Clinical Cancer Research Targets AACR Membership
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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 Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Morris, M. J.
Right arrow Articles by Scher, H. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Morris, M. J.
Right arrow Articles by Scher, H. I.
Clinical Cancer Research Vol. 8, 679-683, March 2002
© 2002 American Association for Cancer Research

Clinical Trials

Phase I Trial of BCL-2 Antisense Oligonucleotide (G3139) Administered by Continuous Intravenous Infusion in Patients with Advanced Cancer1

Michael J. Morris, William P. Tong, Carlos Cordon-Cardo, Marija Drobnjak, William K. Kelly, Susan F. Slovin, Kathryn L. Terry, Karen Siedlecki, Paul Swanson, Mohmed Rafi, Robert S. DiPaola, Neal Rosen and Howard I. Scher2

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [M. J. M., W. P. T., C. C-C., M. D., W. K. K., S. F. S., K. L. T., K. S., P. S., N. R., H. I. S.]; Department of Medicine, Weill Medical College of Cornell University, New York, New York [M. J. M., W. P. T., C. C-C., M. D., W. K. K., S. F. S., P. S., N. R., H. I. S.]; and The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey [M. R., R. S. D.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: To evaluate the safety and pharmacokinetics of BCL-2 antisense oligonucleotide (G3139) administered by prolonged i.v. infusion in patients with advanced cancer.

Experimental Design: A total of 35 patients was treated in cohorts of 3–6 with 0.6–6.9 mg/kg/day of BCL-2 antisense oligonucleotide as a continuous infusion for 14 or 21 days. Plasma levels of intact antisense oligonucleotide were measured in all patients.

Results: G3139 was generally well tolerated. At the highest dose level examined in this study (6.9 mg/kg/day), fatigue and transient reversible elevations of serum transaminases (grades 2–3) became apparent after >=7 days of treatment. Both reactions were believed to be drug related. Pharmacokinetic analyses showed that steady-state plasma concentrations of G3139 were reached ~10 h after starting the infusion and increased linearly across the range of doses administered <=6.9 mg/kg/day. The terminal plasma half-life was ~2 h. Exploratory studies using Western blots, performed on peripheral blood mononuclear cells on selected patients, demonstrated a decline in bcl-2 protein levels during treatment. No major antitumor responses were observed.

Conclusions: BCL-2 antisense therapy is well tolerated. Relative to other dose-finding studies of G3139, fatigue was somewhat more prominent in this study, possibly because of the protracted i.v. infusion schedule of the antisense oligonucleotide. Current randomized trials are using the highest daily dose established in this study given by shorter infusion periods (i.e., 7 mg/kg/day for 5–7 days) to enhance the antitumor activity of standard cytotoxic drugs.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The BCL-2 gene product is a 239 amino acid integral-membrane mitochondrial protein that inhibits apoptosis (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) . It has been implicated in the growth and development of a variety of solid tumors, including prostate, breast, lung, renal, ovary, and prostate cancers, as well as melanoma (6 , 9, 10, 11 , 13, 14, 15, 16, 17, 18) , and has the potential to confer chemoresistance and radioresistance to established tumors (19) .

The bcl-2 protein dimerizes both with itself and with other members of the bcl-2 family, including bax, bcl-XL, and bcl-Xs (20, 21, 22) . The interaction of these protein dimers influences sensitivity to apoptotic stimuli and has been reviewed extensively elsewhere (23, 24, 25) . Preclinical data demonstrate that BCL-2 antisense therapy has antitumor effects against a variety of solid tumors, including prostate, breast, and melanoma (26, 27, 28) . In human testing, single agent treatment with BCL-2 antisense oligonucleotide has resulted in tumor regression in patients with relapsed non-Hodgkin’s lymphoma (29) . We undertook a Phase I trial to determine the safety, PKs, and preliminary efficacy of BCL-2 antisense oligonucleotide therapy, delivered as a continuous i.v. 14- or 21-day infusion, in patients with solid tumors.

The BCL-2 antisense oligonucleotide used in this study [G3139 (Genasense); Genta, Inc., Berkeley Heights, NJ] is an 18-mer phosphorothioate complementary to the first six codons of Bcl-2 mRNA.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Patient Eligibility.
Eligible patients had progressive solid tumors with no acceptable standard treatment options. Patients with prostate cancer had androgen-independent disease that had progressed despite antiandrogen withdrawal. All patients were required to have a life expectancy of >=6 months, a total leukocyte count > 3,500/mm3, platelet count > 100,000/mm3, aspartate aminotransferase < 3 x the upper limit of normal, creatinine < 2 mg/dl or creatinine clearance > 60 ml/min, and prothrombin time < 14 s.

All patients underwent placement of a central venous catheter. BCL-2 antisense oligonucleotide was administered at a rate of 12 ml/min using a portable continuous infusion pump. For the first 24 h of treatment, all patients were hospitalized for PK3 studies. Remaining treatment was administered as an outpatient. This trial was reviewed and approved in advance by Memorial Sloan-Kettering Cancer Center’s Institutional Review Board, and written informed consent was obtained from each patient.

Study Design.
Cohorts of 3–6 patients each were defined by antisense dose (i.e., 0.6, 1.3, 1.7, 2.3, 3.1, 4.1, 5.3, and 6.9 mg/kg/day). The starting dose of 0.6 mg/kg/day was one-half the s.c. dose at which toxicity had first been observed in a prior study, based on an assumed 60% bioavailability for the s.c. dose. All patients received an initial 2-week infusion of oligonucleotide, followed by an observation period. There were two treatment schedules in the trial:

1) 2 weeks on/4 weeks off for a total of three cycles;

2) 2 weeks on/2 weeks off for one cycle, then 3 weeks on/1 week off for two additional cycles.

Cohorts 5 (3.1 mg/kg/day) and 6 (4.1 mg/kg/day) were pre-established at 6 patients for the purpose of ensuring safety after the infusion duration was increased from 2 weeks to 3, and the duration of the breaks between cycles was reduced from 3 weeks to 1 (see Table 2Citation ).


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

  		Table 2 Treatment, dose escalation, and cycles given per cohort

 
End Points
PK Studies.
Blood was drawn at the start of each cycle at baseline, then 0.5, 2, 4, 6, 24, and 48 h after the pump was started. At termination, blood was drawn before discontinuation and at 0.5, 2, 4, 6, 24, and 48 h thereafter.

Intact oligonucleotide concentration in plasma was detected using a modular high-performance liquid chromatography system that consisted of an SP8800 (Spectra-Physics) gradient pump, an ISS100 autosampler (Perkin-Elmer), a Spectra 100 UV detector (Spectra-Physics) at 254 nm, WINner chromatographic station, and a Pharmacia HiTrap Q 1-ml (Supelco) column. Because the back pressure of this column was low, 10 feet of PEEK tubing (0.005-inch inside diameter) were added between the autosampler and the pump, which allowed the pump to work at 4–500 p.s.i. A short length of tubing (0.5-mm internal diameter) was inserted into the column outlet to reduce possible mixing with the large diameter outlet. The column was then connected to standard tubing with M6 to 10–32 union (Upchurch).

The sample was prepared by adding an equal volume of plasma to 10 mM ammonium hydroxide to denature plasma proteins. This procedure was performed to minimize the protein-bound fraction of the drug, which was not specifically assayed. With this technique, the recovery of drug from plasma samples loaded with a predetermined amount of G3139 exceeded 90%, relative to identically spiked aqueous controls.

The sample was then extracted once with chloroform, and 100 µl of the aqueous solution were injected onto the column. Two solutions were used for the elution. Solution A was composed of 25 mM disodium hydrogen phosphate, and solution B was composed of 25 mM disodium hydrogen phosphate plus 2 M sodium bromide. The sample was gradient eluted over 15 min using 100% solution A, followed by 40% solution A and 60% solution B. The column was then washed 10 min later in solution B for 10 min and was then re-equilibrated using solution A before the next sample was run. This assay has a sensitivity of 0.2 µg/ml and is linear to 10 µg/ml. Interday/intraday variation was <=10%. PK analysis was performed with WinNonlin 2.1, model 2, one compartment with constant i.v. input, first-order output.

Safety and Response Criteria.
Toxicities were assessed by the National Cancer Institute Common Toxicity Criteria version 2.0.4 Standard response criteria were used. Patients were imaged after each cycle of treatment.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients.
Thirty-five patients were registered and treated between August 1997 and September 1999. Their diagnoses, prior treatments, and other demographic characteristics are described in Table 1Citation , and the treatments that patients received are described in Table 2Citation . Seventeen patients received treatment on schedule 1, and 18 patients were treated on schedule 2. Of note, an additional patient was added to Cohort 6 because 1 patient died during the first cycle of treatment attributable to a postobstructive pneumonia. The final 8 patients treated received antisense therapy alone for the first cycle, then antisense in combination with paclitaxel for cycles 2 and 3. Only the data from treatment with BCL-2 antisense alone are presented here. The data regarding combination therapy will be presented in a separate future report.


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

  		Table 1 Patient characteristics (n = 35)

 
Safety.
Table 3Citation describes the adverse events observed during treatment. At the end of the 14-day infusion, 1 patient receiving drug at 2.3 mg/kg/day developed grade 3 leukopenia that resolved spontaneously off treatment <=48 h. Two patients who received antisense oligonucleotide at 6.9 mg/kg/day developed elevated serum transaminase levels, grades 2–3. One patient developed a drug-induced rash and angioedema that resolved with steroids and discontinuation of G3139. One patient died of sepsis related to a tumor-induced postobstructive pneumonia, and 1 patient was hospitalized because of grade 4 dyspnea, likely related to tumor progression. Isolated instances of grade 3 hepatomegaly, palpitations, urinary retention, pathological fracture, and abdominal pain were most likely related to progressive disease.


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

  		Table 3 Adverse events (n = 35)

 
A subgroup of patients (66%) experienced some degree of fatigue with antisense therapy, and in only 1 patient (1.7 mg/kg/day) was it grade 3. Fatigue occurred at all doses, with no correlation between severity and dose. In addition, grade 1–2 anorexia, increased serum creatinine concentration, dyspnea on exertion, hot flashes, malaise, and gastrointestinal complaints were frequent and may have been drug related but not dose related.

Three patients were hospitalized for port-related thromboses or infections. This reaction limited therapy in 1 patient, whereas the other 2 patients were able to continue treatment. These events were possibly related to treatment.

PKs.
The results of PK studies are summarized in Table 4Citation . The maximum serum concentration and the area under the curve increased with dose. The terminal plasma half-life of drug was 2 h at all dose levels. The Css remained constant throughout the infusion. Therefore, the 24-h plasma level represents the Css. In Fig. 1Citation , the mean Css for each cohort is plotted on a linear scale, and the plasma levels increased linearly with doses <=5.3 mg/kg/day. At 6.9 mg/kg/day, the plasma level was higher than projected. The mechanism of elimination was not determined in this study, although predominantly renal excretion has been reported (30) .


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

  		Table 4 Pharmacokinetic propertiesa

 


View larger version (19K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Mean 24-h plasma drug levels (and SD) of each cohort. The increase in plasma level was linear with each cohort until 6.9 mg/kg/day, when the mean plasma level was somewhat higher than expected.

 
Effects on Bcl-2 Protein Expression.
Western blots were performed on PBMCs on selected patients. These studies were exploratory in nature; a sample blot is shown in Fig. 2Citation , illustrating the decline in bcl-2 protein levels observed in 1 patient with treatment.



View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Western blot of bcl-2 levels in PBMCs from a patient treated with bcl-2 antisense at 4.1 mg/kg/day for 2 weeks.

 
Clinical Effects.
No major antitumor responses were observed. Of the 35 patients, 13 (37%) patients had stable disease during treatment. Twenty (57%) patients progressed, and 2 (6%) were not evaluable for response.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study examined the PK profile and side effects of BCL-2 antisense oligonucleotide. Treatment administered as a continuous i.v. infusion was safe, well tolerated, and had a half-life of 2 h. Fatigue and elevated transaminase levels were the only adverse events likely related to treatment that were dose limiting. These effects, as well as hematological abnormalities and other adverse events not seen in this study, have been reported previously with the administration of other phosphorothioate oligonucleotides (31, 32, 33) .

In our study, i.v. BCL-2 antisense oligonucleotide had a half-life of 2 h, whereas the half-life of the same agent delivered s.c. has been reported to be ~7 h (29) . Steady-state serum plasma levels were achieved in <=10 h and remained constant throughout treatment. These data contrast with s.c. delivery in which steady-state plasma levels were not seen until 48 h (29) .

Css varied linearly as a function of delivered dose <=5.3 mg/kg/day. At 6.9 mg/kg/day, the plasma levels were higher than predicted. Css > 1 µg/ml, the level at which BCL-2 antisense oligonucleotide is reported to have antitumor activity and to suppress bcl-2 protein in animal models and humans (30 , 34) , was achieved at doses of >2.3 mg/kg/day. These findings are consistent with those of Jansen et al. (35) , who also tested this molecule by i.v. infusion.

A maximum tolerated cumulative dose of 147.2 mg/m2 (4 mg/kg/day) was reported recently in a trial in which this drug was delivered by continuous s.c. infusion to patients with lymphoma. Dose-limiting reactions in that study were thrombocytopenia, fever, hypotension, and infusion site reactions. The corresponding Css was 3.16 µg/ml (range, 4.17–7.37). By contrast, we observed no such toxicities in patients treated <=5.3 mg/kg/day, with a mean Css of 4.6 µg/ml (SD 0.33). Patients treated at 6.9 mg/kg/day achieved a mean Css 7.67 µg/ml (SD 1), which was associated with reversible transaminitis.

We explored using Western blots of PBMCs to assess changes in bcl-2 protein levels. Although our own data are preliminary, and one cannot assume that changes in PBMCs reflect events within the tumor, recent human trials have shown that treatments using this BCL-2 oligonucleotide are associated with reductions in intratumoral bcl-2 protein levels (29 , 35) . These studies were performed using tissue acquired through superficial tumor biopsies of melanoma patients and circulating lymphoma cells in patients with non-Hodgkin’s lymphoma. Jansen et al. (35) found that protein levels in melanoma cells diminished by 20–70% in <=1 week of initiating the infusion. As prolonged infusions of antisense are not required to decrease bcl-2 protein levels and as doses in the range of 4.1–6.9 mg/kg/day have been reported to have biological activity, dose escalations in our study were stopped in favor of studies involving shorter infusion times using combinations with chemotherapy. These studies are ongoing, as are determinations of the association between clinical effects, dose, and the timing and degree of bcl-2 protein reduction.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by NIH Grants CA-80654 and CA-09207, the PepsiCo Foundation, and a grant from Genta Inc. Back

2 To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-2364; Fax: (212) 717-3817. Back

3 The abbreviations used are: PK, pharmacokinetic; Css, steady-state concentration; PBMC, peripheral blood mononuclear cell. Back

4 Internet address: http://ctep.info.nih.gov. Back

Received 7/ 8/01; revised 10/16/01; accepted 11/ 4/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Hockenbery D., Nunez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature (Lond.), 348: 334-336, 1990.[CrossRef][Medline]
  2. Chen-Levy Z., Nourse J., Cleary M. L. The bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18) translocation. Mol. Cell. Biol., 9: 701-710, 1989.[Abstract/Free Full Text]
  3. Tsujimoto Y., Croce C. M. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl. Acad. Sci. USA, 83: 5214-5218, 1986.[Abstract/Free Full Text]
  4. Vaux D. L., Cory S., Adams J. M. Bcl-2 gene promotes hematopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature (Lond.), 335: 440-442, 1988.[CrossRef][Medline]
  5. Krajewska M., Krajewski S., Epstein J. I., Shabaik A., Sauvageot J., Song K., Kitada S., Reed J. C. Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am. J. Pathol., 148: 1567-1576, 1996.[Abstract]
  6. Colombel M., Symmans F., Gil S., O’Toole K. M., Chopin D., Benson M., Olsson C. A., Korsmeyer S., Buttyan R. Detection of the apoptosis-suppressing oncoprotein bcl-2 in hormone refractory human prostate cancers. Am. J. Pathol., 143: 390-399, 1993.[Abstract]
  7. Bubendorf L., Sauter G., Moch H., Jordan P., Blochlinger A., Gasser T. C., Mihatsch M. J. Prognostic significance of bcl-2 in clinically localized prostate cancer. Am. J. Pathol., 148: 1557-1565, 1996.[Abstract]
  8. Taniguchi T., Moriyama N., Kurimoto S., Kameyama S., Kawabe K. Histochemical detection of intranuclear DNA fragmentation and its relation to the expression of bcl-2 oncoprotein in human prostatic cancer. Br. J. Urol., 77: 719-723, 1996.[Medline]
  9. McDonnell T. J., Troncoso P., Brisbay S. M., Logothetis C., Chung L. W. K., Hsieh J., Tu S., Campbell M. L. Expression of the proto-oncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res., 52: 6940-6944, 1992.[Abstract/Free Full Text]
  10. Raffo A. J., Perlman H., Chen M. W., Day M. L., Streitman J. S. X., Buttyan R. Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res., 55: 4438-4445, 1995.[Abstract/Free Full Text]
  11. Pezzella F., Turley H., Kuzu I., Tungekar M. F., Dunnill M. S., Pierce C. B., Harris A., Gatter K. C., Mason D. Y. Bcl-2 protein in non-small-cell lung carcinoma. N. Engl. J. Med., 329: 690-694, 1993.[Abstract/Free Full Text]
  12. Apolinario R. M., van der Valk P., de Jong J. S., Deville W., van Ark-Otte J., Dingemans A. M., van Mourik J. C., Postmus P. E., Pinedo H. M., Giaccone G. Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small-cell lung cancer. J. Clin. Oncol., 15: 2456-2466, 1997.[Abstract/Free Full Text]
  13. Cerroni L., Soyer H. P., Kerl H. Bcl-2 protein expression in cutaneous malignant melanoma and benign melanocytic nevi. Am. J. Dermatopathol., 17: 7-11, 1995.[Medline]
  14. Leek R. D., Kaklamanis L., Pezella F., Gatter K. C., Hanes A. L. Bcl-2 in normal human breast and carcinoma, association with estrogen receptor-positive, epidermal growth factor receptor-negative tumors in situ cancer. Br. J. Cancer, 69: 135-139, 1994.[Medline]
  15. Colombel M., Symmans F., Gil S., O’Toole K. M., Chopin D., Benson M., Olsson C. A., Korsmeyer S., Buttyan R. Detection of the apoptosis-suppressing oncoprotein bcl-2 in hormone-refractory human prostate cancers. Am. J. Pathol., 143: 390-400, 1993.
  16. Lee C. T., Russo P., Hutchinson B., Kattan M. W., Fearn P. A., Reuter V. Patterns of Bcl2 expression in pT3 primary and metastatic renal cell carcinoma (Abstract 1330). Proc. Am. Soc. Clin. Oncol., 18: 345 1999.
  17. Pammer J., Exner M., Regele H., Haitel A., Weninger W., Horvat R., Susani M. Expression of bcl-2, bcl-x, bax, and bak in renal parenchyma, oncocytomas, and renal cell carcinomas. Pathol. Res. Pract., 194: 837-845, 1998.[Medline]
  18. Chandler D., el-Naggar A. K., Brisbay S., Redline R. W., McDonnell T. J. Apoptosis and expression of the bcl-2 proto-oncogene in the fetal and adult human kidney: evidence for the contribution of bcl-2 expression to renal carcinogenesis. Hum. Pathol., 25: 789-796, 1994.[CrossRef][Medline]
  19. Reed J. C. Bcl-2: prevention of apoptosis as a mechanism of drug resistance. Hematol. Oncol. Clin. N. Am., 9: 451-474, 1995.[Medline]
  20. Sato T., Hanada M., Bodrug S., Irie S., Iwama N., Boise L. H., Thompson C. B., Golemis E., Fong L., Wang H-G., Reed J. C. Interactions among members of the bcl-2 protein family analyzed with a yeast two-hybrid system. Proc. Natl. Acad. Sci. USA, 91: 9238-9242, 1994.[Abstract/Free Full Text]
  21. Oltvai Z., Milliman C., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell, 74: 285-291, 1993.
  22. Yang E., Zha J., Jockel J., Boise L. H., Thompson C. B., Korsmeyer S. J. Bad: a heterodimeric partner for bcl-XL and bcl-2, displaces bax and promotes cell death. Cell, 80: 285-291, 1995.[CrossRef][Medline]
  23. Reed J. C. Dysregulation of apoptosis in cancer. J. Clin. Oncol., 17: 2941-2953, 1999.[Abstract/Free Full Text]
  24. Reed J. C. Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr. Opin. Oncol., 7: 541-546, 1995.[Medline]
  25. Reed J. C. Bcl-2 and the regulation of programmed cell death. J. Cell Biol., 124: 1-6, 1994.[Free Full Text]
  26. Gleave M. E., Miayake H., Goldie J., Nelson C., Tolcher A. Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. Urology, 54: 36-46, 1999.[CrossRef][Medline]
  27. Yang D., Ling Y., Almazan M., Guo R., Murray A., Brown B., Lippman M. E. Tumor regression of human breast carcinomas by combination therapy of anti-bcl-2 antisense oligonucleotide and chemotherapeutic drugs. Proc. Am. Assoc. Cancer Res., 40: 729 1999.
  28. Jansen B., Schlagbauer-Wadl H., Brown B. D., Bryan R. N., van Elsas A., Muller M., Wolff K., Eichler H. G., Pehamberger H. Bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat. Med., 4: 232-234, 1998.[CrossRef][Medline]
  29. Waters J. S., Webb A., Cunningham D., Clarke P. A., Raynaud F., di Stefano F., Cotter F. E. 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]
  30. Raynaud F. I., Orr R. M., Goddard P. M., Lacey H., Lancashire H., Judson I. R., Beck T., Bryan B., Cotter F. E. Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to bcl-2, after intravenous administration or continuous subcutaneous infusion to mice. J. Pharmacol. Exp. Ther., 281: 420-427, 1997.[Abstract/Free Full Text]
  31. Rudin C. M., Holmlund J., Fleming G. F., Mani S., Stadler W. M., Schumm P., Monia B. P., Johnston J. F., Geary R., Yu R. Z., Kwoh T. J., Dorr F. A., Ratain M. J. Phase I trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer. Clin. Cancer Res., 7: 1214-1220, 2001.[Abstract/Free Full Text]
  32. Yuen A. R., Halsey J., Fisher G. A., Holmlund J. T., Geary R. S., Kwoh T. J., Dorr A., Sikic B. I. Phase I study of an antisense oligonucleotide to protein kinase c-a (ISIS 3521/CGP 64128A) in patients with cancer. Clin. Cancer Res., 5: 3357-3363, 1999.[Abstract/Free Full Text]
  33. Cunningham C. C., Holmlund J. T., Geary R. S., Kwoh T. J., Dorr A., Johnston J. F., Monia B., Nemunaitis J. A phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma. Cancer (Phila.), 92: 1265-1271, 2001.[CrossRef][Medline]
  34. Fingert H. J., Klem R. E. Clinical pharmacokinetics and pharmacodynamics of G3139 (Genta Incorporated) antisense oligonucleotide targeting BCL-2. Clin. Cancer Res., 5: 3847s (3585) 1999.
  35. Jansen B., Wacheck V., Heere-Ress E., Schlagbauer-Wadl H., Hoeller C., Lucas T., Hoermann M., Hollenstein U., Wolff K., Pehamberger H. Chemosensitization of malignant melanoma by BCL2 antisense therapy. Lancet, 356: 1728-1733, 2000.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
S. L. Moulder, W. F. Symmans, D. J. Booser, T. L. Madden, C. Lipsanen, L. Yuan, A. M. Brewster, M. Cristofanilli, K. K. Hunt, T. A. Buchholz, et al.
Phase I/II Study of G3139 (Bcl-2 Antisense Oligonucleotide) in Combination with Doxorubicin and Docetaxel in Breast Cancer
Clin. Cancer Res., December 1, 2008; 14(23): 7909 - 7916.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
J. Rom, G. von Minckwitz, W. Eiermann, M. Sievert, B. Schlehe, F. Marme, F. Schuetz, A. Scharf, M. Eichbaum, H.-P. Sinn, et al.
Oblimersen combined with docetaxel, adriamycin and cyclophosphamide as neo-adjuvant systemic treatment in primary breast cancer: final results of a multicentric phase I study
Ann. Onc., October 1, 2008; 19(10): 1698 - 1705.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
G. Liu, J. Kolesar, D. G. McNeel, C. Leith, K. Schell, J. Eickhoff, F. Lee, A. Traynor, R. Marnocha, D. Alberti, et al.
A Phase I Pharmacokinetic and Pharmacodynamic Correlative Study of the Antisense Bcl-2 Oligonucleotide G3139, in Combination with Carboplatin and Paclitaxel, in Patients with Advanced Solid Tumors
Clin. Cancer Res., May 1, 2008; 14(9): 2732 - 2739.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Subramanian and C. Shaha
Up-Regulation of Bcl-2 through ERK Phosphorylation Is Associated with Human Macrophage Survival in an Estrogen Microenvironment
J. Immunol., August 15, 2007; 179(4): 2330 - 2338.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. R. Rheingold, M. D. Hogarty, S. M. Blaney, J. A. Zwiebel, C. Sauk-Schubert, R. Chandula, M. D. Krailo, and P. C. Adamson
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
J. Clin. Oncol., April 20, 2007; 25(12): 1512 - 1518.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
Y. Otake, S. Soundararajan, T. K. Sengupta, E. A. Kio, J. C. Smith, M. Pineda-Roman, R. K. Stuart, E. K. Spicer, and D. J. Fernandes
Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA
Blood, April 1, 2007; 109(7): 3069 - 3075.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
S. Anai, S. Goodison, K. Shiverick, Y. Hirao, B. D. Brown, and C. J. Rosser
Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts
Mol. Cancer Ther., January 1, 2007; 6(1): 101 - 111.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
D. A. Kocisko, A. Vaillant, K. S. Lee, K. M. Arnold, N. Bertholet, R. E. Race, E. A. Olsen, J.-M. Juteau, and B. Caughey
Potent Antiscrapie Activities of Degenerate Phosphorothioate Oligonucleotides
Antimicrob. Agents Chemother., March 1, 2006; 50(3): 1034 - 1044.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
M. M. Mita, L. Ochoa, E. K. Rowinsky, J. Kuhn, G. Schwartz, L. A. Hammond, A. Patnaik, I.-T. Yeh, E. Izbicka, K. Berg, et al.
A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (GenasenseTM, G3139) and irinotecan in patients with metastatic colorectal cancer
Ann. Onc., February 1, 2006; 17(2): 313 - 321.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
K. W. Yip, J. D. Mocanu, P.Y. B. Au, G. T. Sleep, D. Huang, P. Busson, W.-C. Yeh, R. Gilbert, B. O'Sullivan, P. Gullane, et al.
Combination Bcl-2 Antisense and Radiation Therapy for Nasopharyngeal Cancer
Clin. Cancer Res., November 15, 2005; 11(22): 8131 - 8144.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. J. Cohen, R. B. Cohen, and N. J. Meropol
Targeting Signal Transduction Pathways in Colorectal Cancer--More Than Skin Deep
J. Clin. Oncol., August 10, 2005; 23(23): 5374 - 5385.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. Z. Badros, O. Goloubeva, A. P. Rapoport, B. Ratterree, N. Gahres, B. Meisenberg, N. Takebe, M. Heyman, J. Zwiebel, H. Streicher, 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., June 20, 2005; 23(18): 4089 - 4099.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
S.-J. He, G. Stevens, A. W. Braithwaite, and M. R. Eccles
Transfection of melanoma cells with antisense PAX3 oligonucleotides additively complements cisplatin-induced cytotoxicity
Mol. Cancer Ther., June 1, 2005; 4(6): 996 - 1003.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
A. A. Desai, R. L. Schilsky, A. Young, L. Janisch, W. M. Stadler, N. J. Vogelzang, S. Cadden, J. A. Wright, and M. J. Ratain
A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors
Ann. Onc., June 1, 2005; 16(6): 958 - 965.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
G. Marcucci, W. Stock, G. Dai, R. B. Klisovic, S. Liu, M. I. Klisovic, W. Blum, C. Kefauver, D. A. Sher, M. Green, 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., May 20, 2005; 23(15): 3404 - 3411.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. W. Tolcher, K. Chi, J. Kuhn, M. Gleave, A. Patnaik, C. Takimoto, G. Schwartz, I. Thompson, K. Berg, S. D'Aloisio, 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., May 15, 2005; 11(10): 3854 - 3861.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
G. Dai, K. K. Chan, S. Liu, D. Hoyt, S. Whitman, M. Klisovic, T. Shen, M. A. Caligiuri, J. Byrd, M. Grever, 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., April 15, 2005; 11(8): 2998 - 3008.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
R. B. Bhisitkul, G. S. Robinson, R. S. Moulton, K. P. Claffey, E. S. Gragoudas, and J. W. Miller
An Antisense Oligodeoxynucleotide Against Vascular Endothelial Growth Factor in a Nonhuman Primate Model of Iris Neovascularization
Arch Ophthalmol, February 1, 2005; 123(2): 214 - 219.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. A. DiVito, A. J. Berger, R. L. Camp, M. Dolled-Filhart, D. L. Rimm, and H. M. Kluger
Automated Quantitative Analysis of Tissue Microarrays Reveals an Association between High Bcl-2 Expression and Improved Outcome in Melanoma
Cancer Res., December 1, 2004; 64(23): 8773 - 8777.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
V. A. Barvaux, P. Lorigan, M. Ranson, A. M. Gillum, R. S. McElhinney, T. B. H. McMurry, and G. P. Margison
Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase
Mol. Cancer Ther., October 1, 2004; 3(10): 1215 - 1220.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
J. Marshall, H. Chen, D. Yang, M. Figueira, K. B. Bouker, Y. Ling, M. Lippman, S. R. Frankel, and D. F. Hayes
A phase I trial of a Bcl-2 antisense (G3139) and weekly docetaxel in patients with advanced breast cancer and other solid tumors
Ann. Onc., August 1, 2004; 15(8): 1274 - 1283.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. W. Tolcher, J. Kuhn, G. Schwartz, A. Patnaik, L. A. Hammond, I. Thompson, H. Fingert, D. Bushnell, S. Malik, J. Kreisberg, 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., August 1, 2004; 10(15): 5048 - 5057.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
W. R. Parulekar and E. A. Eisenhauer
Phase I Trial Design for Solid Tumor Studies of Targeted, Non-Cytotoxic Agents: Theory and Practice
J Natl Cancer Inst, July 7, 2004; 96(13): 990 - 997.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. S. Herbst and S. R. Frankel
Oblimersen Sodium (Genasense bcl-2 Antisense Oligonucleotide): A Rational Therapeutic to Enhance Apoptosis in Therapy of Lung Cancer
Clin. Cancer Res., June 15, 2004; 10(12): 4245S - 4248S.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
C. M. Rudin, M. Kozloff, P. C. Hoffman, M. J. Edelman, R. Karnauskas, R. Tomek, L. Szeto, and E. E. Vokes
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., March 15, 2004; 22(6): 1110 - 1117.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
H. Niwa, A. L. Wentzel, M. Li, W. E. Gooding, V. W. Y. Lui, and J. R. Grandis
Antitumor Effects of Epidermal Growth Factor Receptor Antisense Oligonucleotides in Combination with Docetaxel in Squamous Cell Carcinoma of the Head and Neck
Clin. Cancer Res., October 15, 2003; 9(13): 5028 - 5035.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Braga-Basaria and M. D. Ringel
Beyond Radioiodine: A Review of Potential New Therapeutic Approaches for Thyroid Cancer
J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 1947 - 1960.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Loomis, R. Carbone, M. Reiss, and J. Lacy
Bcl-2 Antisense (G3139, Genasense) Enhances the in Vitro and in Vivo Response of Epstein-Barr Virus-associated Lymphoproliferative Disease to Rituximab
Clin. Cancer Res., May 1, 2003; 9(5): 1931 - 1939.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
G. Marcucci, J. C. Byrd, G. Dai, M. I. Klisovic, P. J. Kourlas, D. C. Young, S. R. Cataland, D. B. Fisher, D. Lucas, K. K. Chan, 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, January 15, 2003; 101(2): 425 - 432.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
O. Smaletz, H. I. Scher, E. J. Small, D. A. Verbel, A. McMillan, K. Regan, W. K. Kelly, and M. W. Kattan
Nomogram for Overall Survival of Patients With Progressive Metastatic Prostate Cancer After Castration
J. Clin. Oncol., October 1, 2002; 20(19): 3972 - 3982.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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 Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Morris, M. J.
Right arrow Articles by Scher, H. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Morris, M. J.
Right arrow Articles by Scher, H. I.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online