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Phase I Study of G3139, a bcl-2 Antisense Oligonucleotide, Combined With Carboplatin and Etoposide in Patients With Small-Cell Lung Cancer

From the University of Chicago, Chicago; Ingalls Hospital, Harvey, IL, and the University of Maryland, Baltimore, MD.

Address reprint requests to Charles M. Rudin, MD, PhD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, Room 344, 1650 Orleans St, Baltimore, MD 21231; e-mail: rudin{at}jhmi.edu

	ABSTRACT

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PURPOSE: Bcl-2 is expressed in the majority of cases of small cell lung cancer (SCLC) and may contribute to chemotherapeutic resistance. Bcl-2 suppression by G3139 (oblimersen sodium), a phosphorothioate oligonucleotide complementary to the bcl-2 mRNA, has the potential to enhance the antitumor efficacy of standard cytotoxic chemotherapy. A dose-finding study was performed evaluating the combination of G3139, carboplatin, and etoposide in patients with previously untreated extensive stage SCLC.

PATIENTS AND METHODS: Sixteen patients were treated in three consecutive cohorts. Cohort 1 (n = 5) received G3139 5 mg/kg/d on days 1 to 8 of a 21 day cycle, with carboplatin area under the curve (AUC) = 6 on day 6, and etoposide 80 mg/m²/d on days 6 to 8. In cohort 2 (n = 4), carboplatin dose was reduced to AUC = 5. In cohort 3 (n = 7), G3139 dose was escalated to 7 mg/kg/d. G3139 plasma concentrations and Bcl-2 protein levels in peripheral blood mononuclear cells were evaluated.

RESULTS: Two of three assessable patients in cohort 1 experienced cycle 1 dose-limiting toxicity (grade 4 neutropenia). No cycle 1 dose-limited toxicity was observed in cohorts 2 or 3. Of 14 patients assessable for response, partial response was documented in 12 patients (86%), and stable disease in two. Median time to progression was 5.9 months. Carboplatin and etoposide administration did not appear to alter G3139 pharmacokinetics. No evidence of Bcl-2 suppression in peripheral blood mononuclear cells was observed.

CONCLUSION: The combination of G3139, carboplatin, and etoposide is well tolerated and results in an encouraging response rate and time to progression in patients with extensive stage SCLC.

	INTRODUCTION

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Lung cancer is the leading cause of cancer deaths for both men and women in the United States [1]. Approximately 20% of lung cancers are of small cell histology. Small cell lung cancer (SCLC) is distinguished from non–small-cell lung cancer by its characteristic cellular appearance, rapid proliferation, and early dissemination to metastatic sites. Median survival from the time of diagnosis in patients with extensive stage SCLC remains less than 1 year, and nearly all patients are dead within 2 years [2]. Clearly, new approaches are needed for the treatment of this disease.

Etoposide is one of the most active agents for the treatment of SCLC, with reported single agent response rate of 40% to 90% in untreated patients [3-5]. The combination of etoposide and cisplatin (or carboplatin) has represented a standard of care for newly diagnosed SCLC for over 20 years [6-9]. However, the responses observed with even the best available therapies are typically of short duration [6,7].

Bcl-2 is an apoptotic inhibitor that may contribute to therapeutic resistance. Bcl-2 was the first oncogene found to function through production of an inhibitor of programmed cell death [10,11]. bcl-2 is a member of a large family of related genes which encode both positive and negative apoptotic regulators. Apoptotic inhibition by overexpression of Bcl-2 or related family members has been associated with increased resistance to both chemotherapy and radiation [12-21]. The broad-spectrum resistance conferred by Bcl-2 suggests that antiapoptotic gene expression may be an important determinant of chemotherapeutic efficacy.

Bcl-2 is overexpressed in 83% to 90% of SCLCs [22-24]. Recent data have demonstrated that Bcl-2 expression in SCLC cell lines is associated with chemotherapeutic resistance [25]. Suppression of Bcl-2 has synergistic effects with chemotherapeutic agents, including cisplatin and etoposide, against SCLC in vitro and in xenograft models [26]. We hypothesized that inhibiting Bcl-2 expression might increase the efficacy of standard cytotoxic chemotherapy in patients with SCLC.

G3139 is an 18-mer phosphorothioate oligonucleotide complementary to the first six codons of the bcl-2 mRNA [27]. The phosphorothioate backbone serves to increase stability of the oligonucleotide by conferring resistance to intracellular nucleases [28,29]. Cell culture experiments demonstrate that this antisense oligonucleotide can be taken up by cells, where it hybridizes to the cognate bcl-2 mRNA, leading to RNaseH-mediated mRNA degradation [30-34]. Message degradation in tumor cells can lead to decreased Bcl-2 protein production. Potential antitumor activity of G3139 has been supported by xenograft models [31-35] and by early phase clinical trials [36-38].

We previously evaluated G3139 in combination with paclitaxel in patients with recurrent chemorefractory SCLC, a population for which no therapy has been shown to be of clinical benefit [38]. The combination of paclitaxel at 150 mg/m² on day 8 and G3139 at 3 mg/kg/d on days 1 to 8 was found to be feasible and well tolerated. Disease stabilization over at least 4 months was seen in two patients, one of whom remained on therapy for over 10 months without progression of disease. G3139 plasma levels were found to be highest in the two patients with prolonged stable disease, suggesting that individual variation in metabolism and clearance of the antisense oligonucleotide might influence activity, and suggesting that a higher dose of G3139 might be more effective.

We hypothesized that the putative chemosensitizing effect of G3139 might be most evident when applied in the context of previously untreated disease, rather than extensively pretreated chemoresistant disease. Here we report the results of a phase I trial restricted to patients with previously untreated SCLC. The goals of this study were to define a dose for the combination of G3139 with standard first-line chemotherapy (carboplatin and etoposide), and to permit initial assessment of potential efficacy in patients with newly diagnosed extensive stage SCLC.

	PATIENTS AND METHODS

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Patients
The trial was limited to adults (age 18 years) of Zubrod performance status 2, with histologically proven extensive stage SCLC. No prior chemotherapy was allowed. Patients with CNS metastases were eligible if treated with radiation and if they were neurologically stable. Adequate hematologic (WBC count 3000/µL; absolute neutrophil count 1500/µL; platelets 100,000/µL), hepatic (bilirubin within normal institutional limits; AST/ALT 2.5 x institutional upper limit of normal), and renal (creatinine within normal institutional limits or calculated creatinine clearance 60 mL/min/1.73 m²) function was required. All patients provided written informed consent before study enrollment or performance of study-related procedures, in accordance with institutional and federal guidelines. G3139 was provided by the National Cancer Institute Cancer Therapy Evaluation Program.

Schedules of Administration
Several previous trials have used a G3139 dose of 7 mg/kg/d. To test this new combination regimen, we chose an initial dose of 5 mg/kg/d, with a plan to escalate to 7 mg/kg/d if tolerated. Infusion duration of G3139 over 7 days (days 1 to 8) was chosen in order to permit maximal suppression of Bcl-2 at the time of cytotoxic chemotherapy infusion (days 6 to 8), while avoiding the significant transaminase elevations noted in the second/third week in patients treated with more prolonged continuous infusion G3139 [39]. Cohorts of patients were treated on three different sequentially tested regimens (Fig 1; Table 1). Cohort 1 (n = 5) received G3139 5 mg/kg/d by continuous intravenous (IV) infusion on days 1 to 8 of a 21 day cycle, with carboplatin area under the curve (AUC) = 6 IV over 30 minutes on day 6, and etoposide 80 mg/m²/d IV over 1 hour on days 6 to 8. Cohort 2 (n = 4) received G3139 5 mg/kg/d IV days 1 to 8, carboplatin AUC = 5 on day 6, and etoposide 80 mg/m²/d on days 6 to 8. Cohort 3 (n = 7) received G3139 7 mg/kg/d IV days 1 to 8, carboplatin AUC = 5 on day 6, and etoposide 80 mg/m²/d on days 6 to 8. Six was the maximum allowable number of cycles.

View larger version (8K): [in this window] [in a new window]   Fig 1. Schedule of administration. Schedule of administration was the same for each cohort. G3139 was given by continuous intravenous infusion on days 1 to 8. Carboplatin was administered on day 6, and etoposide on days 6, 7, and 8. Cycles were repeated every 21 days.

Pharmacokinetic Evaluation
Plasma concentrations of G3139 as well as of the N-1 and N-2 metabolites of G3139 were determined by high-performance liquid chromatography assay as previously described [38]. Blood draws for pharmacokinetic evaluation were performed in cycle 1 before initiation of G3139 (day 1), immediately before carboplatin/etoposide administration (day 6), immediately before discontinuation of G3139 (day 8), and 2 hours after discontinuation of G3139 (day 8).

Bcl-2 Determination in Peripheral Blood
Bcl-2 protein levels were evaluated in peripheral blood mononuclear cells isolated from all patients treated at the University of Chicago (Chicago,IL). Two blood draws were performed before initiation of therapy, the second immediately before initiation of G3139 on day 1 of cycle 1. A third blood draw was performed on day 6 of cycle 1, immediately before initiation of carboplatin and etoposide. Mononuclear cell isolation was performed and total protein lysates prepared immediately on freshly collected blood as previously described [38]. Samples were stored at -80°C. Western blotting was performed as previously described [38], using monoclonal anti-Bcl-2 clone 124 (DAKO Corp, Carpinteria, CA), and monoclonal anti-ß-actin clone AC-15 (Sigma-Aldrich, St Louis, MO). Quantitative densitometry was assessed using the ChemiImager 5500 system (Alpha Innotech, San Leandro, CA).

	RESULTS

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Dose Cohorts and Toxicity Analysis
A total of 16 patients were enrolled onto this study. Patient characteristics are indicated in Table 2. A total of five patients were enrolled in dose cohort 1, and received G3139 5 mg/kg/d on days 1 to 8, carboplatin AUC 6 on day 6, and etoposide 80 mg/m²/d on days 6 to 8. One of these five patients experienced rapid disease progression concurrent with initiation of therapy, and discontinued all treatment before initiation of carboplatin and etoposide. Of the remaining four patients, two experienced dose-limiting toxicity, consisting of grade 4 neutropenia in both cases, during cycle 1 (Table 3). With a dose reduction to carboplatin AUC 5, these four patients were able to continue on therapy for a total duration of six cycles.

In cohort 3, G3139 dose was escalated to 7 mg/kg/d, days 1 to 8. The carboplatin and etoposide doses were identical to the cohort 2 regimen: carboplatin AUC 5 on day 6, and etoposide 80 mg/m²/d on days 6 to 8. A total of seven patients were enrolled in cohort 3; one patient in this group was inadvertently treated with carboplatin AUC 6 in cycle 1, and was therefore considered ineligible for toxicity assessment. However, we note that, consistent with the dose-limiting myelosuppression observed in cohort 1, this patient experienced dose-limiting grade 4 neutropenia in cycle 1. This patient was given a dose reduction in cycle 2 to carboplatin AUC 5, and received a total of five cycles of therapy. Of the other six patients enrolled in cohort 3, two experienced transient grade 3 neutropenia in cycle 1 (Table 3). Through all cycles of therapy, five of six assessable patients in cohort 3 experienced at least one episode of grade 3 or 4 neutropenia, and four of six patients experienced grade 3 thrombocytopenia.

Nonhematologic toxicity was minimal in all cohorts, with rare grade 3 or 4 toxicities occurring in isolated cases (Table 4). The only grade 4 nonhematologic toxicity was an episode of grade 4 dyspnea requiring hospitalization. This occurred during G3139 infusion in the patient in cohort 1 who failed to complete cycle 1 and was ultimately found to have rapid disease progression.

Response and Survival
Of the 14 patients assessable for response, 12 (86%) experienced a partial response. Two patients, both in cohort 2, had stable disease. All patients in cohort 3, the recommended phase II dose, experienced partial response. No complete responses were observed in any cohort.

The mean duration of response was 162 days (median, 150 days; range, 81 to 271 days). Of the 16 patients enrolled onto the study, 15 have progressed with a median progression-free survival of 5.9 months (95% CI, 4.6 to 8.0 months). Thirteen of 16 patients have died in a median follow-up of 12.6 months. The median survival duration was 8.6 months (95% CI, 6.1 to 14.6 months).

Pharmacokinetic Analysis
Previous analysis of G3139 administered as a single agent demonstrated that steady-state plasma level is reached by 12 hours, and that G3139 half-life following discontinuation of therapy is approximately 2 hours [39]. G3139 is estimated to be 85% protein bound in circulation, and has a volume of distribution of approximately 0.28 L/kg [41,42]. Phosphorothioate oligonucleotides are metabolized by exonuclease-mediated cleavage to shortened oligonucleotides and mononucleotide metabolite: these are further catabolized similarly to endogenous nucleotides and are excreted as low molecular weight metabolites, primarily in the urine [43].

Limited G3139 pharmacokinetics were performed in cycle 1 only, to determine whether carboplatin and etoposide administration affected G3139 steady-state level and terminal half-life. Determination of G3139 plasma concentration was performed before initiation of G3139 on day 1, on day 6 before carboplatin and etoposide administration, and on day 8 before and 2 hours after discontinuation of G3139.

As demonstrated in Figure 2 and Table 5, G3139 plasma levels were similar on day 6 and day 8, suggesting that G3139 pharmacokinetics are unaffected by coadministration of carboplatin and etoposide. Pooling the day 6 and 8 data, average G3139 plasma concentration at G3139 dose of 5 mg/kg/d was 2.01 µg/mL (± standard deviation [SD] 1.12 µg/mL), and at the dose of 7 mg/kg/d was 3.03 µg/mL (±SD 1.79 µg/mL). G3139 half-life following drug discontinuation on day 8 was estimated as 1.86 hours (±SD 1.70), consistent with previous single agent data, suggesting that carboplatin and etoposide do not significantly alter G3139 metabolism and clearance (Table 5).

View larger version (19K): [in this window] [in a new window]   Fig 2. G3139 plasma concentrations by dose and day. Mean G3139 concentrations (+ standard deviation) in patients treated with G3139 5 mg/kg/d (cohorts 1 and 2) and 7 mg/kg/d (cohort 3) on day 6 and 8. G3139 plasma concentration did not appear to be affected by carboplatin/etoposide. Css, concentration, steady state.

View larger version (17K): [in this window] [in a new window]   Fig 3. Western blot. Protein extracts were prepared from peripheral blood mononuclear cells isolated twice before therapy (day -2 and 1), and on day 6 of cycle 1. Top: blot probed for Bcl-2; bottom: stripped and reprobed for ß-actin. No significant change in Bcl-2 protein was observed.

	DISCUSSION

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The response rate observed on this trial was encouraging. However, as is typical in patients with extensive stage SCLC, the responses observed were not durable. At the time of this report, 15 of 16 patients enrolled onto the study have experienced progressive disease, and 13 of 16 have died, with all deaths attributable to recurrent or progressive SCLC. Assessment of the ultimate value of this regimen will require subsequent phase II and phase III evaluation.

Bcl-2 protein expression in peripheral blood mononuclear cells did not appear to change with G3139 therapy. In contrast to prior studies of this agent, duplicate blood draws were performed before initiation of G3139 therapy to ensure that a reproducible baseline level of Bcl-2 expression could be obtained. Although somewhat surprising, these data are in fact consistent with prior clinical reports of patients treated with G3139. Waters et al [44] reported on use of G3139 as a single agent in a series of patients with lymphoma. Bcl-2 protein level was assessed in peripheral blood mononuclear cells from a total of 10 patients, five of whom demonstrated a decrease in Bcl-2 of 15% to 36%, but five of whom demonstrated no change in Bcl-2. Marcucci et al [45] evaluated Bcl-2 levels in peripheral blood mononuclear cells in five patients with acute leukemia treated with G3139. Bcl-2 levels on day 5 of therapy were decreased in two patients, but increased in three patients relative to baseline. In a recent phase I study of G3139 alone, Bcl-2 level in peripheral blood mononuclear cells appeared to be unchanged on day 8 (no quantitation reported) but was decreased by the final day of a 14-day infusion in the one patient shown [39]. Flow cytometry has also been used to quantitate Bcl-2 levels in peripheral blood mononuclear cells in a series of patients treated with G3139 and mitoxantrone [46]. No statistically significant change in Bcl-2 protein levels could be demonstrated.

It is not clear to what extent suppression of Bcl-2 in the peripheral blood might be reflective of suppression in the tumor. It has been previously suggested that the lack of evident suppression in Bcl-2 level may in fact reflect selective cytotoxicity for cells with intermediate or low Bcl-2 expression, resulting in relative retention of Bcl-2 high expressors [47]. Others have argued that the cytotoxicity observed with G3139 may in fact be in part due to effects other than interaction with the bcl-2 mRNA [48].

Ultimately, whether G3139 can increase chemotherapeutic efficacy will be determined by randomized clinical trials. The data reported here define a regimen appropriate for further testing in previously untreated extensive stage SCLC. Based on these findings, a randomized phase II trial has been initiated in the Cancer and Leukemia Group B, comparing G3139, carboplatin, and etoposide (using the dose and schedule defined by this report) to identical doses of carboplatin and etoposide alone.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Kristin Hoving, Esther Bit-Ivan, and Ruth Smith for coordination of patient care and data management, and Dezheng Huo for statistical analysis.

	NOTES

 
This study was supported by NIH N01 CM-07003-74 and U01 CA69854-08.

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

	REFERENCES

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1. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer J Clin 52:23-47, 2002[Abstract/Free Full Text]

2. Chute JP, Chen T, Feigal E, et al: Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: Perceptible progress. J Clin Oncol 17:1794-1801, 1999[Abstract/Free Full Text]

3. Bork E, Ersboll J, Dombernowsky P, et al: Teniposide and etoposide in previously untreated small-cell lung cancer: A randomized study. J Clin Oncol 9:1627-1631, 1991[Abstract]

4. Slevin ML, Clark PI, Joel SP, et al: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7:1333-1340, 1989[Abstract]

5. Clark PI, Slevin ML, Joel SP, et al: A randomized trial of two etoposide schedules in small-cell lung cancer: The influence of pharmacokinetics on efficacy and toxicity. J Clin Oncol 12:1427-1435, 1994[Abstract]

6. Bunn PA Jr, Carney DN: Overview of chemotherapy for small cell lung cancer. Semin Oncol 24:S7-69-S7-74, 1997 (2 suppl 7)

7. Sandler AB: Current management of small cell lung cancer. Semin Oncol 24:463-476, 1997[Medline]

8. Skarlos DV, Samantas E, Kosmidis P, et al: Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 5:601-607, 1994[Abstract/Free Full Text]

9. Kosmidis PA, Samantas E, Fountzilas G, et al: Cisplatin/etoposide versus carboplatin/etoposide chemotherapy and irradiation in small cell lung cancer: A randomized phase III study. Hellenic Cooperative Oncology Group for Lung Cancer Trials. Semin Oncol 21:23-30, 1994[Medline]

10. Gross A, McDonnell JM, Korsmeyer SJ: BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899-1911, 1999[Free Full Text]

11. Rudin CM, Thompson CB: Apoptosis and disease: Regulation and clinical relevance of programmed cell death. Annu Rev Med 48:267-281, 1997[CrossRef][Medline]

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

13. Fisher DE: Apoptosis in cancer therapy: Crossing the threshold. Cell 78:539-542, 1994[CrossRef][Medline]

14. Lotem J, Sachs L: Regulation by bcl-2, c-myc, and p53 of susceptibility to induction of apoptosis by heat shock and cancer chemotherapy compounds in differentiation-competent and -defective myeloid leukemic cells. Cell Growth Differ 4:41-47, 1993[Abstract]

15. Campos L, Rouault JP, Sabido O, et al: High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81:3091-3096, 1993[Abstract/Free Full Text]

16. Miyashita T, Reed JC: Bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 52:5407-5411, 1992[Abstract/Free Full Text]

17. Miyashita T, Reed JC: Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81:151-157, 1993[Abstract/Free Full Text]

18. Walton MI, Whysong D, O'Connor PM, et al: Constitutive expression of human Bcl-2 modulates nitrogen mustard and camptothecin induced apoptosis. Cancer Res 53:1853-1861, 1993[Abstract/Free Full Text]

19. 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]

20. Fisher TC, Milner AE, Gregory CD, et al: Bcl-2 modulation of apoptosis induced by anticancer drugs: Resistance to thymidylate stress is independent of classical resistance pathways. Cancer Res 53:3321-3326, 1993[Abstract/Free Full Text]

21. Minn AJ, Rudin CM, Boise LH, et al: Expression of bcl-xL can confer a multidrug resistance phenotype. Blood 86:1903-1910, 1995[Abstract/Free Full Text]

22. Yan JJ, Chen FF, Tsai YC, et al: Immunohistochemical detection of Bcl-2 protein in small cell carcinomas. Oncology 53:6-11, 1996[CrossRef][Medline]

23. Jiang SX, Sato Y, Kuwao S, et al: Expression of bcl-2 oncogene protein is prevalent in small cell lung carcinomas. J Pathol 177:135-138, 1995[CrossRef][Medline]

24. Ikegaki N, Katsumata M, Minna J, et al: Expression of bcl-2 in small cell lung carcinoma cells. Cancer Res 54:6-8, 1994[Abstract/Free Full Text]

25. Sartorius UA, Krammer PH: Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines. Int J Cancer 97:584-592, 2002[CrossRef][Medline]

26. Zangemeister-Wittke U, Schenker T, Luedke GH, et al: Synergistic cytotoxicity of bcl-2 antisense oligodeoxynucleotides and etoposide, doxorubicin and cisplatin on small-cell lung cancer cell lines. Br J Cancer 78:1035-1042, 1998[Medline]

27. 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]

28. Marcusson EG, Yacyshyn BR, Shanahan WR Jr, et al: Preclinical and clinical pharmacology of antisense oligonucleotides. Mol Biotechnol 12:1-11, 1999[CrossRef][Medline]

29. Galderisi U, Cascino A, Giordano A: Antisense oligonucleotides as therapeutic agents. J Cell Physiol 181:251-257, 1999[CrossRef][Medline]

30. 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]

31. Cotter FE, Johnson P, Hall P, et al: Antisense oligonucleotides suppress B-cell lymphoma growth in a SCID-hu mouse model. Oncogene 9:3049-3055, 1994[Medline]

32. Jansen B, Schlagbauer-Wadl H, Brown BD, et al: Bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat Med 4:232-234, 1998[CrossRef][Medline]

33. Leung S, Miyake H, Zellweger T, et al: Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl-2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model. Int J Cancer 91:846-850, 2001[CrossRef][Medline]

34. Yang D, Ling Y, Almazan M: 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 (abstr 4814)

35. Klasa RJ, Bally MB, Ng R, et al: Eradication of human non-Hodgkin's lymphoma in SCID mice by BCL-2 antisense oligonucleotides combined with low-dose cyclophosphamide. Clin Cancer Res 6:2492-2500, 2000[Abstract/Free Full Text]

36. Webb A, Cunningham D, Cotter F, et al: BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 349:1137-1141, 1997[CrossRef][Medline]

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

38. Rudin CM, Otterson GA, Mauer AM, et al: A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer. Ann Oncol 13:539-545, 2002[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]

40. 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]

41. Wasan EK, Waterhouse D, Sivak O, et al: Plasma protein binding, lipoprotein distribution and uptake of free and lipid-associated BCL-2 antisense oligodeoxynucleotides (G3139) in human melanoma cells. Int J Pharm 241:57-64, 2002[CrossRef][Medline]

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

43. Raynaud FI, Orr RM, Goddard PM, et al: 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]

44. 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]

45. 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]

46. 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]

47. Klasa RJ, Gillum AM, Klem RE, et al: Oblimersen Bcl-2 antisense: Facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 12:193-213, 2002[CrossRef][Medline]

48. Dias N, Stein CA: Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. Eur J Pharm Biopharm 54:263-269, 2002[CrossRef][Medline]

Submitted October 21, 2003; accepted December 22, 2003.

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				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]

				C. L. Hann, V. C. Daniel, E. A. Sugar, I. Dobromilskaya, S. C. Murphy, L. Cope, X. Lin, J. S. Hierman, D. L. Wilburn, D. N. Watkins, et al. Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer Cancer Res., April 1, 2008; 68(7): 2321 - 2328. [Abstract] [Full Text] [PDF]

				C. M. Rudin, R. Salgia, X. Wang, L. D. Hodgson, G. A. Masters, M. Green, and E. E. Vokes Randomized Phase II Study of Carboplatin and Etoposide With or Without the bcl-2 Antisense Oligonucleotide Oblimersen for Extensive-Stage Small-Cell Lung Cancer: CALGB 30103 J. Clin. Oncol., February 20, 2008; 26(6): 870 - 876. [Abstract] [Full Text] [PDF]

				B. E. Johnson, C. M. Rudin, and R. Salgia Novel and Targeted Agents for Small Cell Lung Cancer ASCO Educational Book, January 1, 2008; 2008(1): 363 - 367. [Abstract] [Full Text] [PDF]

				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]

				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]

				S. K. Tahir, X. Yang, M. G. Anderson, S. E. Morgan-Lappe, A. V. Sarthy, J. Chen, R. B. Warner, S.-C. Ng, S. W. Fesik, S. W. Elmore, et al. Influence of Bcl-2 Family Members on the Cellular Response of Small-Cell Lung Cancer Cell Lines to ABT-737 Cancer Res., February 1, 2007; 67(3): 1176 - 1183. [Abstract] [Full Text] [PDF]

				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]

				J. C. Reed and M. Pellecchia Apoptosis-based therapies for hematologic malignancies Blood, July 15, 2005; 106(2): 408 - 418. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

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