Gemcitabine uptake in glioblastoma multiforme: potential as a radiosensitizer.
Glioblastoma multiforme (GBM), the most frequent malignant brain tumor, has a poor prognosis, but is relatively sensitive to radiation. Both gemcitabine and its metabolite difluorodeoxyuridine (dFdU) are potent radiosensitizers. The aim of this phase 0 study was to investigate whether gemcitabine passes the blood-tumor barrier, and is phosphorylated in the tumor by deoxycytidine kinase (dCK) to gemcitabine nucleotides in order to enable radiosensitization, and whether it is deaminated by deoxycytidine deaminase (dCDA) to dFdU. Gemcitabine was administered at 500 or 1000 mg/m(2) just before surgery to 10 GBM patients, who were biopsied after 1-4 h. Plasma gemcitabine and dFdU levels varied between 0.9 and 9.2 microM and 24.9 and 72.6 microM, respectively. Tumor gemcitabine and dFdU levels varied from 60 to 3580 pmol/g tissue and from 29 to 72 nmol/g tissue, respectively. The gene expression of dCK (beta-actin ratio) varied between 0.44 and 2.56. The dCK and dCDA activities varied from 1.06 to 2.32 nmol/h/mg protein and from 1.51 to 5.50 nmol/h/mg protein, respectively. These enzyme levels were sufficient to enable gemcitabine phosphorylation, leading to 130-3083 pmol gemcitabine nucleotides/g tissue. These data demonstrate for the first time that gemcitabine passes the blood-tumor barrier in GBM patients. In tumor samples, both gemcitabine and dFdU concentrations are high enough to enable radiosensitization, which warrants clinical studies using gemcitabine in combination with radiation.
Sigmond
J
J
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Honeywell
R J
RJ
Postma
T J
TJ
Dirven
C M F
CM
de Lange
S M
SM
van der Born
K
K
Laan
A C
AC
Baayen
J C A
JC
Van Groeningen
C J
CJ
Bergman
A M
AM
Giaccone
G
G
Peters
G J
GJ
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D001706:Biopsy; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D003564:Cytidine Deaminase; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000378:metabolism; D005260:Female; D005467:Floxuridine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D009700:Nucleoside Deaminases / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D011838:Radiation-Sensitizing Agents; D005467:Floxuridine; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase; C011530:deoxycytidine deaminase; D000093542:Gemcitabine