Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1512-1518
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.09.5125
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rheingold, S. R.
Right arrow Articles by Adamson, P. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rheingold, S. R.
Right arrow Articles by Adamson, P. C.

Phase I Trial of G3139, a bcl-2 Antisense Oligonucleotide, Combined With Doxorubicin and Cyclophosphamide in Children With Relapsed Solid Tumors: A Children's Oncology Group Study

Susan R. Rheingold, Michael D. Hogarty, Susan M. Blaney, James A. Zwiebel, Calies Sauk-Schubert, Reddy Chandula, Mark D. Krailo, Peter C. Adamson

From the Children's Hospital of Philadelphia, Philadelphia, PA; Texas Children's Cancer Center at Baylor College of Medicine, Houston, TX; Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, MD; Genta Inc, Berkeley Heights, NJ; Children's Oncology Group, Arcadia; and University of Southern California Keck School of Medicine, Los Angeles, CA

Address reprint requests to Peter C. Adamson, MD, Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, ARC 916, 34th St & Civic Center Blvd, Philadelphia, PA 19104; e-mail: adamsonp{at}mail.med.upenn.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose: To determine the maximum-tolerated dose, toxicity, pharmacokinetics, and biologic effects of G3139 when administered with doxorubicin and cyclophosphamide to children with relapsed solid tumors.

Patients and Methods: Patients received a 7-day continuous infusion of 3, 5, or 7 mg/kg/d of G3139 every 21 days. Doxorubicin, cyclophosphamide, and dexrazoxane were administered on days 5 and 6 of the infusion. Pharmacokinetics and biology studies were performed during the first course.

Results: Thirty-seven patients, median age 14 years (range, 1 to 19 years), were enrolled, of whom 29 were fully assessable for toxicity. Because of dose-limiting neutropenia, doses of doxorubicin 30 mg/m2/d for 2 days, dexrazoxane 300 mg/m2/d for 2 days, and cyclophosphamide 500 mg/m2/d for 2 days were reduced initially, but with the addition of granulocyte colony-stimulating factor (GCSF), could be re-escalated to starting doses. At the 7 mg/kg/d dose level, only one of six patients experienced DLT (neutropenia > 7 days). At this dose, the average (± standard deviation) steady-state G3139 concentration was 2.04 ± 1 µg/mL, a concentration associated with biologic activity. Eleven of 15 patients had reduced bcl-2 expression in peripheral-blood mononuclear cells at the first assessable time point of G3139 exposure, and in eight of 14 patients with serial specimens this reduction persisted through day 6.

Conclusion: The recommended phase II dose of G3139 is 7 mg/kg/d as a 7-day continuous infusion, with cyclophosphamide 500 mg/m2/d and doxorubicin 30 mg/m2/d on days 5 and 6, followed by GCSF. G3139 may accentuate the myelosuppressive effects of doxorubicin and cyclophosphamide. Evidence for biologic effects of G3139 was demonstrated.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
G3139 (oblimersen sodium, bcl-2 antisense, Genasense; Genta Inc, Berkeley Heights, NJ) is an 18-mer phosphorothioate oligodeoxynucleotide antisense (5'-TCTCCCAGCGTGCGCCAT-3') designed to bind to the first six codons of the human bcl-2 mRNA. The members of the bcl-2 family of proteins are key regulators of the intrinsic or mitochondrial apoptosis pathway mediating cytochrome c release and effector caspase activation.1 Bcl-2, an antiapoptotic family member, contributes to neoplastic progression by enhancing cell survival through repression of mitochondrial death signaling.2-4 Overexpression of bcl-2 results in a resistance to apoptosis-inducing agents including radiation and chemotherapy, and has been associated with poor clinical response and shorter survival.4-6 Targeted downregulation of bcl-2 expression by G3139 may result in apoptosis of tumor cells, especially when coadministered with cytotoxic drugs.5,6

A spectrum of pediatric solid tumor cell lines, including neuroblastoma,7,8 Ewing sarcoma,9,10 Wilms' tumor,11,12 and synovial sarcoma,13 overexpress bcl-2. In neuroblastoma cell lines, the expression of bcl-2 is associated with inhibition of chemotherapy-induced apoptosis,8,14,15 and cell lines expressing high levels of bcl-2 demonstrate broad chemotherapy resistance. High bcl-2 expression has been associated with unfavorable histology and MYCN gene amplification, suggesting an association with poor prognosis.14-16 Finally, bcl-2 expression is increased in histologically differentiated neuroblastoma, suggesting that downregulation of bcl-2 may be correlated with terminal differentiation.17-20

In adult trials, G3139 in doses up to 7 mg/kg/d for 5 to 7 days is well tolerated, with reduction of bcl-2 expression in peripheral-blood mononuclear cells (PBMCs) occurring within 3 to 4 days of initiation of the infusion.21,22 Clinical trials have combined G3139 with a number of different chemotherapeutic agents, including dacarbazine,23 mitoxantrone,24 docetaxel,22,25 paclitaxel,26 cytarabine,27 fludarabine,27 and daunorubicin.28 In general, G3139 toxicity has not been dose limiting, and dose escalation was stopped when steady-state concentrations of G3139 exceeded target concentrations. Non–dose-limiting G3139 toxicities when administered in combination with cytotoxic chemotherapy include neutropenia, anemia, thrombocytopenia, lymphopenia, leukopenia, fatigue, mucositis, fever, nausea, arthralgias, myalgias, and transient elevations in serum creatinine, hepatic aminotransferases, and glucose.21,22,24-26

Anthracyclines and alkylating agents have significant activity in a broad range of childhood cancers. Doxorubicin and cyclophosphamide are used in both first-line and relapse chemotherapy protocols for children with solid tumors, including neuroblastoma, Wilms' tumor, Ewing sarcoma, and other soft tissue sarcomas. Both drugs are capable of initiating the apoptosis cascade through the generation of genotoxic stress and activation of cellular DNA damage response pathways. Thus, pharmacologic downregulation of bcl-2 by G3139 may potentially enhance chemotherapy responsiveness of tumor cells to these drugs.

We conducted a pediatric phase I trial of G3139 in combination with doxorubicin and cyclophosphamide. The primary aims of this study were to determine the maximum-tolerated dose (MTD) or recommended phase II dose, describe the dose-limiting toxicities (DLTs), and define the pharmacokinetics (PK) of G3139 administered as a 7-day continuous intravenous infusion (CI) in children with relapsed and refractory solid tumors. Secondary aims included assessing the biologic activity of G3139 in PBMCs and preliminarily defining the antitumor activity of this combination.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Eligibility Criteria
Eligibility criteria included age older than 1 year and younger than 22 years; a diagnosis of a malignant solid tumor (excluding lymphoma and CNS tumors) refractory to conventional therapy; Karnofsky (children older than 10 years) or Lansky (children ≤ 10 years) score ≥ 50; life expectancy ≥ 8 weeks; recovery from prior therapy; no chemotherapy within 2 weeks (6 weeks for prior nitrosourea therapy) and no biologic agent or growth factor therapy within 1 week of study entry; no substantial radiotherapy to the bone marrow within 6 weeks of study entry; no allogeneic stem-cell transplantation within 6 months of study entry and no active graft-versus-host disease; normal age-adjusted serum creatinine or glomerular filtration rate ≥ 70 mL/min/1.73 m2; serum bilirubin concentration ≤ 1.5x and serum ALT ≤ 3x the upper limit of the normal for age; and a cardiac shortening fraction ≥ 28% or an ejection fraction ≥ 45%.

Initially, patients were allowed to enroll onto the study with the following hematologic requirements: an absolute neutrophil count ≥ 500/µL, a platelet count ≥ 50,000/µL, and a hemoglobin concentration ≥ 8 g/dL. Once the initial DLT was found to be myelosuppression, patients had to have an absolute neutrophil count ≥ 1,000/µL, a platelet count ≥ 100,000/µL, and a hemoglobin concentration ≥ 8 g/dL. Study exclusion criteria were uncontrolled infection or systemic illness, total lifetime anthracycline dose more than 450 mg/m2, and pregnancy or lactation. No limitation was placed on the number of prior chemotherapy regimens.

Institutional review boards at participating institutions approved the study. Informed consent was obtained from patients age ≥ 18 years and permission was obtained from parents or legal guardians of children, with child assent when appropriate, according to individual institutional policies.

Trial Design
G3139 was administered as a 7-day CI. Doxorubicin 30 mg/m2/d with dexrazoxane 300 mg/m2/d and cyclophosphamide 500 mg/m2/d were administered on days 5 and 6 of the G3139 infusion. A course was defined as 21 days, and the maximum allowable interruption between courses was 14 days. The starting dose of G3139 was 3 mg/kg/d, with subsequent dose escalations to 5 and 7 mg/kg/d. Intrapatient dose escalation was not allowed.

Patients who exceeded a lifetime dose of 750 mg/m2 of doxorubicin could continue therapy with G3139 and cyclophosphamide only. Patients who experienced a DLT that resolved could continue treatment with 25% reduction of the cytotoxic drug dosing. Protocol therapy stopped due to disease progression, patient choice, or when an irreversible DLT occurred.

At least three patients were studied at each dose level. If none of these three patients experienced a DLT, the subsequent three patients were enrolled at the next higher dose level. If one of three patients at a given dose level experienced a DLT, then up to three more patients were treated at the same level. When DLT was observed in at least two patients in a cohort of three to six, the MTD was exceeded and an additional three patients were treated at the next lower dose level provided only three assessable patients had been enrolled previously at that level. The MTD was defined as the dose level at which zero of six or one of six patients experienced DLT with at least two of three or two of six patients encountering DLT at the next higher dose.

Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Dose-limiting hematologic toxicity was defined as any grade 4 neutropenia or thrombocytopenia lasting more than 7 days. Hematologic toxicity that caused a delay of ≥ 14 days beyond the planned interval between treatment courses was also considered a DLT. Any patient who developed ≥ grade 3 hematologic toxicity attributable to G3139 before day 5 initiation of cytotoxic chemotherapy was considered dose limited and did not receive the doxorubicin and cyclophosphamide for that cycle. Nonhematologic DLT was defined as any grade 3 or grade 4 nonhematologic toxicity attributable to G3139 with the specific exclusion of grade 3/4 nausea and vomiting, grade 3 aminotransferase (AST/ALT) elevation that returned to grade 1 or baseline before the next treatment course, grade 3/4 fever, or grade 3 infection. All patients with measurable disease were assessed for response using the Response Evaluation Criteria in Solid Tumors criteria.29

Dosage and Drug Administration
G3139 was provided by the Cancer Therapy Evaluation Program (National Cancer Institute, Bethesda, MD) as a sterile solution containing 300 mg of drug in 10 mL of sterile isotonic normal saline. Drug was diluted further with sterile normal saline to allow for administration via a continuous ambulatory drug delivery infusion pump during 7 days.

Pharmacokinetics
Plasma blood samples were collected before treatment; at 96 and 120 hours into the G3139 infusion; at the end of the infusion (168 hours); and 1, 2, 3, 4, 6, 8, 22, and 24 hours after discontinuation. Samples were analyzed by validated high-performance liquid chromatography method, with a lower limit of quantitation of 200 ng/mL for G3139 and its N-1 and N-2 metabolites.30 The PK of G3139 and its metabolites were determined by noncompartmental methods using WinNonLin (Pharsight Corp, Mountain View, CA). Given that the time course of drug accumulation could not be characterized, the area under the plasma concentration-time curve from the first steady-state concentration (Css; 96 hours) to time of last quantifiable concentration was calculated by the linear trapezoidal rule. The average Css was calculated by averaging the 96-, 120-, and 168-hour concentrations. Clearance was determined by dividing the dose rate by the Css. Plasma concentrations less than the lower limit of quantitation were considered as zero in the PK analysis.

Biologic Studies
Peripheral blood (3 to 5 mL) was collected pretreatment and on days 5, 6, and 8 of the first course of therapy. PBMCs were prepared at the treating institution and shipped to The Children's Hospital of Philadelphia. For analysis, cell pellets were thawed and resuspended in lysis buffer. Cell suspensions underwent five freeze-thaw cycles by immersion in liquid nitrogen for lysis, and whole protein lysates were isolated by centrifugation at 14,000 rpm at 4°C. Whole protein lysate (20 µg) was denatured and fractionated through a 10.5% to 14% Tris-HCl–polyacrylamide gel electrophoresis gradient gel. Protein was then transferred to polyvinylidene difluoride membranes and bcl-2 detection was performed using anti–bcl-2 antibody at 1:1000 dilution (SC-7328; Santa Cruz Biotechnology, Santa Cruz, CA) and an alkaline phosphatase–labeled goat antimouse secondary antibody (BioRad, Hercules, CA). Actin was detected to control for protein loading using an antiactin antibody at 1:100 dilution (SC-8432; Santa Cruz Biotechnology). Protein lysates from the neuroblastoma cell line SY5Y were included on each gel as a quality-control measure to ensure bcl-2/actin signals remained within the linear dynamic range of the assay. For each sample, bcl-2 band intensity was normalized to actin using National Institutes of Health Image software (http://rsb.info.nih.gov/nih-image/), and for each time point, bcl-2 expression was determined by quantifying the area under the densitometry curve normalized to the area under the curve for actin. Each patient served as his or her own control for bcl-2 changes over time. Relative (not absolute) changes in the bcl-2/actin expression ratios between patients were compared.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
A total of 37 patients were enrolled onto Children's Oncology Group trial ADVL 0211 (Table 1). All patients were eligible, but eight were not fully assessable for toxicity: two never started drug therapy, one never completed the G3139 infusion due to family preference, one was diagnosed with myelodysplastic syndrome [t(3,8) translocation] within 2 weeks of enrolling onto the study, three did not have scheduled laboratory evaluations to accurately determine duration of neutropenia, and one did not receive a proper dose of drug due to pump malfunction (PK results for this patient, who received 4.25 mg/kg/d of G3139, are included in Table 2). Patients received a median of two courses (range, two to 12 courses).


View this table:
[in this window]
[in a new window]

  		Table 1. Patient Characteristics

 

View this table:
[in this window]
[in a new window]

  		Table 2. Pharmacokinetics

 
Toxicity
Overall, the G3139 infusion was well tolerated and the primary toxicities of the combination were hematologic. Two strategies were used when myelosuppression was found to be the DLT at the initial dose level. First, doses of the cytotoxic drugs were reduced to doxorubicin 22.5 mg/m2/d for 2 days (dexrazoxane 225 mg/m2/d for 2 days) and cyclophosphamide 400 mg/m2/d for 2 days. When only isolated neutropenia remained as the DLT, granulocyte colony-stimulating factor (GCSF) was administered at 5 µg/kg/d starting day 8 until the postnadir absolute neutrophil count was more than 1,500/µL. These changes allowed for subsequent G3139 escalation to 5 and 7 mg/kg/d. Once 7 mg/kg/d was tolerated in a cohort of patients, the doses of cytotoxics were successfully re-escalated to their initial dose; however, additional increase in cytotoxics was not tolerated (Table 3). Therefore, the MTDs for this regimen were G3139 7 mg/kg/d as a 7-day CI, cyclophosphamide 500 mg/m2/d and doxorubicin 30 mg/m2/d on days 5 and 6, followed by GCSF.


View this table:
[in this window]
[in a new window]

  		Table 3. Toxicity Summary

 
There was one nonhematologic DLT. The patient, who also received gentamicin and had undergone a computed tomography scan with intravenous contrast within 24 hours of starting 3 mg/kg/d G3139, developed a grade 3 elevation in serum creatinine (maximum, 4.1 g/dL) on day 3 of his infusion. His serum creatinine returned to baseline within 2 weeks of drug discontinuation. Other ≥ grade 1 nonhematologic non-DLTs that occurred in more than 10% of patients are listed in Table 4. Nonhematologic toxicities did not appear to be correlated to dose level of drug.


View this table:
[in this window]
[in a new window]

  		Table 4. Non–Dose-Limiting, Nonhematologic Toxicities Related to Protocol Therapy and Observed in More Than 10% of 29 Assessable Pediatric Patients With Refractory Solid Tumors

 
Disease Response
One patient with Ewing sarcoma had a partial response to therapy, and eight patients (synovial sarcoma, n = 2; neuroblastoma, n = 2; osteosarcoma, n = 2; renal cell carcinoma, n = 1; thymoma, n = 1) had prolonged stable disease, receiving a median of seven courses (range, four to 12 courses).

PK Studies
PK of G3139 and its two metabolites, 4016n1 and 4017n2, were characterized at least partially in 15 patients (Table 2). G3139 area under the time-concentration curve from 96 to 192 hours and Css seemed to increase in proportion to dose. The average ± standard deviation Css of G3139 at a dose of 7 mg/kg/d (2.04 ± 1 µg/mL) exceeded the 1 µg/mL target concentration determined in preclinical animal studies and adult clinical trials.21,22 The median plasma G3139 clearance was 0.14 L/kg/h (range, 0.08 to 0.23 L/kg/h). The terminal elimination phase could not be characterized adequately.

Biology Studies
To assess biologic efficacy, PBMCs were obtained from 21 patients. Six were excluded from additional analyses: three had no day 1 (pretreatment) specimen, and three had insufficient protein harvested. The remaining 15 patients had adequate PBMC samples from day 1 in addition to at least two additional samples (from days 5, 6, and/or 8).

The pretreatment normalized PBMC bcl-2 expression ratio for the 15 patients ranged from 0.3 to 70.9 (mean, 8.3 ± 19.0; median, 2.1), predominantly reflecting interpatient variability in PBMC actin isoform abundance. Marked interpatient variability in bcl-2 bioresponse in PBMCs was apparent (Fig 1). Eleven (73%) of 15 patients demonstrated a reduction in PBMC bcl-2, defined by a reduction in bcl-2/actin ratio at the earliest assessed time point (day 5, n = 6; or day 6, n = 5; Fig 2). Eight (57%) of 14 patients with serial samples demonstrated a decrease in bcl-2 expression across all assessable time points. In these eight patients, the median maximal bcl-2 reduction was 71% (range, 20% to 86%). After cytotoxic chemotherapy, the relative bcl-2 levels obtained on day 8 were more variable (data not shown). In the seven patients who had both PK and biologic assays performed, there was no correlation between Css and decrease in bcl-2 expression.


Figure 1
View larger version (11K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 1. bcl-2 and actin expression during G3139 exposure. Representative immunoblots are shown for four study patients, at time points from day 1 (preinfusion) through day 8. Peripheral-blood mononuclear cell lysates were immunoblotted for actin (internal reference) and bcl-2 protein expression. The dose level for each study patient and the percent bcl-2 change from pretreatment is shown.

 

Figure 2
View larger version (6K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 2. Bcl-2 response based on G3139 dose level. Relative change in bcl-2 protein content from day 0 to day 5 is shown for each of the three dose levels investigated (*two patients had no day 5 sample obtained, so a day 6 response is shown).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
In this phase I trial, we evaluated the toxicities of G3139 administered by CI for 7 days in 21-day cycles with concomitant cytotoxic chemotherapy on days 5 and 6 of a cycle. Cyclophosphamide and doxorubicin were selected based on their known activity in the treatment of a spectrum of pediatric solid tumors.

The median plasma G3139 clearance of 0.14 L/kg/h in children seems to be greater than the plasma G3139 clearance of 0.09 L/kg/h reported in an adult study that used the same bioanalytical methodology.31 A range of plasma drug clearances, however, has been observed in adult patients,28,30,32-35 but methodologies have differed, making direct comparisons more difficult. The interpatient variability in drug clearance in both adult and pediatric patients is high, and thus additional studies will be needed to determine whether a true difference in drug disposition exists. Importantly, the children treated at the 7 mg/kg/d dose level achieved drug exposures that have been associated with targeted effects in animal models.

We found significant interpatient variability in PBMC bcl-2 levels after exposure to G3139, both in direction and magnitude of responses. Similar to previous reports,33 bcl-2 protein expression in surrogate tissues decreased after antisense exposure in the majority of patients (11 of 15), supporting a targeted biologic effect. Six of these patients had reductions in PBMC bcl-2 to less than 50% of pretreatment levels. Day 8 bcl-2 levels tended to be higher than levels on days 5 or 6, possibly reflecting effects of cytotoxic drugs on PBMC composition and/or protein content. No correlation was found between bcl-2 protein change and G3139 dose level or Css. There was no correlation between PBMC bcl-2 reduction and disease response.

Antisense oligonucleotide effects reflect a series of complex stoichiometric interactions: cellular exposure, oligonucleotide uptake, antisense-hybridization and mRNA degradation (via passive and active mechanisms), and diminished protein synthesis that fails to sustain protein abundance in the setting of normal degradation. In prior adult phase I and II G3139 trials, bcl-2 knockdown has not correlated with either drug dose or plasma Css.24,33,34,36-39 Various assays have been used to assess bioresponse, including bcl-2 mRNA or bcl-2 protein assessment, with generally similar results.24,38 Recent studies have demonstrated that intracellular G3139 concentration is more closely correlated to biologic activity (bcl-2 mRNA or protein reduction) than plasma G3139 concentration. Furthermore, although intracellular G3139 levels increased over time of exposure in all patients, there was marked interpatient variability, whereas plasma concentrations were largely invariant36,37 and did not correlate with the intracellular concentration achieved or bioresponse. Thus, the lack of correlation in our study between steady-state plasma G3139 concentrations and surrogate biologic effect may reflect inherent interpatient differences in cellular uptake of G3139.

In summary, G3139 administered as a 7-day CI with cytotoxic chemotherapy to children with relapsed or refractory solid tumors was generally well tolerated, and at a dose of 7 mg/kg/d, was associated with biologic activity. G3139 may have accentuated the myelosuppressive effects of doxorubicin and cyclophosphamide in heavily pretreated pediatric patients, but cytotoxic doses of these drugs were delivered with an acceptable degree of myelosuppression. When combined with G3139, the recommended phase II doses for children with relapsed solid tumors are cyclophosphamide 500 mg/m2/d for 2 days, dexrazoxane 300 mg/m2/d for 2 days, and doxorubicin 30 mg/m2/d for 2 days, followed by GCSF. In future studies, bcl-2 target knockdown studies in leukemia cells or surrogate PBMCs should also assess intracellular G3139 concentrations associated with this effect.


   AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 REFERENCES
 
Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Reddy Chandula, Genta Inc Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
REFERENCES
 
Conception and design: Susan R. Rheingold, Michael D. Hogarty, Susan M. Blaney, Mark D. Krailo, Peter C. Adamson

Administrative support: Susan M. Blaney, Peter C. Adamson

Provision of study materials or patients: Susan R. Rheingold, Susan M. Blaney, Peter C. Adamson

Collection and assembly of data: Susan R. Rheingold, Michael D. Hogarty, Calies Sauk-Schubert, Reddy Chandula

Data analysis and interpretation: Susan R. Rheingold, Michael D. Hogarty, Susan M. Blaney, James A. Zwiebel, Calies Sauk-Schubert, Reddy Chandula, Mark D. Krailo, Peter C. Adamson

Manuscript writing: Susan R. Rheingold, Michael D. Hogarty, Reddy Chandula, Mark D. Krailo, Peter C. Adamson

Final approval of manuscript: Susan R. Rheingold, Michael D. Hogarty, James A. Zwiebel, Peter C. Adamson


   NOTES
 
Supported by National Cancer Institute Grants No. U01 CA97452, M01 RR00188, M01 RR00084, M01 RR000037, M01 RR00585, and MO1 RR02172. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm.

Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Kim R: Recent advances in understanding the cell death pathways activated by anticancer therapy. Cancer 103:1551-1560, 2005[CrossRef][Medline]

2. Reed JC, Stein C, Subasinghe C, et al: Antisense-mediated inhibition of BCL2 protooncogene expression and leukemic cell growth and survival: Comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides. Cancer Res 50:6565-6570, 1990[Abstract/Free Full Text]

3. Smith MR, Abubakr Y, Mohammad R, et al: Antisense oligodeoxyribonucleotide down-regulation of bcl-2 gene expression inhibits growth of the low-grade non-Hodgkin's lymphoma cell line WSU-FSCCL. Cancer Gene Ther 2:207-212, 1995[Medline]

4. Reed JC: bcl-2: prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 9:451-473, 1995[Medline]

5. Kitada S, Takayama S, De Riel K, et al: Reversal of chemoresistance of lymphoma cells by antisense-mediated reduction of bcl-2 gene expression. Antisense Res Dev 4:71-79, 1994[Medline]

6. Campos L, Sabido O, Rouault JP, et al: Effects of BCL-2 antisense oligodeoxynucleotides on in vitro proliferation and survival of normal marrow progenitors and leukemic cells. Blood 84:595-600, 1994[Abstract/Free Full Text]

7. Ramani P, Lu QL: Expression of bcl-2 gene product in neuroblastoma. J Pathol 172:273-278, 1994[CrossRef][Medline]

8. Dole M, Nunez G, Merchant AK, et al: Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Cancer Res 54:3253-3259, 1994[Abstract/Free Full Text]

9. Fulda S, Debatin KM: Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors. Med Pediatr Oncol 35:616-618, 2000[CrossRef][Medline]

10. Soldatenkov VA, Dritschilo A: Apoptosis of Ewing's sarcoma cells is accompanied by accumulation of ubiquitinated proteins. Cancer Res 57:3881-3885, 1997[Abstract/Free Full Text]

11. Mayo MW, Wang CY, Drouin SS, et al: WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene. EMBO J 18:3990-4003, 1999[CrossRef][Medline]

12. Re GG, Hazen-Martin DJ, El Bahtimi R, et al: Prognostic significance of bcl-2 in Wilms' tumor and oncogenic potential of Bcl-X(L) in rare tumor cases. Int J Cancer 84:192-200, 1999[CrossRef][Medline]

13. Kawauchi S, Fukuda T, Oda Y, et al: Prognostic significance of apoptosis in synovial sarcoma: Correlation with clinicopathologic parameters, cell proliferative activity, and expression of apoptosis-related proteins. Mod Pathol 13:755-765, 2000[CrossRef]

14. Hoehner JC, Hedborg F, Wiklund HJ, et al: Cellular death in neuroblastoma: In situ correlation of apoptosis and bcl-2 expression. Int J Cancer 62:19-24, 1995[Medline]

15. Mejia MC, Navarro S, Pellin A, et al: Study of bcl-2 protein expression and the apoptosis phenomenon in neuroblastoma. Anticancer Res 18:801-806, 1998[Medline]

16. Castle VP, Heidelberger KP, Bromberg J, et al: Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification. Am J Pathol 143:1543-1550, 1993[Abstract]

17. Krajewski S, Chatten J, Hanada M, et al: Immunohistochemical analysis of the bcl-2 oncoprotein in human neuroblastomas. Comparisons with tumor cell differentiation and N-Myc protein. Lab Invest 72:42-54, 1995

18. Hanada M, Krajewski S, Tanaka S, et al: Regulation of bcl-2 oncoprotein levels with differentiation of human neuroblastoma cells. Cancer Res 53:4978-4986, 1993[Abstract/Free Full Text]

19. Lasorella A, Iavarone A, Israel MA: Differentiation of neuroblastoma enhances bcl-2 expression and induces alterations of apoptosis and drug resistance. Cancer Res 55:4711-4716, 1995[Abstract/Free Full Text]

20. Kim CJ, Kim HO, Choe YJ, et al: Bcl-2 expression in neuroblastoma is differentially regulated by differentiation inducers. Anticancer Res 15:1997-2000, 1995[Medline]

21. Jansen B, Wacheck V, Heere-Ress E, et al: Clinical, pharmacologic, and pharmacodynamic study of Genasense and dacarbazine in patients with malignant melanoma. Proc Am Soc Clin Oncol 20:357a, 2001 (abstr 1426)

22. De Bona J, Rowinsky, E., Kuhn, J: Phase I pharmacokinetic and pharmacodynamic trial of bcl-2 antisense and docetaxel in hormone refractory prostate cancer. Proc Am Soc Clin Oncol 20:107a, 2001 (abstr 424)

23. Jansen B, Wacheck V, Heere-Ress E, et al: Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 356:1728-1733, 2000[CrossRef][Medline]

24. Chi KN, Gleave ME, Klasa R, et al: A phase I dose-finding study of combined treatment with an antisense bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer. Clin Cancer Res 7:3920-3927, 2001[Abstract/Free Full Text]

25. Chen H, Marshall J, Trocky N, et al: A phase I study of BCL-2 antisense and weekly docetaxel in patients with advanced breast cancer and other solid tumors. Proc Am Soc Clin Oncol 19:178a, 2000 (abstr 692)

26. Scher H, Morris M, Tong W, et al: A phase I trial of a BCL-2 antisense drug, by continuous infusion as a single agent and with weekly taxol. Proc Am Soc Clin Oncol 19:199a, 2000 (abstr 774)

27. Marcucci G, Byrd JC, Dai G, et al: Phase 1 and pharmacodynamic studies of G3139, a bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood 101:425-432, 2003[Abstract/Free Full Text]

28. Marcucci G, Stock W, Dai G, et al: Phase I study of oblimersen sodium, an antisense to bcl-2, in untreated older patients with acute myeloid leukemia: Pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol 23:3404-3411, 2005[Abstract/Free Full Text]

29. 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[Abstract/Free Full Text]

30. O'Brien SM, Cunningham CC, Golenkov AK, et al: Phase I to II multicenter study of oblimersen sodium, a bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J Clin Oncol 23:7697-7702, 2005[Abstract/Free Full Text]

31. Demidov LV, Kharkevitch G, Itri LM, et al: A pharmacokinetic (PK) study of oblimersen sodium (G3139) + dacarbazine (DTIC) in patients with metastatic melanoma (MM). Proc Am Soc Clin Oncol 22:156, 2003 (abstr 623)

32. Rudin CM, Kozloff M, Hoffman PC, et al: Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 22:1110-1117, 2004[Abstract/Free Full Text]

33. Tolcher AW, Chi K, Kuhn J, et al: A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 11:3854-3861, 2005[Abstract/Free Full Text]

34. Tolcher AW, Kuhn J, Schwartz G, et al: A phase I pharmacokinetic and biological correlative study of oblimersen sodium (genasense, g3139), an antisense oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 10:5048-5057, 2004[Abstract/Free Full Text]

35. Waters JS, Webb A, Cunningham D, et al: Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J Clin Oncol 18:1812-1823, 2000[Abstract/Free Full Text]

36. Dai G, Chan KK, Liu S, et al: Cellular uptake and intracellular levels of the bcl-2 antisense g3139 in cultured cells and treated patients with acute myeloid leukemia. Clin Cancer Res 11:2998-3008, 2005[Abstract/Free Full Text]

37. Dai S, Wan T, Wang B, et al: More efficient induction of HLA-A*0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells. Clin Cancer Res 11:7554-7563, 2005[Abstract/Free Full Text]

38. Badros AZ, Goloubeva O, Rapoport AP, et al: Phase II study of G3139, a bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. J Clin Oncol 23:4089-4099, 2005[Abstract/Free Full Text]

39. Morris MJ, Tong WP, Cordon-Cardo C, et al: Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res 8:679-683, 2002[Abstract/Free Full Text]

Submitted October 13, 2006; accepted January 22, 2007.




This article has been cited by other articles:


Home page
 J. Virol.Home page
V. F. Tumilasci, S. Oliere, T. L.-A. Nguyen, A. Shamy, J. Bell, and J. Hiscott
Targeting the Apoptotic Pathway with BCL-2 Inhibitors Sensitizes Primary Chronic Lymphocytic Leukemia Cells to Vesicular Stomatitis Virus-Induced Oncolysis
J. Virol., September 1, 2008; 82(17): 8487 - 8499.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rheingold, S. R.
Right arrow Articles by Adamson, P. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rheingold, S. R.
Right arrow Articles by Adamson, P. C.

About
JCO		 Editorial
Roster		 Advertising
Information		 Librarians &
Institutions		 Rights &
Permissions		 PDA Services

Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online