Divergent patterns of incorporation of bromodeoxyuridine and iododeoxyuridine in human colorectal tumor cell lines.
Using a panel of four human colorectal tumor (HCT) cell lines, we have quantitatively characterized the incorporation of bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd) into DNA, both as individual agents and in combination with fluoropyrimidines. The intrinsic ability of these cell lines to incorporate BrdUrd, as reflected by the concentration required to achieve half-maximal incorporation, varied almost 4-fold across this panel, from 1.6 microM for HuTu80 cells to 6.1 microM for HT29 cells. Three of the four cell lines (HT29, SW480, SW620) responded to fluoropyrimidines as expected, displaying 100-150% increases in BrdUrd incorporation when combined with growth inhibitory concentrations of fluorouracil (FUra). In contrast, neither FUra nor fluorodeoxyuridine (FdUrd) was able to increase BrdUrd incorporation in HuTu80 cells by more than 25%, even in the presence of 100 microM leucovorin. IdUrd incorporation was modulated to a substantially higher degree in both HT29 and HuTu80 cell lines. Finally we demonstrate the feasibility of a technique for evaluating the net effect of fluoropyrimidine treatments on de novo thymidine nucleotide production in a single specimen, using a combination of normotopic and stable-isotope labeled BrdUrd. We propose that this approach may be useful in evaluating the response of an individual tumor to fluoropyrimidines in vivo.
Maybaum
J
J
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
Burton
E C
EC
Shelton
D A
DA
Jing
H W
HW
Dusenbury
C E
CE
Ensminger
W D
WD
Stetson
P L
PL
D001973:Bromodeoxyuridine / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D005467:Floxuridine / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007065:Idoxuridine / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004273:DNA, Neoplasm; D011838:Radiation-Sensitizing Agents; D005467:Floxuridine; D001973:Bromodeoxyuridine; D007065:Idoxuridine; D005472:Fluorouracil