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1.  Phase II Study of Irinotecan and Temozolomide in Children With Relapsed or Refractory Neuroblastoma: A Children's Oncology Group Study 
Journal of Clinical Oncology  2010;29(2):208-213.
This phase II study was conducted to determine the response rate associated with use of irinotecan and temozolomide for children with relapsed/refractory neuroblastoma.
Patients and Methods
Patients with relapsed/refractory neuroblastoma measurable by cross-sectional imaging (stratum 1) or assessable by bone marrow aspirate/biopsy or metaiodobenzylguanidine (MIBG) scan (stratum 2) received irinotecan (10 mg/m2/dose 5 days a week for 2 weeks) and temozolomide (100 mg/m2/dose for 5 days) every 3 weeks. Response was assessed after three and six courses using International Neuroblastoma Response Criteria. Of the first 25 evaluable patients on a given stratum, five or more patients with complete or partial responses were required to conclude that further study would be merited.
Fifty-five eligible patients were enrolled. The objective response rate was 15%. Fourteen patients (50%) on stratum 1 and 15 patients (56%) on stratum 2 had stable disease. Objective responses were observed in three of the first 25 evaluable patients on stratum 1 and five of the first 25 evaluable patients on stratum 2. Less than 6% of patients experienced ≥ grade 3 diarrhea. Although neutropenia was observed, less than 10% of patients developed evidence of infection while neutropenic.
The combination of irinotecan and temozolomide was well tolerated. The objective response rate of 19% in stratum 2 suggests that this combination may be effective for patients with neuroblastoma detectable by MIBG or marrow analysis. Although fewer objective responses were observed in patients with disease measurable by computed tomography/magnetic resonance imaging, patients in both strata seem to have derived clinical benefit from this therapy.
PMCID: PMC3058276  PMID: 21115869
2.  Phase I Trial of Fenretinide Delivered Orally in a Novel Organized Lipid Complex in Patients with Relapsed/Refractory Neuroblastoma: A Report from the New Approaches to Neuroblastoma Therapy (NANT) Consortium 
Pediatric blood & cancer  2013;60(11):1801-1808.
A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma.
4-HPR/LXS powder (352 - 2210 mg/m2/day) was administered on Days 0 – 6, in 21-day courses, by standard 3+3 design.
Thirty-two patients (median age = 8 years, range 3 – 27 years) enrolled with thirty evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), 125/131I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m2/day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m2/day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1700 mg/m2/day. Of twenty-nine response-evaluable patients, six had stable disease (SD)(4 – 26 courses); four with marrow- or bone disease-only had complete responses (CR)(10 - 46 courses). 4-HPR plasma levels were several fold higher (P<0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1700 mg/m2/day was 21 μM. An MTD was not reached.
4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1500 mg/m2/day, TID, on Days 0 – 6, of a 21-day course.
PMCID: PMC4066886  PMID: 23813912
fenretinide; neuroblastoma; pediatric; powder; Lym-X-Sorb™
3.  Antitumor Activity of Hu14.18-IL2 in Patients With Relapsed/Refractory Neuroblastoma: A Children's Oncology Group (COG) Phase II Study 
Journal of Clinical Oncology  2010;28(33):4969-4975.
The hu14.18-IL2 fusion protein consists of interleukin-2 molecularly linked to a humanized monoclonal antibody that recognizes the GD2 disialoganglioside expressed on neuroblastoma cells. This phase II study assessed the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory neuroblastoma.
Patients and Methods
Hu14.18-IL2 was given intravenously (12 mg/m2/daily) for 3 days every 4 weeks for patients with disease measurable by standard radiographic criteria (stratum 1) and for patients with disease evaluable only by [123I]metaiodobenzylguanidine (MIBG) scintigraphy and/or bone marrow (BM) histology (stratum 2). Response was established by independent radiology review as well as BM histology and immunocytology, and durability was assessed by repeat evaluation after more than 3 weeks.
Thirty-nine patients were enrolled (36 evaluable). No responses were seen in stratum 1 (n = 13). Of 23 evaluable patients in stratum 2, five patients (21.7%) responded; all had a complete response (CR) of 9, 13, 20, 30, and 35+ months duration. Grade 3 and 4 nonhematologic toxicities included capillary leak, hypoxia, pain, rash, allergic reaction, elevated transaminases, and hyperbilirubinemia. Two patients required dopamine for hypotension, and one patient required ventilatory support for hypoxia. Most toxicities were reversible within a few days of completing a treatment course and were expected based on phase I results.
Patients with disease evaluable only by MIBG and/or BM histology had a 21.7% CR rate to hu14.8-IL2, whereas patients with bulky disease did not respond. Hu14.18-IL2 warrants further testing in children with nonbulky high-risk neuroblastoma.
PMCID: PMC3020698  PMID: 20921469
4.  Phase II Study of Fenretinide (NSC 374551) in Adults With Recurrent Malignant Gliomas: A North American Brain Tumor Consortium Study 
Fenretinide induces apoptosis in malignant gliomas in vitro. This two-stage phase II trial was conducted to determine the efficacy of fenretinide in adults with recurrent malignant gliomas.
Patients and Methods
Twenty-two patients with anaplastic gliomas (AG) and 23 patients with glioblastoma (GBM) whose tumors had recurred after radiotherapy and no more than two chemotherapy regimens were enrolled. Fenretinide was given orally on days 1 to 7 and 22 to 28 in 6-week cycles in doses of 600 or 900 mg/m2 bid.
Six of 21 (29%) patients in the AG arm and two of 23 (9%) patients in the GBM arm had stable disease at 6 months. One patient with AG treated at 900 mg/m2 bid dosage had a partial radiologic response. Median progression-free survival (PFS) was 6 weeks for the AG arm and 6 weeks for the GBM arm. PFS at 6 months was 10% for the AG arm and 0% for the GBM arm. Grade 1 or 2 fatigue, dryness of skin, anemia, and hypoalbuminemia were the most frequent toxicities reported. The trial was closed after the first stage because of the inadequate activity at the fenretinide doses used. The first-administration mean plasma Cmax for fenretinide was 832 ± 360 ng/mL at the 600 mg/m2 bid dosage and 1,213 ± 261 ng/mL at the 900 mg/m2 bid dosage.
Fenretinide was inactive against recurrent malignant gliomas at the dosage used in this trial. However, additional studies using higher doses of the agent are warranted based on the tolerability of the agent and the potential for activity of a higher fenretinide dosage, as suggested in this trial.
PMCID: PMC3820102  PMID: 15514370
5.  Combination of Cladribine plus Topotecan for Relapsed or Refractory Pediatric Acute Myeloid Leukemia 
Cancer  2010;116(1):98-105.
The prognosis after relapse of pediatric acute myeloid leukemia (AML) is poor and effective salvage regimens are urgently needed.
In Phase I and pilot studies, we evaluated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a 5-day course of cladribine (2-CDA) followed by topotecan in pediatric patients with relapsed/refractory AML. The 2-CDA dose was escalated as follows: 9.1, 13.6, 16.3, and 19.5 mg/m2 per day (8.9 mg/m2 per day in the pilot study). Outcome was analyzed according to the absence (stratum 1) vs. presence (stratum 2) of previous allogeneic hematopoietic stem cell transplantation. Twenty-six patients (20 in stratum 1, 6 in stratum 2) were treated.
The MTD was not reached in stratum 1, but DLT occurred at the lowest 2-CDA dosage (9.1 mg/m2 per day) in stratum 2. Febrile neutropenia was common in both strata. Nine (34.6%) of 26 patients experienced a complete response and 7 (30.4%) had a partial response; 5 (19.2%) are long-term survivors. Clinical outcome was not associated with 2-CDA or topotecan systemic exposure.
The combination was well tolerated in stratum 1, and the response rate is encouraging. This regimen offers a post-relapse treatment alternative for patients, especially those who have received anthracycline-containing chemotherapy.
PMCID: PMC2920745  PMID: 19885837
acute myeloid leukemia; cladribine; pediatric; relapse; topotecan
6.  Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study 
BMC Research Notes  2014;7:256.
Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study.
Case presentation
On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient’s condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity.
After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.
PMCID: PMC4006848  PMID: 24755475
Ceftriaxone; Fenretinide; Acetaminophen; Drug interaction; Biliary sludge; Fulminant hepatic failure
7.  Phase I Trial of Lapatinib in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study 
Journal of Clinical Oncology  2010;28(27):4221-4227.
To estimate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic properties of lapatinib, a selective epidermal growth factor receptor (EGFR) and ERBB2 inhibitor, in children with refractory or recurrent CNS malignancies.
Patients and Methods
Lapatinib was administered orally twice daily at escalating doses starting at 300 mg/m2 to patients who were not (stratum I) or were (stratum II) receiving steroids. Pharmacokinetic studies were performed during the first two courses. Expression of the four ERBB receptors and downstream signaling elements in tumor tissue was evaluated by immunohistochemistry.
Fifty-nine patients were enrolled (stratum I, n = 32; stratum II, n = 27). Of 29 patients evaluable for toxicity in stratum I, one experienced a DLT (diarrhea) at 520 mg/m2 twice daily, and all three receiving 1,150 mg/m2 twice daily experienced DLTs (one each of rash, diarrhea, and fatigue). Two of 21 patients evaluable for toxicity in stratum II experienced DLTs of rash at 900 mg/m2 twice daily. Lapatinib dosage was related linearly to area under the [concentration-time] curve from start time to 12 hours later (AUC0-12) and dose-normalized maximum serum concentration and AUC values for patients in stratum II were both significantly higher (P = .001) than those for patients in stratum I. Frequent, high-level expression of activated (phosphorylated) EGFR and ERBB2 receptors and downstream signal intermediates were observed in tumors, particularly in ependymomas that displayed prolonged stable disease on lapatinib therapy.
Lapatinib is well tolerated in children with recurrent CNS malignancies, with rash, diarrhea, and fatigue identified as DLTs. The recommended phase II dose, regardless of steroid use, is 900 mg/m2 twice daily.
PMCID: PMC2953974  PMID: 20713864
8.  Phase I Study of Decitabine with Doxorubicin and Cyclophosphamide in Children with Neuroblastoma and Other Solid Tumors: A Children’s Oncology Group Study 
Pediatric blood & cancer  2010;55(4):629-638.
Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors.
Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hour decitabine infusion for 7 days, followed by doxorubicin (45mg/m2) and cyclophosphamide (1g/m2) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells.
The maximum-tolerated dose of decitabine was 5 mg/m2/d for 7 days. Dose-limiting toxicities at 10 mg/m2/d were neutropenia and thrombocytopenia. Decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for ≥4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16 respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis.
Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deactelyase inhibitors should be explored.
PMCID: PMC3025700  PMID: 20589651
demethylation; decitabine; pediatric solid tumor; neuroblastoma
9.  Evaluation of a mucoadhesive fenretinide patch for local intraoral delivery: a strategy to reintroduce fenretinide for oral cancer chemoprevention 
Carcinogenesis  2012;33(5):1098-1105.
Systemic delivery of fenretinide in oral cancer chemoprevention trials has been largely unsuccessful due to dose-limiting toxicities and subtherapeutic intraoral drug levels. Local drug delivery, however, provides site-specific therapeutically relevant levels while minimizing systemic exposure. These studies evaluated the pharmacokinetic and growth-modulatory parameters of fenretinide mucoadhesive patch application on rabbit buccal mucosa. Fenretinide and blank-control patches were placed on right/left buccal mucosa, respectively, in eight rabbits (30 min, q.d., 10 days). No clinical or histological deleterious effects occurred. LC-MS/MS analyses of post-treatment samples revealed a delivery gradient with highest fenretinide levels achieved at the patch-mucosal interface (no metabolites), pharmacologically active levels in fenretinide-treated oral mucosa (mean: 5.65 μM; trace amounts of 4-oxo-4-HPR) and undetectable sera levels. Epithelial markers for cell proliferation (Ki-67), terminal differentiation (transglutaminase 1—TGase1) and glucuronidation (UDP-glucuronosyltransferase1A1—UGT1A1) exhibited fenretinide concentration-specific relationships (elevated TGase1 and UGT1A1 levels <5 μM, reduced Ki-67 indices >5μM) relative to blank-treated epithelium. All fenretinide-treated tissues showed significantly increased intraepithelial apoptosis (TUNEL) positivity, implying activation of intersecting apoptotic and differentiation pathways. Human oral mucosal correlative studies showed substantial interdonor variations in levels of the enzyme (cytochrome P450 3A4—CYP3A4) responsible for conversion of fenretinide to its highly active metabolite, 4-oxo-4-HPR. Complementary in vitro assays in human oral keratinocytes revealed fenretinide and 4-oxo-4-HPR’s preferential suppression of DNA synthesis in dysplastic as opposed to normal oral keratinocytes. Collectively, these data showed that mucoadhesive patch-mediated fenretinide delivery is a viable strategy to reintroduce a compound known to induce keratinocyte differentiation to human oral cancer chemoprevention trials.
PMCID: PMC3334520  PMID: 22427354
10.  Phase I Study of SU5416, a Small Molecule Inhibitor of the Vascular Endothelial Growth Factor Receptor (VEGFR) in Refractory Pediatric Central Nervous System Tumors 
Pediatric blood & cancer  2009;52(2):169-176.
SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (Stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110mg/m2 while stratum II started at 48mg/m2. Thirty-three eligible patients were treated on stratum I (n=23) and stratum II (n=10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas and 2 choroid plexus carcinomas. The MTD in Stratum I was initially estimated to be 110mg/m2. The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145mg/m2 dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in Stratum I were 26.1 ± 12.5 liter/h/m2, 41.9 ± 21.4 liter/m2, and 1.11 ± 0.41 h, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum 1 patients.
PMCID: PMC2775441  PMID: 19065567
VEGF; Anti-angiogenesis; Brain tumor; SU5416
11.  Phase 2 study of idarubicin in pediatric brain tumors: Pediatric Oncology Group study POG 9237. 
Neuro-Oncology  2003;5(4):261-267.
Idarubicin (IDA), the 4-demethoxy analog of daunomycin, has had significant cytotoxicity in many malignancies. In previous reports, the alcohol metabolite of IDA, 4-demethoxydaunorubicinol (idarubicinol, or IDOL), had cytotoxic activity and the ability to penetrate the blood-brain barrier. For this reason, the Pediatric Oncology Group conducted a Phase 2 trial of IDA for children with recurrent or progressive brain tumors. Ninety-one eligible children were entered on this study, with ages ranging from 3 months to 19 years. Patients were stratified by tumor types into 6 categories: stratum 1, low-grade astrocytoma; stratum 2, malignant glioma (glioblastoma multiforme and anaplastic astrocytoma); stratum 3, medulloblastoma; stratum 4, brainstem glioma; stratum 5, ependymoma; and stratum 6, miscellaneous malignant tumors not included in the previous diagnoses. IDA(18 mg/m2) was infused over 4 h and followed by granulocyte colony-stimulating factor (G-CSF) beginning day 5 after infusion of IDA. G-CSF was continued until blood cell count recovery. Cycles were repeated at approximately 21-day intervals until patients developed progressive disease or had completed 6 cycles with stable or improved disease. Pharmacokinetic plasma and cerebrospinal fluid (CSF) samples were collected from a subset of these patients. Response was poor in all strata. Most patients developed progressive disease; however, in 21 patients with medulloblastoma there was 1 partial response, and 6 patients had stable disease (SD) that in 4 patients lasted more than 20 weeks. Grades 3/4 hematopoietic toxicities were the most common toxic events, and 14 infection-related events resulted in hospitalization of patients. Only 1 patient developed reduced cardiac function. The systemic clearance data for IDA and IDOL were nearly identical to those published on patients with leukemia, and the plasma elimination of the IDOL metabolite was substantially longer than that of the parent drug IDA. The peak CSF:plasma ratios of IDA and IDOL were very low. The overall response rates to IDA were disappointing despite periods of prolonged SD in nearly a fourth of the patients. We conclude from this data and from that in nonhuman primates that it is unlikely that IDA, daunomycin, or other related anthracyclines will be useful for treating primary CNS tumors.
PMCID: PMC1920677  PMID: 14565163
12.  Phase I Pharmacokinetic and Pharmacodynamic Study of the Multikinase Inhibitor Sorafenib in Combination With Clofarabine and Cytarabine in Pediatric Relapsed/Refractory Leukemia 
Journal of Clinical Oncology  2011;29(24):3293-3300.
To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia.
Patients and Methods
Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m2) and clofarabine (stratum one: 40 mg/m2, n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m2, n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m2 and 150 mg/m2 twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8.
At sorafenib 200 mg/m2, two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m2. Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3–internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission.
Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.
PMCID: PMC3158600  PMID: 21768474
13.  A Phase II Study of Oxaliplatin Combined with Continuous Infusion Topotecan for Patients with Previously Treated Ovarian Cancer 
Phase II trials suggest that prolonged intravenous (IV) infusion of the topoisomerase-1 inhibitor topotecan may be less toxic than when given by standard IV bolus 5-day administration. Oxaliplatin exhibits efficacy in platinum- pretreated disease and shows preclinical synergy with topoisomerase-I inhibitors. We sought to determine the efficacy and safety of oxaliplatin plus infusion topotecan in recurrent platinum-pretreated ovarian cancer.
Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers previously treated with 1–2 prior regimens including a platinum and taxane received oxaliplatin (85 mg/m2 day 1, 15) and topotecan (0.4 mg/m2/day) by continuous IV infusion over 14 days every 4 weeks. The primary objective of the trial was to estimate the objective response rate in platinum-resistant disease (stratum I) and in platinum-sensitive disease (stratum II). Toxicities were assessed in all patients.
Thirty-eight patients received 144 cycles of therapy (median 4, range 1–6). The most common grade 3/4 toxicities included thrombocytopenia (37% grade 3, 19% grade 4), neutropenia (37% grade 3, 11% grade 4) and anemia (15% grade 3). Response occurred in 4 of 19 patients in stratum I (21%, 95% confidence intervals [CI] 6%, 46%) and 9 of 19 patients in stratum II (47%, 95% CI 24%, 71%). Three in each stratum had lengthy complete responses.
Biweekly oxaliplatin plus a 14-day continuous IV infusion of topotecan, given monthly, is an active regimen in platinum-pretreated ovarian cancer and merits additional evaluation.
PMCID: PMC3869398  PMID: 24172094
14.  Fenretinide-induced caspase-8 activation and apoptosis in an established model of metastatic neuroblastoma 
BMC Cancer  2009;9:97.
Resistance of high-risk metastatic neuroblastoma (HR-NB) to high dose chemotherapy (HD-CT) raises a major therapeutic challenge in pediatric oncology. Patients are treated by maintenance CT. For some patients, an adjuvant retinoid therapy is proposed, such as the synthetic retinoid fenretinide (4-HPR), an apoptotic inducer. Recent studies demonstrated that NB metastasis process is enhanced by the loss of caspase-8 involved in the Integrin-Mediated Death (IMD) process. As the role of caspase-8 appears to be critical in preventing metastasis, we aimed at studying the effect of 4-HPR on caspase-8 expression in metastatic neuroblasts.
We used the human IGR-N-91 MYCN-amplified NB experimental model, able to disseminate in vivo from the primary nude mouse tumor xenograft (PTX) into myocardium (Myoc) and bone marrow (BM) of the animal. NB cell lines, i.e., IGR-N-91 and SH-EP, were treated with various doses of Fenretinide (4-HPR), then cytotoxicity was analyzed by MTS proliferation assay, apoptosis by the propidium staining method, gene or protein expressions by RT-PCR and immunoblotting and caspases activity by colorimetric protease assays.
The IGR-N-91 parental cells do not express detectable caspase-8. However the PTX cells established from the primary tumor in the mouse, are caspase-8 positive. In contrast, metastatic BM and Myoc cells show a clear down-regulation of the caspase-8 expression. In parallel, the caspases -3, -9, -10, Bcl-2, or Bax expressions were unchanged. Our data show that in BM, compared to PTX cells, 4-HPR up-regulates caspase-8 expression that parallels a higher sensitivity to apoptotic cell death. Stable caspase-8-silenced SH-EP cells appear more resistant to 4-HPR-induced cell death compared to control SH-EP cells. Moreover, 4-HPR synergizes with drugs since apoptosis is restored in VP16- or TRAIL-resistant-BM cells. These results demonstrate that 4-HPR in up-regulating caspase-8 expression, restores and induces apoptotic cell death in metastatic neuroblasts through caspase-8 activation.
This study provides basic clues for using fenretinide in clinical treatment of HR-NB patients. Moreover, since 4-HPR induces cell death in caspase-8 negative NB, it also challenges the concept of including 4-HPR in the induction of CT of these patients.
PMCID: PMC2670318  PMID: 19331667
15.  A Phase II Study of O6-Benzylguanine and Temozolomide in Pediatric Patients with Recurrent or Progressive High Grade Gliomas and Brainstem Gliomas: A Pediatric Brain Tumor Consortium Study 
Journal of neuro-oncology  2011;106(3):643-649.
To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide® (TMZ).
Patients and Methods
Patients received O6BG 120 mg/m2/d IV followed by TMZ 75 mg/m2/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed.
Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas.
The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.
PMCID: PMC3518022  PMID: 21968943
glioma; pediatric; resistance; alkylating agent; brainstem glioma; AGT; MGMT
16.  Sorafenib in Patients with Platinum Treated Extensive Stage Small Cell Lung Cancer (SCLC): A Southwest Oncology Group (SWOG 0435) Phase II Trial 
Sorafenib is a multi-kinase inhibitor affecting pathways involved in tumor progression and angiogenesis. We conducted a phase II trial of Sorafenib in platinum-treated extensive stage small cell lung cancer (SCLC) patients to determine the tumor response rate, toxicity and overall survival.
Patients with histologically confirmed, measurable disease, Zubrod performance status 0–1 and no more than 1 prior platinum based treatment were eligible. Patients were stratified by platinum-sensitivity status: sensitive (progression >90 days after platinum) or refractory (progression during or ≤90 days after platinum). Pts were treated with sorafenib 400mg PO BID continuously on a 28 day cycle.
Of 89 pts registered; 82 were evaluable for toxicity assessment and 83 were evaluable for response There were 4 partial responses seen among the 38 patients in the platinum sensitive stratum, for an estimated response rate of 11% (95% confidence interval: 3% – 25%); and one partial response among the 45 patients in the platinum refractory stratum for an estimated response rate of 2% (95% confidence interval: 0% – 12%). The median overall survival estimates were 5.3 months (95% confidence interval: 3.3–7.5 months) and 6.7 months (95% confidence interval: 6.1–9.1 months) for the platinum-refractory and platinum-sensitive strata respectively. Nineteen patients discontinued treatment due to adverse events or side effects from therapy.
Based on the lack of disease control seen in our trial, further investigation of single-agent sorafenib in the SCLC population is not recommended. Combination trials of Sorafenib and chemotherapy are ongoing.
PMCID: PMC3676180  PMID: 20881645
Sorafenib; Platinum Treated; Lung Cancer
17.  Fenretinide Targets Chronic Myeloid Leukemia Stem/Progenitor Cells by Regulation of Redox Signaling 
Antioxidants & Redox Signaling  2014;20(12):1866-1880.
Aims: We have recently shown that fenretinide preferentially targets CD34+ cells of acute myeloid leukemia (AML), and here, we test whether this agent exerts the effect on CD34+ cells of chronic myeloid leukemia (CML), which are refractory to imatinib. Results: As tested by colony-forming cell assays using clinical specimens, both number and size of total colonies derived from CD34+ CML cells were significantly reduced by fenretinide, and by combining fenretinide with imatinib. In particular, colonies derived from erythroid progenitors and more primitive pluripotent/multipotent progenitors were highly sensitive to fenretinide/fenretinide plus imatinib. Accordantly, fenretinide appeared to induce apoptosis in CD34+ CML cells, particularly with regard to the cells in the subpopulation of CD34+CD38−. Through cell quiescent assays, including Ki-67 negativity test, we added evidence that nonproliferative CD34+ CML cells were largely eliminated by fenretinide. Transcriptome and molecular data further showed that mechanisms underlying the apoptosis in CD34+ CML cells were highly complex, involving multiple events of oxidative stress responses. Innovation and Conclusion: As compared with CD34+ AML cells, the apoptotic effects of fenretinide on CD34+ CML cells were more prominent whereas less varied among the samples of different patients, and also various stress-responsive events appeared to be more robust in fenretinide-treated CD34+ CML cells. Thus, the combination of fenretinide with imatinib may represent a more sophisticated strategy for CML treatment, in which imatinib mainly targets leukemic blast cells through the intrinsic pathway of apopotosis, whereas fenretinide primarily targets CML stem/progenitor cells through the oxidative/endoplasmic reticulum stress-mediated pathway. Antioxid. Redox Signal. 20, 1866–1880.
PMCID: PMC3967369  PMID: 24021153
18.  Lack of Efficacy of Bevacizumab Plus Irinotecan in Children With Recurrent Malignant Glioma and Diffuse Brainstem Glioma: A Pediatric Brain Tumor Consortium Study 
Journal of Clinical Oncology  2010;28(18):3069-3075.
A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG).
Patients and Methods
Eligible patients received two doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast–enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ.
Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure.
BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.
PMCID: PMC2903337  PMID: 20479404
19.  Phase II Chemoprevention Trial with High Dose Fenretinide for Oral Pre-Malignant Lesions 
In a previous phase II trial, we demonstrated that fenretinide 200 mg/day had limited activity in retinoid-refractory leukoplakia (34% response rate), possibly due to the lack of achievement of high serum levels which would be required to elicit retinoid-receptor independent apoptosis in pre-malignant cells. We therefore designed this single-arm, phase II trial to investigate whether fenretinide at a higher dose would improve the leukoplakia response rate from our previous study’s historical control.
Patients and Methods
Patients with high-risk leukoplakia were treated with 4 three-week cycles of fenretinide (900 mg/m2 orally twice daily, days 1–7). At week 12, objective clinical responses were determined and blood samples were collected for serum drug level assessment. The original sample size was 25 patients to detect a 55% response rate (90% power, one-sided 10% type I error rate). A futility analysis was planned after accrual of the first 16 patients to allow for early trial closure if ≤4 patients responded.
Fenretinide was well tolerated, with only one grade 3 toxicity (diarrhea) observed. However, only 3 of the initial 15 patients (20%) had a partial response, leading to early trial termination due to lack of efficacy. Serum levels of fenretinide rose from 0 (baseline) to 0.122 μM ± 0.093 (week 12), indicating that high serum levels of the drug were achieved during the initial days of the cycle.
Despite high serum levels, fenretinide for oral leukoplakia, at the dose and schedule studied herein, failed to improve historical response rates.
PMCID: PMC4161148  PMID: 19139014
fenretinide; oral pre-malignant lesion; leukoplakia; chemoprevention
20.  Therapy of acute wounds with water-filtered infrared-A (wIRA) 
Water-filtered infrared-A (wIRA) as a special form of heat radiation with a high tissue penetration and with a low thermal load to the skin surface acts both by thermal and thermic as well as by non-thermal and non-thermic effects. wIRA produces a therapeutically usable field of heat in the tissue and increases tissue temperature, tissue oxygen partial pressure, and tissue perfusion. These three factors are decisive for a sufficient tissue supply with energy and oxygen and consequently as well for wound healing and infection defense.
wIRA can considerably alleviate the pain (with remarkably less need for analgesics) and diminish an elevated wound exudation and inflammation and can show positive immunomodulatory effects. wIRA can advance wound healing or improve an impaired wound healing both in acute and in chronic wounds including infected wounds. Even the normal wound healing process can be improved.
A prospective, randomized, controlled, double-blind study with 111 patients after major abdominal surgery at the University Hospital Heidelberg, Germany, showed with 20 minutes irradiation twice a day (starting on the second postoperative day) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a significant and relevant pain reduction combined with a markedly decreased required dose of analgesics: during 230 single irradiations with wIRA(+VIS) the pain decreased without any exception (median of decrease of pain on postoperative days 2-6 was 13.4 on a 100 mm visual analog scale VAS 0-100), while pain remained unchanged in the control group (p<0.001). The required dose of analgesics was 57-70% lower in the subgroups with wIRA(+VIS) compared to the control subgroups with only VIS (median 598 versus 1398 ml ropivacaine, p<0.001, for peridural catheter analgesia; 31 versus 102 mg piritramide, p=0.001, for patient-controlled analgesia; 3.4 versus 10.2 g metamizole, p=0.005, for intravenous and oral analgesia). During irradiation with wIRA(+VIS) the subcutaneous oxygen partial pressure rose markedly by approximately 30% and the subcutaneous temperature by approximately 2.7°C (both in a tissue depth of 2 cm), whereas both remained unchanged in the control group: after irradiation the median of the subcutaneous oxygen partial pressure was 41.6 (with wIRA) versus 30.2 mm Hg in the control group (p<0.001), the median of the subcutaneous temperature was 38.9 versus 36.4°C (p<0.001). The overall evaluation of the effect of irradiation, including wound healing, pain and cosmesis, assessed on a VAS (0-100 with 50 as indifferent point of no effect) by the surgeon (median 79.0 versus 46.8, p<0.001) or the patient (79.0 versus 50.2, p<0.001) was markedly better in the group with wIRA compared to the control group. This was also true for single aspects: Wound healing assessed on a VAS by the surgeon (median 88.6 versus 78.5, p<0.001) or the patient (median 85.8 versus 81.0, p=0.040, trend) and cosmetic result assessed on a VAS by the surgeon (median 84.5 versus 76.5, p<0.001) or the patient (median 86.7 versus 73.6, p=0.001). In addition there was a trend in favor of the wIRA group to a lower rate of total wound infections (3 of 46, approximately 7%, versus 7 of 48, approximately 15%, p=0.208) including late infections after discharge, caused by the different rate of late infections after discharge: 0 of 46 in the wIRA group and 4 of 48 in the control group. And there was a trend towards a shorter postoperative hospital stay: 9 days in the wIRA group versus 11 days in the control group (p=0.037). The principal finding of this study was that postoperative irradiation with wIRA can improve even a normal wound healing process.
A prospective, randomized, controlled, double-blind study with 45 severely burned children at the Children’s Hospital Park Schönfeld, Kassel, Germany, showed with 30 minutes irradiation once a day (starting on the first day, day of burn as day 1) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a markedly faster reduction of wound size. On the fifth day (after 4 days with irradiation) decision was taken, whether surgical debridement of necrotic tissue was necessary because of deeper (second degree, type b) burns (11 of 21 in the group with wIRA, 14 of 24 in the control group) or non-surgical treatment was possible (second degree, type a, burns). The patients treated conservatively were kept within the study and irradiated till complete reepithelialization. The patients in the group with wIRA showed a markedly faster reduction of wound area: a median reduction of wound size of 50% was reached already after 7 days compared to 9 days in the control group, a median reduction of wound size of 90% was already achieved after 9 days compared to 13 days in the control group. In addition the group with wIRA showed superior results till 3 months after the burn in terms of the overall surgical assessment of the wound, cosmesis, and assessment of effects of irradiation compared to the control group.
In a prospective, randomized, controlled study with 12 volunteers at the University Medical Center Charité, Berlin, Germany, within each volunteer 4 experimental superficial wounds (5 mm diameter) as an acute wound model were generated by suction cup technique, removing the roof of the blister with a scalpel and a sterile forceps (day 1). 4 different treatments were used and investigated during 10 days: no therapy, only wIRA(+VIS) (approximately 75% wIRA, 25% VIS; 30 minutes irradiation once a day), only dexpanthenol (= D-panthenol) cream once a day, wIRA(+VIS) and dexpanthenol cream once a day. Healing of the small experimental wounds was from a clinical point of view excellent with all 4 treatments. Therefore there were only small differences between the treatments with slight advantages of the combination wIRA(+VIS) and dexpanthenol cream and of dexpanthenol cream alone concerning relative change of wound size and assessment of feeling of the wound area. However laser scanning microscopy with a scoring system revealed differences between the 4 treatments concerning the formation of the stratum corneum (from first layer of corneocytes to full formation) especially on the days 5-7: fastest formation of the stratum corneum was seen in wounds treated with wIRA(+VIS) and dexpanthenol cream, second was wIRA(+VIS) alone, third dexpanthenol cream alone and last were untreated wounds. Bacterial counts of the wounds (taken every 2 days) showed, that wIRA(+VIS) and the combination of wIRA(+VIS) with dexpanthenol cream were able to inhibit the colonisation with physiological skin flora up to day 5 when compared with the two other groups (untreated group and group with dexpanthenol cream alone). At any investigated time, the amount of colonisation under therapy with wIRA(+VIS) alone was lower (interpreted as more suppressed) compared with the group with wIRA(+VIS) and dexpanthenol cream.
During rehabilitation after hip and knee endoprosthetic operations the resorption of wound seromas and wound hematomas was both clinically and sonographically faster and pain was reduced by irradiation with wIRA(+VIS).
wIRA can be used successfully for persistent postoperative pain e.g. after thoracotomy.
As perspectives for wIRA it seems clinically prudent to use wIRA both pre- and postoperatively, e.g. in abdominal and thoracic operations. wIRA can be used preoperatively (e.g. during 1-2 weeks) to precondition donor and recipient sites of skin flaps, transplants or partial-thickness skin grafts, and postoperatively to improve wound healing and to decrease pain, inflammation and infections at all mentioned sites. wIRA can be used to support routine pre- or intraoperative antibiotic administration or it might even be discussed to replace this under certain conditions by wIRA.
PMCID: PMC2831241  PMID: 20204084
water-filtered infrared-A (wIRA); wound healing; acute wounds; prospective, randomized, controlled, double-blind studies; reduction of pain; problem wounds; wound infections; infection defense; wound exudation; inflammation; thermal and non-thermal effects; thermic and non-thermic effects; energy supply; oxygen supply; tissue oxygen partial pressure; tissue temperature; tissue blood flow; visual analog scales (VAS); quality of life
21.  Response, Survival and Toxicity after 131I-MIBG Therapy for Neuroblastoma in Pre-Adolescents, Adolescents and Adults 
Cancer  2011;117(18):4286-4293.
Adolescent and adult patients with neuroblastoma appear to have a more indolent disease course but a lower survival than their younger counterparts. The majority of neuroblastoma tumors specifically accumulate the radiolabeled norepinephrine analogue 131I-metaiodobenzylguanidine (MIBG). 131I-MIBG has therefore become increasingly used as targeted radiotherapy for relapsed or refractory neuroblastoma. The aim of this study was to characterize the toxicity and activity of this therapy in older patients.
We performed a retrospective analysis of 39 consecutive patients ages 10 years and older with relapsed or refractory neuroblastoma who were treated with 131I-MIBG monotherapy at UCSF under Phase I, Phase II, and compassionate access protocols.
Sixteen patients were ≥18 years old at MIBG treatment initiation, whereas twenty-three were 10–17 years old. The median cumulative administered dose of 131I-MIBG was 17.8 mCi/kg. The majority of treatments led to grade 3 or 4 hematologic toxicities which were similar in frequency among age strata. Three patients subsequently developed hematologic malignancy or myelodysplasia. The overall rate of complete plus partial response was 46%. Patients ≥18 years old at time of first MIBG treatment had a significantly higher response rate compared to patients 10–17 years old (56% vs 39%, p=0.023). Median overall survival was 23 months with a trend toward longer overall survival for the ≥18 year old subgroup (p = 0.12).
Our findings suggest that 131I-MIBG is a highly effective salvage agent for adolescents and adults with neuroblastoma.
PMCID: PMC3125487  PMID: 21387264
neuroblastoma; adult; adolescent; MIBG; radiopharmaceutical
22.  Daily Oral Everolimus Activity in Patients With Metastatic Pancreatic Neuroendocrine Tumors After Failure of Cytotoxic Chemotherapy: A Phase II Trial 
Journal of Clinical Oncology  2009;28(1):69-76.
No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs.
Patients and Methods
This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed.
By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus.
Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.
PMCID: PMC4295034  PMID: 19933912
23.  Radiolabeled Metaiodobenzylguanidine for the Treatment of Neuroblastoma 
Nuclear medicine and biology  2008;35(Suppl 1):S35-S48.
Neuroblastoma is the most common pediatric extracranial solid cancer. This tumor is characterized by metaiodobenzylguanidine (MIBG) avidity in 90% of cases, prompting the use of radiolabeled MIBG for targeted radiotherapy in these tumors.
The available English language literature was reviewed for original research investigating in vitro, in vivo, and clinical applications of radiolabeled MIBG for neuroblastoma.
MIBG is actively transported into neuroblastoma cells by the norepinephrine transporter. Preclinical studies demonstrate substantial activity of radiolabeled MIBG in neuroblastoma models, with 131I-MIBG showing enhanced activity in larger tumors compared to 125I-MIBG. Clinical studies of 131I-MIBG in patients with relapsed or refractory neuroblastoma have identified myelosuppression as the main dose-limiting toxicity, necessitating stem cell reinfusion at higher doses. Most studies report a response rate of 30–40% with 131I-MIBG in this population. More recent studies have focused on the use of 131I-MIBG in combination with chemotherapy or myeloablative regimens.
131I-MIBG is an active agent for the treatment of patients with neuroblastoma. Future studies will need to define the optimal role of this targeted radiopharmaceutical in the therapy of this disease.
PMCID: PMC2633223  PMID: 18707633
Metaiodobenzylguanidine; neuroblastoma; pediatric; radionuclide
24.  Preclinical evaluation of lestaurtinib (CEP-701) in combination with retinoids for neuroblastoma 
Cancer chemotherapy and pharmacology  2011;68(6):1469-1475.
Lestaurtinib (CEP-701), a multi-kinase inhibitor with potent activity against the Trk family of receptor tyrosine kinases, has undergone early phase clinical evaluation in children with relapsed neuroblastoma. We studied the interaction of CEP-701 with isotretinoin (13cRA) and fenretinide (4HPR), two retinoids that have been studied in children with high-risk neuroblastoma.
In vitro growth inhibition was assessed following a 72-hour drug exposure using the sulforhodamine B (SRB) assay in eight neuroblastoma cell lines with variable TrkB expression. When appropriate, the combination index (CI) of Chou-Talalay was used to characterize the interaction of 13cRA (non-constant ratio) or 4HPR (constant ratio) with CEP-701.
The median (range) IC50 of single-agent CEP-701 across all cell lines was 0.09 (0.08–0.3) μM. The combination of 13cRA and CEP-701 resulted in additive to synergistic interactions in four of the five cell lines studied. Addition of 1 or 5 μM of 13cRA decreased the median (range) CEP-701 IC50 1.5-fold (1.1–2.8-fold) and 1.7-fold (1.5–1.8-fold), respectively. With 10 μM 13cRA, less than 50% of cells survived when combined with various concentrations of CEP-701. The combination of 4HPR and CEP-701 trended toward being antagonistic, with a median (range) CI at the ED50 of 1.3 (1.1–1.5).
The combination of 13cRA and CEP-701 was additive or synergistic in a spectrum of neuroblastoma cell lines, suggesting that these agents can be potentially studied together in the setting of minimal residual disease following intensive chemoradiotherapy for children with high-risk neuroblastoma.
PMCID: PMC4135359  PMID: 21484309
Neuroblastoma; Retinoid; Lestaurtinib (CEP-701); In vitro
25.  4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells 
PLoS ONE  2010;5(10):e13362.
The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a polar metabolite of fenretinide (4-HPR) very effective in killing cancer cells of different histotypes, able to inhibit 4-HPR-resistant cell growth and to act synergistically in combination with the parent drug. Unlike 4-HPR and other retinoids, 4-oxo-4-HPR inhibits tubulin polymerization, leading to multipolar spindle formation and mitotic arrest. Here we investigated whether 4-oxo-4-HPR, like 4-HPR, triggered cell death also via reactive oxygen species (ROS) generation and whether its antimicrotubule activity was related to a ROS-dependent mechanism in ovarian (A2780), breast (T47D), cervical (HeLa) and neuroblastoma (SK-N-BE) cancer cell lines.
Methodology/Principal Findings
We provided evidence that 4-oxo-4-HPR, besides acting as an antimicrotubule agent, induced apoptosis through a signaling cascade starting from ROS generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and upregulation of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Through time-course analysis and inhibition of the ROS-related signaling pathway (upstream by vitamin C and downstream by PLAB silencing), we demonstrated that the antimitotic activity of 4-oxo-4-HPR was independent from the oxidative stress induced by the retinoid. In fact, ROS generation occurred earlier than mitotic arrest (within 30 minutes and 2 hours, respectively) and abrogation of the ROS-related signaling pathway did not prevent the 4-oxo-4-HPR-induced mitotic arrest.
These data indicate that 4-oxo-4-HPR anticancer activity is due to at least two independent mechanisms and provide an explanation of the ability of 4-oxo-4-HPR to be more potent than the parent drug and to be effective also in 4-HPR-resistant cell lines. In addition, the double mechanism of action could allow 4-oxo-4-HPR to efficiently target tumour and to eventually counteract the development of drug resistance.
PMCID: PMC2954786  PMID: 20976277

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