title: Mitoxantrone in patients with prostate specific antigen progression after local therapy for prostate carcinoma.
abstract: BACKGROUND
  Molecular mechanisms of chemotherapy resistance are present in prostate carcinoma, some of which increase after androgen ablation (AA) therapy. Therefore, the authors hypothesized that chemotherapy in patients with prostate specific antigen (PSA) progression after local therapy, before androgen ablation therapy, will have greater antitumor activity.
  
  
  METHODS
  Twenty-three hormone-naive patients with PSA progression after prostatectomy or radiation therapy were registered in this study. Twenty-two were treated with 10 mg/m(2) of mitoxantrone initially, followed by 12 mg/m(2) every 3 weeks for a maximum of 8 cycles. Prostatectomy specimens were assessed, when possible, for topoisomerase II alpha, multidrug resistance protein MRP, and bcl-2 by immunohistochemistry.
  
  
  RESULTS
  Twenty-two patients received a total of 131 cycles of therapy. Three patients had transient Grade 3 or 4 neutropenia without fever. During treatment, 10 of 22 patients showed a decrease in PSA, without an associated decrease in testosterone. In this group of 10 patients, the mean PSA decrease was 29% at 3 months and 43% at 6 months. Overall, 4 of 22 patients had a decrease in PSA of greater than or equal to 50%. The PSA decreased in three of seven patients whose cancer overexpressed MRP and in three of seven patients who overexpressed bcl-2. No patient with overexpression of topoisomerase II alpha (n = 4) had a decrease in PSA during the study.
  
  
  CONCLUSIONS
  To the authors' knowledge, this is the first reported study of mitoxantrone in patients with hormone-naive prostate carcinoma and PSA progression after local therapy; mitoxantrone was safe and biochemically active, similar to prior studies in hormone refractory prostate carcinoma, suggesting that critical molecular mechanisms of chemotherapy resistance are present independent of AA. Further studies are warranted to determine whether pharmacogenomic assessment of topoisomerase II, MRP, or bcl-2 may predict for response to mitoxantrone.
authors.affiliation: Department of Medicine, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. dipaolrs@umdnj.edu
authors.forename: R S
authors.initials: RS
authors.lastname: DiPaola
authors.forename: E S
authors.initials: ES
authors.lastname: Chenven
authors.forename: W J
authors.initials: WJ
authors.lastname: Shih
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: P
authors.initials: P
authors.lastname: Amenta
authors.forename: S
authors.initials: S
authors.lastname: Goodin
authors.forename: A
authors.initials: A
authors.lastname: Shumate
authors.forename: T
authors.initials: T
authors.lastname: Capanna
authors.forename: M
authors.initials: M
authors.lastname: Cardiella
authors.forename: K B
authors.initials: KB
authors.lastname: Cummings
authors.forename: J
authors.initials: J
authors.lastname: Aisner
authors.forename: M B
authors.initials: MB
authors.lastname: Todd
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017211:Treatment Failure
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015415:Biomarkers; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D008942:Mitoxantrone; D017430:Prostate-Specific Antigen; D004250:DNA Topoisomerases, Type II