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Oblimersen and α-interferon in metastatic renal cancer: a phase II study of the California Cancer Consortium

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Abstract

Purpose

Oblimersen is an 18-base oligodeoxynucleotide encoding antisense to the gene for bcl-2, an anti-apoptotic protein that is upregulated in renal and other cancers. This study was designed to evaluate the combination of oblimersen with α-Interferon in advanced renal cancer. Trial endpoints were antitumor efficacy and toxicity, pharmacokinetics, and evidence of apoptosis in peripheral blood mononuclear cells.

Methods

Patients with measurable advanced renal cancer and 0–1 prior therapy were eligible. Treatment consisted of oblimersen, 7 mg/kg/day, as a continuous intravenous infusion 7 days of every 14 day cycle, plus α-IFN, 5 million units/m2 subcutaneously, days 4 and 6 of the first oblimersen infusion, then thrice weekly. Blood for laboratory correlates was collected before treatment, during oblimersen, and during therapy with both agents.

Results

Twenty-three patients were enrolled, five of whom had prior systemic therapy (three with prior high-dose interleukin-2). The median number of treatment cycles was 4 (range 1–12). One patient had a partial response lasting 2.5 months. The Grade 3–4 toxicities were fatigue, fever, myelosuppression, hepatic enzyme and metabolic abnormalities. Laboratory analyses of CD3+ lymphocyte apoptotic markers demonstrated no change between pre-treatment and on-treatment levels of bcl-2 or Annexin/PI positivity by flow cytometry. Mean oblimersen steady-state plasma concentration and clearance was 2.3 ± 0.9 μg/ml and 0.15 ± 0.07 l/h/kg, respectively.

Conclusions

Oblimersen given in this dose and schedule with α-IFN does not appear sufficiently active to warrant further study in advanced renal cancer. Combinations with newer targeted agents may show greater promise.

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References

  • Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326

    Article  PubMed  CAS  Google Scholar 

  • Barvaux VA, Lorigan P, Ranson M et al (2004) Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O 6-alkylguanine-DNA alkyltransferase. Mol Cancer Ther 3:1215–1220

    PubMed  CAS  Google Scholar 

  • Bhargava V, Kell DL, van de Rijn M, Warnke RA (1994) Bc1-2 Immunoreactivity in breast carcinoma correlates with hormone receptor positivity. Am J Pathol 145:535-540

    PubMed  CAS  Google Scholar 

  • Chandler D, el-Naggar AK, Brisbay S et al (1994) 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

    Article  PubMed  CAS  Google Scholar 

  • Colombel M, Symmans F, Gil S et al (1993) Detection of the apoptosis-suppressing oncoprotein bcl-2 in hormone-refractory human prostate cancers. Am J Pathol 143:390–4009

    PubMed  CAS  Google Scholar 

  • Dai G, Wei X, Liu Z et al (2005) Characterization and quantification of Bcl-2 antisense oblimersen and metabolites in plasma and urine by ion-pair reversed phase HPLC coupled with electrospray ion-trap mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 825:201–213

    Article  PubMed  CAS  Google Scholar 

  • Demir G, Ozguroglu M, Sayhan N et al (1999) Immunomodulating therapy with rIL-2 and interferon alpha-induces in vivo expression of bcl-2, Fas (APO-1/CD95), and Fas ligand on peripheral lymphocytes (a pilot study). Anticancer Res 19:3517–3520

    PubMed  CAS  Google Scholar 

  • Devarajan P, De Leon M, Talasazan F et al (2001) The von Hippel–Lindau gene product inhibits renal cell apoptosis via bcl-2-dependent pathways. J Biol Chem 276:40599–40605

    Article  PubMed  CAS  Google Scholar 

  • Fosså SD (2000) Interferon in metastatic renal cell carcinoma. Semin Oncol 27:187–193

    PubMed  Google Scholar 

  • McDonnell TJ, Korsmeyer SJ (1991) Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the †(14;18). Nature 349:254–256

    Article  PubMed  CAS  Google Scholar 

  • Gaulard P, d’Agay MF, Peuchmaur M et al (1992) Expression of the bcl-2 gene product in follicular lymphoma. Am J Pathol 140:1089–1095

    PubMed  CAS  Google Scholar 

  • Hara I, Hara S, Miyake H et al (2001) Bcl-2 modulates Fas-mediated apoptosis in human renal cell carcinoma cell lines. Int J Oncol 18:1181–1185

    PubMed  CAS  Google Scholar 

  • Henry SP, Monteith D, Levin AA (1997) Antisense oligonucleotide inhibitors for the treatment of cancer. 2. Toxicological properties of phosphorothioate oligonucleotides. Anti-Cancer Drug Des 12:395–408

    CAS  Google Scholar 

  • Ikegaki N, Katsumata M et al (1994) Expression of bcl-2 in small cell lung carcinoma cells. Cancer Res 54:6–8

    PubMed  CAS  Google Scholar 

  • Jiang SX, Yuichi S et al (1995) Expression of bcl-2 oncogene protein is prevalent in small cell lung carcinomas. J Pathol 177:135–138

    Article  PubMed  CAS  Google Scholar 

  • Leek RD, Kaklamanis L et al (1994) Bcl-2 in normal human breast and carcinoma, association with estrogen receptor-positive, epidermal growth factor receptor-negative tumours and in situ cancer. Br J Cancer 69:135–139

    PubMed  CAS  Google Scholar 

  • Lu QL, Elia G et al (1993) Bcl-2 Proto-oncogene expression in Epstein-Barr-Virus associated nasopharyngeal carcinoma. Int J Cancer 53:29–35

    Article  PubMed  CAS  Google Scholar 

  • Marcucci G, Byrd JC, Dai G et al (2003) Phase 1 and pharmacodynamic studies of oblimersen, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood 101:425–432

    Article  PubMed  CAS  Google Scholar 

  • Marcucci G, Stock W, Dai G et al (2005) 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

    Article  PubMed  CAS  Google Scholar 

  • Margolin KA (2000) Interleukin-2 in the treatment of renal cancer. Semin Oncol 27:194–203

    PubMed  CAS  Google Scholar 

  • Mita MM, Ochoa L, Rowinsky EK et al (2006) A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (GenasenseTM, oblimersen) and irinotecan in patients with metastatic colorectal cancer. Ann Oncol 17:313–321

    Article  PubMed  CAS  Google Scholar 

  • O’Brien SM, Cunningham CC, Golenkov AK et al (2005) 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

    Article  PubMed  CAS  Google Scholar 

  • O’Donnell TJ, Troncoso P et al (1992) Expression of the protooncogene bcl2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 52:6940–6944

    Google Scholar 

  • Paraf F, Chauveau D, Chretien Y et al (2000) Renal lesions in von Hippel–Lindau disease: immunohistochemical expression of nephron differentiation molecules, adhesion molecules and apoptosis proteins. Histopathology 36:457–465

    Article  PubMed  CAS  Google Scholar 

  • Rudin CM, Kozloff M, Hoffman PC et al (2004) Phase I Study oblimersen, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 22:1110–1117

    Article  PubMed  CAS  Google Scholar 

  • Semino C, Ferlazzo G, Pietra G et al (1992) Heterogeneity of the alpha-interferon-mediated-gamma to carcinoma patients enhances expression of tumor-associated glycoprotein-72 and carcinoembryonic antigen on malignant ascites cells. J Clin Oncol 10:735–746

    Google Scholar 

  • Silvestrini R, Veneroni S, Daidone MG et al (1994) The Bcl-2 protein: a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients. J Natl Canc Inst 86:499–504

    Article  CAS  Google Scholar 

  • Sinicrope FA, Ruan SB et al (1995) Bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res 55:237–241

    PubMed  CAS  Google Scholar 

  • Stein CA, Benimetskaya L, Mani S (2005) Antisense strategies for oncogene inactivation. Semin Oncol 32:563–572

    Article  PubMed  CAS  Google Scholar 

  • Therasse P, Arbuck S, Eisenhauer E, Wanders J et al (2006) New guidelines to evaluate the response to treatment in solid tumors. JNCI 92:205–216

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Tolcher AW, Kim C, Kuhn J et al (2005) 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

    Article  PubMed  CAS  Google Scholar 

  • Waters JS, Webb A, Cunningham D et al (2000) 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

    PubMed  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Division of Medical Oncology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010-3000, USA

    Kim Margolin, Timothy W. Synold & Bixin **

  2. University of California, Davis, CA, USA

    Primo Lara & David R. Gandara

  3. Division of Information Sciences, City of Hope, Duarte, CA, USA

    Paul Frankel & Tracey Baratta

  4. Laboratory of Vaccine Research, City of Hope, Duarte, CA, USA

    Simon F. Lacey & Don J. Diamond

  5. USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    David I. Quinn

  6. Our Lady of Mercy Medical Center, Bronx, NY, USA

    Janice P. Dutcher

Authors
  1. Kim Margolin
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  2. Timothy W. Synold
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  3. Primo Lara
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  4. Paul Frankel
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  5. Simon F. Lacey
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  7. Tracey Baratta
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  8. Janice P. Dutcher
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  9. Bixin **
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  10. Don J. Diamond
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  11. David R. Gandara
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Corresponding author

Correspondence to Kim Margolin.

Additional information

Study support: National Cancer Institute (N-01-CM-17101).

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Margolin, K., Synold, T.W., Lara, P. et al. Oblimersen and α-interferon in metastatic renal cancer: a phase II study of the California Cancer Consortium. J Cancer Res Clin Oncol 133, 705–711 (2007). https://doi.org/10.1007/s00432-007-0200-6

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  • DOI: https://doi.org/10.1007/s00432-007-0200-6

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