28,29 The HDACi used in this study, VPA, has an extensive safety history and well-established PKs. The concentration to inhibit 50% growth of VPA in cell culture models ranges between 1 and 3 mmol/L when used as a single agent. For VPA-induced sensitization of cancer cells to topo II inhibitors, 48-hour exposure times and concentrations of 0.25 to 0.5 mmol/L were sufficient. However, sensitization was more pronounced at higher VPA concentrations, which led us to determine the maximum-tolerated dose of VPA at a 48-hour exposure, rather than chronic exposures at lower doses. Recommended therapeutic concentrations used for VPA as an anticonvulsant range between 50 and 130 µg/mL (0.3 to 0.8 mmol/L), according to prescribing information. Patients received delayed-release VPA for the oral doses. To ensure a rapid increase in VPA plasma concentration, patients initially received an intravenous loading. Because of undesirable neurovestibular toxicities, the VPA infusion was replaced with an oral loading dose at 75 mg/kg. Oral loading was feasible but resulted in more variable VPA peak levels, without affecting day 3 levels (Fig 2). Given the VPA-induced sensitization of tumor cells to epirubicin in preclinical studies, we were concerned about exacerbating epirubicin toxicities. However, the major DLTs were neurovestibular and GI (diarrhea), which were solely attributable to VPA. There was one episode of febrile neutropenia seen as a DLT, which is comparable to the frequency seen with epirubicin alone. Grade 3 or 4 epirubicin-induced neutropenia was common, however as shown in Figure 1, it was not related to VPA. Thrombocytopenia and liver enzyme abnormalities, which have been previously described with VPA, were not seen in this study, suggesting that these toxicities may be a result of chronic VPA exposure. Grade 2 and 3 QTc prolongations were observed in several patients; all of these events were rapidly corrected with potassium and magnesium supplementation. Grade 3 hyponatremia was seen in five patients (11%), but most patients had mild underlying hyponatremia (131 to 135 mmol/L). Although hyponatremia is common in patients with advanced malignancies, the possibility of an electrolyte-wasting syndrome should be evaluated in future trials. We did not observe any episodes of grade 3 or 4 congestive heart failure despite a median number of four cycles of epirubicin, and 17 (41%) of 41 patients had more than 600 mg/m2 of cumulative epirubicin or epirubicin-equivalent dose. One patient who received two cycles of epirubicin had an asymptomatic decrease in LVEF from 61% to 45%. Furthermore, no VPA dose relationship was seen with changes in ejection fraction, suggesting that VPA did not increase epirubicin cardiotoxicity in this limited sample (Fig 1). A notable degree of antitumor activity was seen in this heavily pretreated patient population when compared with historical controls or with our institutional phase I experience. In patients with metastatic melanoma who had experienced progression on a median of two prior chemotherapy regimens (range, one to four regimens), two of 11 patients had partial responses, and two more patients had stable disease. Additional responses were seen in anthracycline-resistant breast cancer, cervical cancer, non–small-cell lung cancer, and small-cell lung cancer. However, responses with epirubicin in metastatic breast cancer patients are not unexpected. In treatment-naive breast cancer patients, response rates of up to 48% have been reported.33 The true benefits will have to be validated in larger, randomized studies. However, prior studies with epirubicin in melanoma suggested no or minimal (< 10%) discernible efficacy,34-36 and the durable responses in two of 11 melanoma patients exceed historical efficacy and may warrant further exploration of this combination. Although the efficacy in the patients with lung, prostate, cervical, and pancreatic cancer is encouraging, the sample size of the study is too small to warrant further speculations. The effects of VPA on histone acetylation have been evaluated in peripheral-blood mononuclear cells and showed a significant linear increase with VPA dose and plasma concentration, despite notable interpatient variability (Fig 3). Furthermore, all patients with a partial response had at least a two-fold increase in H4 histone acetylation. However, given the small sample size, the significance of this will have to be further evaluated in larger samples. In summary, this trial suggests that VPA is a tolerable and clinically relevant HDACi, and the combination of VPA followed by epirubicin seems active without exacerbation of epirubicin-induced toxicity. Objective responses were seen in 22% of patients despite extensive pretreatment, and an additional 39% of patients had stable disease. Responses were seen in patients who experienced treatment failure with anthracyclines as well as in patients with tumors thought to be epirubicin resistant. A limited phase II trial in patients with metastatic breast cancer adding fluorouracil and cyclophosphamide to this combination is ongoing, and a phase II neoadjuvant trial is planned.
The authors indicated no potential conflicts of interest.
Conception and design: Pamela Münster, Adil Daud, Daniel Sullivan Financial support: Pamela Münster, Adil Daud Administrative support: George Simon, Richard Lush Provision of study materials or patients: Pamela Münster, Ronald DeConti, George Simon, Mayer Fishman, Susan Minton, Chris Garrett, Alberto Chiappori, Daniel Sullivan, Adil Daud Collection and assembly of data: Pamela Münster, Douglas Marchion, Elona Bicaku, Morgen Schmitt, Richard Lush Data analysis and interpretation: Pamela Münster, Douglas Marchion, Ji Hyun Lee Manuscript writing: Pamela Münster, Mayer Fishman, Daniel Sullivan, Adil Daud Final approval of manuscript: Pamela Münster, Ronald DeConti, George Simon
We acknowledge the editorial assistance of Anita Bruce, the staff of the Clinical Research Unit, and Mark Lloyd at the Microscopy Core at Moffitt. Our profound thanks go to all of the patients and their families who participated in this trial.
Supported by The Komen Foundation and by Grants No. PDF0402820 and NIH R21 CA105875. Study drug was supplied by Pfizer Global Research and Development, Ann Arbor, MI. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Grunstein M: Histone acetylation in chromatin structure and transcription. Nature 389: 349-352, 1997[CrossRef][Medline] 2. Marks P, Rifkind RA, Richon VM, et al: Histone deacetylases and cancer: Causes and therapies. Nat Rev Cancer 1: 194-202, 2001[CrossRef][Medline] 3. Sandor V, Bakke S, Robey RW, et al: Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res 8: 718-728, 2002 4. Kelly WK, O'Connor OA, Krug, LM, et al: Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23: 3923-3931, 2005 5. Marshall JL, Rizvi N, Kauh J, et al: A phase I trial of depsipeptide (FR901228) in patients with advanced cancer. J Exp Ther Oncol 2: 325-332, 2002[CrossRef][Medline] 6. Gilbert J, Baker SD, Bowling MK, et al: A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res 7: 2292-2300, 2001 7. O'Connor OA, Heaney ML, Schwartz L, et al: Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 24: 166-173, 2006 8. Byrd JC, Marcucci G, Parthun MR, et al: A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 105: 959-967, 2005 9. Bug G, Ritter M, Wassmann B, et al: Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer 104: 2717-2725, 2005[CrossRef][Medline] 10. Reid T, Valone F, Lipera W, et al: Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer. Lung Cancer 45: 381-386, 2004[CrossRef][Medline] 11. Ryan QC, Headlee D, Acharya M, et al: Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol 23: 3912-3922, 2005 12. Minucci S, Horn V, Bhattacharyya N, et al: A histone deacetylase inhibitor potentiates retinoid receptor action in embryonal carcinoma cells. Proc Natl Acad Sci U S A 94: 11295-11300, 1997 13. Kim MS, Blake M, Baek JH, et al: Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63: 7291-7300, 2003 14. Kurz EU, Wilson SE, Leader KB, et al: The histone deacetylase inhibitor sodium butyrate induces DNA topoisomerase II alpha expression and confers hypersensitivity to etoposide in human leukemic cell lines. Mol Cancer Ther 1: 121-131, 2001 15. Marchion DC, Bicaku E, Daud AI, et al: Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. J Cell Biochem 92: 223-237, 2004[CrossRef][Medline] 16. Marchion DC, Bicaku E, Daud AI, et al: Valproic acid alters chromatin structure by regulation of chromatin modulation proteins. Cancer Res 65: 3815-3822, 2005 17. Tsai SC, Valkov N, Yang WM, et al: Histone deacetylase interacts directly with DNA topoisomerase II. Nat Genet 26: 349-353, 2000[CrossRef][Medline] 18. Fuino L, Bali P, Wittmann S, et al: Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2: 971-984, 2003 19. Nimmanapalli R, Fuino L, Stobaugh C, et al: Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood 101: 3236-3239, 2003 20. Kuendgen A, Schmid M, Schlenk R, et al: The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer 106: 112-119, 2006[CrossRef][Medline] 21. Pauer LR, Olivares J, Cunningham C, et al: Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors. Cancer Invest 22: 886-896, 2004[CrossRef][Medline] 22. Kramer OH, Zhu P, Ostendorff HP, et al: The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. Embo J 22: 3411-3420, 2003[CrossRef][Medline] 23. Gottlicher M: Valproic acid: An old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol 83: S91-S92, 2004 (suppl 1)[Medline] 24. Gurvich N, Tsygankova OM, Meinkoth JL, et al: Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res 64: 1079-1086, 2004 25. Werling U, Siehler S, Litfin M, et al: Induction of differentiation in F9 cells and activation of peroxisome proliferator-activated receptor delta by valproic acid and its teratogenic derivatives. Mol Pharmacol 59: 1269-1276, 2001 26. Cinatl J Jr, Cinatl J, Scholz M, et al: Antitumor activity of sodium valproate in cultures of human neuroblastoma cells. Anticancer Drugs 7: 766-773, 1996[Medline] 27. Hsieh J, Nakashima K, Kuwabara T, et al: Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci U S A 101: 16659-16664, 2004 28. Marchion DC, Bicaku E, Turner JG, et al: Synergistic interaction between histone deacetylase and topoisomerase II inhibitors is mediated through topoisomerase IIbeta. Clin Cancer Res 11: 8467-8475, 2005 29. Marchion DC, Bicaku E, Daud AI, et al: In vivo synergy between topoisomerase II and histone deacetylase inhibitors: Predictive correlates. Mol Cancer Ther 4: 1993-2000, 2005 30. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205-216, 2000 31. Perucca E: Pharmacological and therapeutic properties of valproate: A summary after 35 years of clinical experience. CNS Drugs 16: 695-714, 2002[CrossRef][Medline] 32. Dutta S, Zhang Y, Selness DS, et al: Comparison of the bioavailability of unequal doses of divalproex sodium extended-release formulation relative to the delayed-release formulation in healthy volunteers. Epilepsy Res 49: 1-10, 2002[CrossRef][Medline] 33. Michelotti A, Venturini M, Tibaldi C, et al: Single agent epirubicin as first line chemotherapy for metastatic breast cancer patients. Breast Cancer Res Treat 59: 133-139, 2000[CrossRef][Medline] 34. Berman E, Casper ES, Howard J, et al: Phase II trial of 4'-epi-doxorubicin in patients with advanced malignant melanoma. Cancer Treat Rep 68: 679-680, 1984[Medline] 35. Rosenthal MA, Green M, Wiernik P, et al: Epirubicin has modest single-agent activity in head and neck cancer but limited activity in metastatic melanoma and colorectal cancer: Phase II studies by the Eastern Cooperative Oncology Group. Am J Clin Oncol 21: 509-512, 1998[CrossRef][Medline] 36. Lopez M, Perno CF, Papaldo P, et al: Phase II study of epirubicin in advanced malignant melanoma. Invest New Drugs 2: 315-317, 1984[Medline] Submitted August 4, 2006; accepted December 4, 2006. Related Editorial
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, P < .001) and 4 hours after oral loading (•, P = .09). (B) Correlation between VPA dose and total VPA plasma levels (
, P < .001) and free VPA plasma levels (224, P = .002) on day 3.
) and eight of nine patients with a partial response (•). A more than two-fold increase in H4 acetylation was found in all responders.
