title: Variability of cyclophosphamide uptake into human bronchial carcinoma: consequences for local bioactivation.
abstract: OBJECTIVE
  The alkylating cytostatic prodrug cyclophosphamide is bioactivated by the human cytochrome P450 enzyme system. Since these enzymes are not only expressed in human liver, but also in extrahepatic tissue, local bioactivation of this drug may play an important role in its antineoplastic effects, e.g., chemotherapy of lung tumors. This would require uptake of significant amounts of cyclophosphamide into tumor tissue, which has not yet been demonstrated.
  
  
  METHODS
  We used a recently developed, ex vivo isolated, ventilated and perfused human lung model to study cyclophosphamide uptake into bronchial carcinoma and healthy lung tissue. Following a standard lobectomy, lung samples containing the tumor were perfused with buffer containing 2 mM cyclophosphamide for 2 h. Cyclophosphamide concentrations in perfusate and healthy peripheral tissue were measured during the perfusion and in tumors at the end of perfusion.
  
  
  RESULTS
  In all tissue samples, cyclophosphamide uptake was relatively poor, indicated by a tissue to perfusate ratio of 0.021. Moreover, in tumor samples, cyclophosphamide concentrations were significantly lower (P < 0.05) than in healthy lung tissue and showed pronounced interindividual variability. Median concentrations were 36.8 microg/g (26.9 44.2 microg/g) in healthy tissue and 5.1 microg/g (0.0-26.8 microg/g) in tumor samples. Tumor cyclophosphamide concentrations varied between 0 and 75% of those reached in healthy tissue.
  
  
  CONCLUSIONS
  Our results indicate that CP tumor concentrations are modulated by factors different from dose and that expression of bioactivating enzymes in human lung or transfection of genes encoding these enzymes into tumor cells does not necessarily lead to local bioactivation of cyclophosphamide.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Bohnenstengel
authors.forename: G
authors.initials: G
authors.lastname: Friedel
authors.forename: C A
authors.initials: CA
authors.lastname: Ritter
authors.forename: M
authors.initials: M
authors.lastname: McClellan
authors.forename: P
authors.initials: P
authors.lastname: Fritz
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: A
authors.initials: A
authors.lastname: Linder
authors.forename: H
authors.initials: H
authors.lastname: Toomes
authors.forename: R
authors.initials: R
authors.lastname: Dierkesmann
authors.forename: H K
authors.initials: HK
authors.lastname: Kroemer
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D001711:Biotransformation; D002283:Carcinoma, Bronchogenic / Q000378:metabolism*; D003520:Cyclophosphamide / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010477:Perfusion
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide