title: A Phase II study of the polyamine analog N1,N11-diethylnorspermine (DENSpm) daily for five days every 21 days in patients with previously treated metastatic breast cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-1000, USA. awolff@jhmi.edu
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Armstrong
authors.forename: John H
authors.initials: JH
authors.lastname: Fetting
authors.forename: M Katherine
authors.initials: MK
authors.lastname: Carducci
authors.forename: Carol D
authors.initials: CD
authors.lastname: Riley
authors.forename: John F
authors.initials: JF
authors.lastname: Bender
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000556:secondary; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D013096:Spermine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; C059685:N(1),N(11)-diethylnorspermine; D013096:Spermine