PURPOSE: Polyamines are ubiquitous intracellular polycationic molecules essential for cell growth and differentiation. Polyamine analogs down-regulate ornithine decarboxylase, induce spermidine/spermine N1-acetyltransferase, deplete natural polyamine pools, inhibit growth, and induce programmed cell death in breast cancer models. This study evaluated the activity of the first-generation analog DENSpm in women with metastatic breast cancer. EXPERIMENTAL DESIGN: The overall accrual goal was 34 patients (30 evaluable) in a two-stage design. The second stage of accrual was to proceed if > or =2 among first 15 evaluable patients were progression free at 4 months. The primary objective was to determine whether > or =20% of metastatic breast cancer patients treated with DENSpm as second- or third-line therapy remained progression free after 4 months. RESULTS: Sixteen patients (median age, 52 years; range, 34-65; median performance status, 1; range, 0-1) enrolled in the first stage received 43 cycles (median, 2; range, 1-6) of 100 mg/m2 DENSpm as a 15-min infusion i.v. on days 1-5 every 21 days. All 16 patients were evaluable for toxicity; 15 were evaluable for response. All patients had disease progression by 4 months, and the study closed after the first stage of accrual. The main toxicities included grade 1-2 abdominal pain, transient perioral numbness, nausea, and grade 1 thrombocytopenia. Two patients had grade 3 abdominal pain during cycle 2 infusion: one was hospitalized, and another was subsequently retreated at 80% dose without pain recurrence. CONCLUSIONS: Although this dose and administration schedule of DENSpm was quite tolerable, no evidence of clinical activity was detected. Encouraging preclinical activity of polyamine analogs alone and in combination with cytotoxic drugs supports the continued evaluation of newer-generation polyamine analogs for the treatment and prevention of breast cancer.
PURPOSE:Polyamines are ubiquitous intracellular polycationic molecules essential for cell growth and differentiation. Polyamine analogs down-regulate ornithine decarboxylase, induce spermidine/spermine N1-acetyltransferase, deplete natural polyamine pools, inhibit growth, and induce programmed cell death in breast cancer models. This study evaluated the activity of the first-generation analog DENSpm in women with metastatic breast cancer. EXPERIMENTAL DESIGN: The overall accrual goal was 34 patients (30 evaluable) in a two-stage design. The second stage of accrual was to proceed if > or =2 among first 15 evaluable patients were progression free at 4 months. The primary objective was to determine whether > or =20% of metastatic breast cancerpatients treated with DENSpm as second- or third-line therapy remained progression free after 4 months. RESULTS: Sixteen patients (median age, 52 years; range, 34-65; median performance status, 1; range, 0-1) enrolled in the first stage received 43 cycles (median, 2; range, 1-6) of 100 mg/m2 DENSpm as a 15-min infusion i.v. on days 1-5 every 21 days. All 16 patients were evaluable for toxicity; 15 were evaluable for response. All patients had disease progression by 4 months, and the study closed after the first stage of accrual. The main toxicities included grade 1-2 abdominal pain, transient perioral numbness, nausea, and grade 1 thrombocytopenia. Two patients had grade 3 abdominal pain during cycle 2 infusion: one was hospitalized, and another was subsequently retreated at 80% dose without pain recurrence. CONCLUSIONS: Although this dose and administration schedule of DENSpm was quite tolerable, no evidence of clinical activity was detected. Encouraging preclinical activity of polyamine analogs alone and in combination with cytotoxic drugs supports the continued evaluation of newer-generation polyamine analogs for the treatment and prevention of breast cancer.
Authors: Tracy Murray Stewart; Apurva A Desai; Michael L Fitzgerald; Laurence J Marton; Robert A Casero Journal: Cancer Chemother Pharmacol Date: 2020-05-23 Impact factor: 3.333
Authors: Vincent Mastrodomenico; Jeremy J Esin; Marion L Graham; Patrick M Tate; Grant M Hawkins; Zachary J Sandler; David J Rademacher; Thomas M Kicmal; Courtney N Dial; Bryan C Mounce Journal: J Virol Date: 2019-06-28 Impact factor: 5.103
Authors: John L A Mitchell; Carrie L Simkus; Thynn K Thane; Phil Tokarz; Michelle M Bonar; Benjamin Frydman; Aldonia L Valasinas; Venodhar K Reddy; Laurence J Marton Journal: Biochem J Date: 2004-12-01 Impact factor: 3.857