title: Phase I and pharmacologic study of the alkylating agent modulator novobiocin in combination with high-dose chemotherapy for the treatment of metastatic breast cancer.
abstract: OBJECTIVE
  Resistance to alkylators may potentially be overcome by drugs that inhibits DNA repair, thus improving the efficacy of high-dose chemotherapy. This trial was performed to determine if novobiocin, an agent that inhibits DNA repair, could be given with high-dose alkylators. Study aims were to define the toxicities and maximal-tolerated dose (MTD) of novobiocin and the pharmacokinetics of novobiocin and high-dose cyclophosphamide and thiotepa.
  
  
  METHODS
  Thirty-eight women with responsive metastatic breast cancer received high-dose cyclophosphamide (3 to 6 g/m2 over 4 days), thiotepa (400 to 800 mg/m2), and novobiocin (0.5 to 5.0 g/d x 7, orally) with autologous marrow support. Toxicity was monitored. The pharmacology of novobiocin, cyclophosphamide, and thiotepa was evaluated.
  
  
  RESULTS
  There were no toxic deaths. The MTD of novobiocin was 4 g/d. All seven patients treated at 5 g/d developed grade III/IV mucositis and vomiting. The severity of mucositis correlated with the plasma levels of novobiocin. Other severe toxicities were not observed. Plasma novobiocin levels > or = 100 micrograms/mL, which are associated with reversal of drug resistance in animal models, were consistently seen at dose levels greater than 2 g. The dispositions of cyclophosphamide and thiotepa were not altered by novobiocin.
  
  
  CONCLUSIONS
  Novobiocin may be given with high-dose alkylators in doses that produce plasma levels that augment the activity of these cytotoxics in experimental models. The pharmacology of high-dose cyclophosphamide and thiotepa is unaffected. Novobiocin 4 g/d orally for 7 days is recommended for future study.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, MD 21287, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: D K
authors.initials: DK
authors.lastname: Armstrong
authors.forename: A M
authors.initials: AM
authors.lastname: Huelskamp
authors.forename: K
authors.initials: K
authors.lastname: Ohly
authors.forename: B V
authors.initials: BV
authors.lastname: Clarke
authors.forename: O M
authors.initials: OM
authors.lastname: Colvin
authors.forename: L B
authors.initials: LB
authors.lastname: Grochow
authors.forename: T L
authors.initials: TL
authors.lastname: Chen
authors.forename: N E
authors.initials: NE
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000741:Anemia, Aplastic / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004351:Drug Resistance; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007902:Length of Stay; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects; D009503:Neutropenia / Q000139:chemically induced; D009675:Novobiocin / Q000008:administration & dosage*; D011446:Prospective Studies; D013280:Stomatitis / Q000139:chemically induced; D013852:Thiotepa / Q000008:administration & dosage
chemical_list: D009675:Novobiocin; D003520:Cyclophosphamide; D013852:Thiotepa