Selective incorporation of iododeoxyuridine into DNA of hepatic metastases versus normal human liver.
Fourteen patients received 5-iodo-2(1)-deoxyuridine (IdUrd) before surgery for placement of a hepatic arterial catheter. Biopsy specimens were obtained at the time of surgery and incorporation of IdUrd into deoxyribonucleic acid (DNA) in tumor and normal hepatic tissue was measured by HPLC and used as an index of drug selectivity. Over a 3-day intravenous infusion of IdUrd at 1000 mg/m2/day, substitution for thymidine in tumor DNA averaged 3.1%. Normal hepatic DNA contained less than 1% substitution by IdUrd. Arterial delivery of IdUrd increased levels in DNA, whereas modulation with fluorodeoxyuridine produced mixed results. In six patients, flow cytometric analysis showed that the tumor contained a median of 32% of tumor cells that had incorporated IdUrd in 3 days, corresponding to a potential doubling time of only 10 days. Thymidylate synthetase activity in tumors was 20-fold greater than in normal liver tissue, whereas thymidine kinase activity was twofold greater in tumors. These pharmacologic studies encourage further clinical trials of IdUrd as a cytotoxic agent or radiosensitizer.
Speth
P A
PA
Clinical Pharmacology Branches, National Cancer Institute, Bethesda, Md.
Kinsella
T J
TJ
Chang
A E
AE
Klecker
R W
RW
Belanger
K
K
Collins
J M
JM
D000328:Adult; D000368:Aged; D004247:DNA / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007065:Idoxuridine / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D013937:Thymidine Kinase / Q000032:analysis
D004273:DNA, Neoplasm; D004247:DNA; D013937:Thymidine Kinase; D007065:Idoxuridine