title: 5-fluorouracil kinetics in the interstitial tumor space: clinical response in breast cancer patients.
abstract: Several anticancer drugs fail to exhibit sufficient activity against solid tumors in vivo despite effective inhibition of tumor cell growth in vitro. This may be due to impaired drug transfer from plasma into solid tumors. The present study, therefore, aimed at measuring interstitial tumor 5-fluorouracil (5-FU) pharmacokinetics and 5-FU transfer rates from plasma into the tumor interstitium in breast cancer patients. Microdialysis probes were inserted into the primary tumor and the periumbilical s.c. adipose layer of 10 breast cancer patients (8 females and 2 males) scheduled to receive neoadjuvant chemotherapy due to locally advanced breast cancer. Thereafter, patients received 5-FU (600 mg/m2, i.v). 5-FU kinetics were followed in plasma and tumor and s.c. interstitial fluid. Mean interstitial 5-FU load, expressed as area under curve (AUC), in breast tumors was 61 +/- 11% (means +/- SE) of the mean plasma 5-FU load. 5-FU displayed similar kinetics in the interstitial space of s.c. adipose tissue and tumor tissue. A high interstitial tumor AUC was associated with increased tumor response. There was no association with tumor response for s.c. or plasma AUC of 5-FU. Measurement of interstitial drug concentrations in breast tumors by in vivo microdialysis may predict response to chemotherapy. This information may explain drug resistance in some patients and help to optimize dosing and administration schedules. In the future, selection of novel cytotoxic compounds with favorable tumor penetration characteristics may become possible.
authors.affiliation: Department of Clinical Pharmacology, Vienna University School of Medicine, Austria. Klin-Pharmakologie@univie.ac.at
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: R M
authors.initials: RM
authors.lastname: Mader
authors.forename: B
authors.initials: B
authors.lastname: Steiner
authors.forename: G G
authors.initials: GG
authors.lastname: Steger
authors.forename: B
authors.initials: B
authors.lastname: Jansen
authors.forename: M
authors.initials: M
authors.lastname: Gnant
authors.forename: T
authors.initials: T
authors.lastname: Helbich
authors.forename: R
authors.initials: R
authors.lastname: Jakesz
authors.forename: H G
authors.initials: HG
authors.lastname: Eichler
authors.forename: B
authors.initials: B
authors.lastname: Blochl-Daum
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D018567:Breast Neoplasms, Male / Q000188:drug therapy / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D017551:Microdialysis; D008875:Middle Aged
chemical_list: D005472:Fluorouracil