5-Fluorouracil, hydroxyurea and escalating doses of iododeoxyuridine with concomitant radiotherapy for malignant gliomas: a clinical and pharmacologic analysis.
BACKGROUND
Iododeoxyuridine (IUdR) is a known radiation enhancer, and interacts biochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU).


METHODS
IUdR was added to the previously studied regimen of continuous infusion 5-FU at 300 mg/m2/day for 5 days, HU 500 mg every 12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days, all administered for 7 consecutive weeks to patients with malignant glioma. IUdR was administered as 5-day continuous intravenous infusion during weeks 1 and 4. The IUdR dose was changed in cohorts of patients. IUdR plasma concentrations were determined during weeks 1 and 4, and IUdR incorporation into the DNA of granulocytes was measured on weeks 2 and 5.


RESULTS
Two patients treated at the initial IUdR dose of 500 mg/m2/day developed grade 3 or 4 myelosuppression and mucositis. Additional dose levels of IUdR tested were 250 mg/m2/day and 125 mg/m2/day; at the latter dose, severe or life-threatening toxicity was seen in only 3 of 8 patients treated. IUdR incorporation into DNA of granulocytes was 10.5(+/- 2.3)% at an IUdR dose of 500 mg/m2/day but decreased to 0.76(+/- 0.3)% at 125 mg/m2/day. Similarly, IUdR plasma concentrations decreased from 436 (+/- 114) ng/ml to 99 (+/- 29) ng/ml.


CONCLUSIONS
The addition of IUdR to 5-FU and HU results in significant systemic toxicity necessitating limitation of the IUdR dose to 125 mg/m2/day. There is a significant biochemical interaction between IUdR, 5-FU and HU leading to increased IUdR incorporation into DNA and to substantial clinical toxicity. Further clinical studies to exploit this interaction at more feasible schedules may be useful.
Department of Medicine, University of Chicago, IL.
E E
EE
Vokes
M E
ME
Dolan
S
S
Krishnasamy
R
R
Mick
M J
MJ
Ratain
F
F
Berezin
D
D
Brachman
G
G
Whitman
R L
RL
Schilsky
J
J
Charette
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D007065:Idoxuridine / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012074:Remission Induction
D007065:Idoxuridine; D005472:Fluorouracil; D006918:Hydroxyurea