A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma

Christopher Ryan, M. Eileen Dolan, Bruce B. Brockstein, Roger McLendon, Shannon M. Delaney, Brian L. Samuels, Edem S. Agamah, Everett E. Vokes

    Research output: Contribution to journalArticle

    30 Citations (Scopus)

    Abstract

    Purpose: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O 6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. Experimental design: Informed consent was obtained from patients with metastatic soft tissue sarcoma naïve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O 6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. Results: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. Conclusions: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.

    Original languageEnglish (US)
    Pages (from-to)634-639
    Number of pages6
    JournalCancer Chemotherapy and Pharmacology
    Volume58
    Issue number5
    DOIs
    StatePublished - Nov 2006

    Fingerprint

    Carmustine
    Sarcoma
    Methyltransferases
    Chemotherapy
    Tissue
    Toxicity
    DNA
    O(6)-Methylguanine-DNA Methyltransferase
    Drug Therapy
    Alkylating Agents
    Adjuvant Chemotherapy
    Neutropenia
    Informed Consent
    Thrombocytopenia
    Design of experiments
    Disease Progression
    Anemia
    Tumors
    Blood Cells
    Blood

    Keywords

    • Carmustine
    • DNA repair
    • Drug resistance
    • O-benzylguanine
    • Sarcoma

    ASJC Scopus subject areas

    • Cancer Research
    • Pharmacology
    • Oncology

    Cite this

    Ryan, C., Dolan, M. E., Brockstein, B. B., McLendon, R., Delaney, S. M., Samuels, B. L., ... Vokes, E. E. (2006). A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma. Cancer Chemotherapy and Pharmacology, 58(5), 634-639. https://doi.org/10.1007/s00280-006-0210-0

    A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma. / Ryan, Christopher; Dolan, M. Eileen; Brockstein, Bruce B.; McLendon, Roger; Delaney, Shannon M.; Samuels, Brian L.; Agamah, Edem S.; Vokes, Everett E.

    In: Cancer Chemotherapy and Pharmacology, Vol. 58, No. 5, 11.2006, p. 634-639.

    Research output: Contribution to journalArticle

    Ryan, C, Dolan, ME, Brockstein, BB, McLendon, R, Delaney, SM, Samuels, BL, Agamah, ES & Vokes, EE 2006, 'A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma', Cancer Chemotherapy and Pharmacology, vol. 58, no. 5, pp. 634-639. https://doi.org/10.1007/s00280-006-0210-0
    Ryan, Christopher ; Dolan, M. Eileen ; Brockstein, Bruce B. ; McLendon, Roger ; Delaney, Shannon M. ; Samuels, Brian L. ; Agamah, Edem S. ; Vokes, Everett E. / A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma. In: Cancer Chemotherapy and Pharmacology. 2006 ; Vol. 58, No. 5. pp. 634-639.
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    abstract = "Purpose: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O 6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. Experimental design: Informed consent was obtained from patients with metastatic soft tissue sarcoma na{\"i}ve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O 6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. Results: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95{\%} CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99{\%} positive staining cells. Conclusions: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.",
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    AU - Ryan, Christopher

    AU - Dolan, M. Eileen

    AU - Brockstein, Bruce B.

    AU - McLendon, Roger

    AU - Delaney, Shannon M.

    AU - Samuels, Brian L.

    AU - Agamah, Edem S.

    AU - Vokes, Everett E.

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    N2 - Purpose: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O 6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. Experimental design: Informed consent was obtained from patients with metastatic soft tissue sarcoma naïve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O 6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. Results: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. Conclusions: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.

    AB - Purpose: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O 6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. Experimental design: Informed consent was obtained from patients with metastatic soft tissue sarcoma naïve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O 6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. Results: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. Conclusions: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.

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