Abstract
Hypoxanthine (Hx) and allopurinol (HPP) have been shown experimentally to reduce the conversion of 5-fluorouracil (FUra) to FUMP by orotate phosphoribosyltransferase (OPRTase). This study was designed to elucidate the major pathway by which FUra was metabolized to ribonucleotides by human colorectal tumors. Consequently, the effect of Hx and HPP on the metabolism of [6-3H]-FUra was examined in 5 human colorectal adenocarcinomas maintained as xenografts in immune-deprived mice. In 2 tumors the formation of ribonucleotides from FUra was depressed by Hx and HPP in combination during the first hour after treatment, while in 3 other lines ribonucleotide concentrations were not reduced. The data suggested that these 5 xenograft lines may be divided into 2 groups: (1) group 1 tumors formed relatively high levels of FUrd and low levels of fluorinated ribonucleotides after the injection of FUra, with no decrease in ribonucleotide concentrations after the administration of Hx and HPP. These tumors possessed high ratios of uridine (Urd) phosphorylase/orotate phosphoribosyltransferase (OPRTase: 7-24) and ribose-1-phosphate (R-1-P)/5-phosphoribosyl-1-pyrophosphate (PRPP; 5), and thus appeared to metabolize FUra by the Urd phosphorylase and Urd kinase pathway; (2) group 2 tumors formed low levels of FUrd, higher concentrations of fluorinated ribonucleotides and a reduction in levels of these nucleotides after administration of the purine combination. Group 2 tumors demonstrated a lower enzyme ratio (1-2), higher endogenous levels of PRPP, a lower R-1-P/PRPP ratio (1) and appeared to metabolize FUra predominantly by the activity of OPRTase. Hypoxanthine and HPP, alone or in combination, caused a rapid depletion of PRPP in each tumor line examined. In group 2 tumors this may be responsible for the decreased formation of FUra ribonucleotides observed.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 807-815 |
| Number of pages | 9 |
| Journal | European Journal of Cancer and Clinical Oncology |
| Volume | 19 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jan 1 1983 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
Cite this
Elucidation of pathways of 5-fluorouracil metabolism in xenografts of human colorectal adenocarcinoma. / Houghton, Janet A.; Houghton, Peter J.
In: European Journal of Cancer and Clinical Oncology, Vol. 19, No. 6, 01.01.1983, p. 807-815.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Elucidation of pathways of 5-fluorouracil metabolism in xenografts of human colorectal adenocarcinoma
AU - Houghton, Janet A.
AU - Houghton, Peter J
PY - 1983/1/1
Y1 - 1983/1/1
N2 - Hypoxanthine (Hx) and allopurinol (HPP) have been shown experimentally to reduce the conversion of 5-fluorouracil (FUra) to FUMP by orotate phosphoribosyltransferase (OPRTase). This study was designed to elucidate the major pathway by which FUra was metabolized to ribonucleotides by human colorectal tumors. Consequently, the effect of Hx and HPP on the metabolism of [6-3H]-FUra was examined in 5 human colorectal adenocarcinomas maintained as xenografts in immune-deprived mice. In 2 tumors the formation of ribonucleotides from FUra was depressed by Hx and HPP in combination during the first hour after treatment, while in 3 other lines ribonucleotide concentrations were not reduced. The data suggested that these 5 xenograft lines may be divided into 2 groups: (1) group 1 tumors formed relatively high levels of FUrd and low levels of fluorinated ribonucleotides after the injection of FUra, with no decrease in ribonucleotide concentrations after the administration of Hx and HPP. These tumors possessed high ratios of uridine (Urd) phosphorylase/orotate phosphoribosyltransferase (OPRTase: 7-24) and ribose-1-phosphate (R-1-P)/5-phosphoribosyl-1-pyrophosphate (PRPP; 5), and thus appeared to metabolize FUra by the Urd phosphorylase and Urd kinase pathway; (2) group 2 tumors formed low levels of FUrd, higher concentrations of fluorinated ribonucleotides and a reduction in levels of these nucleotides after administration of the purine combination. Group 2 tumors demonstrated a lower enzyme ratio (1-2), higher endogenous levels of PRPP, a lower R-1-P/PRPP ratio (1) and appeared to metabolize FUra predominantly by the activity of OPRTase. Hypoxanthine and HPP, alone or in combination, caused a rapid depletion of PRPP in each tumor line examined. In group 2 tumors this may be responsible for the decreased formation of FUra ribonucleotides observed.
AB - Hypoxanthine (Hx) and allopurinol (HPP) have been shown experimentally to reduce the conversion of 5-fluorouracil (FUra) to FUMP by orotate phosphoribosyltransferase (OPRTase). This study was designed to elucidate the major pathway by which FUra was metabolized to ribonucleotides by human colorectal tumors. Consequently, the effect of Hx and HPP on the metabolism of [6-3H]-FUra was examined in 5 human colorectal adenocarcinomas maintained as xenografts in immune-deprived mice. In 2 tumors the formation of ribonucleotides from FUra was depressed by Hx and HPP in combination during the first hour after treatment, while in 3 other lines ribonucleotide concentrations were not reduced. The data suggested that these 5 xenograft lines may be divided into 2 groups: (1) group 1 tumors formed relatively high levels of FUrd and low levels of fluorinated ribonucleotides after the injection of FUra, with no decrease in ribonucleotide concentrations after the administration of Hx and HPP. These tumors possessed high ratios of uridine (Urd) phosphorylase/orotate phosphoribosyltransferase (OPRTase: 7-24) and ribose-1-phosphate (R-1-P)/5-phosphoribosyl-1-pyrophosphate (PRPP; 5), and thus appeared to metabolize FUra by the Urd phosphorylase and Urd kinase pathway; (2) group 2 tumors formed low levels of FUrd, higher concentrations of fluorinated ribonucleotides and a reduction in levels of these nucleotides after administration of the purine combination. Group 2 tumors demonstrated a lower enzyme ratio (1-2), higher endogenous levels of PRPP, a lower R-1-P/PRPP ratio (1) and appeared to metabolize FUra predominantly by the activity of OPRTase. Hypoxanthine and HPP, alone or in combination, caused a rapid depletion of PRPP in each tumor line examined. In group 2 tumors this may be responsible for the decreased formation of FUra ribonucleotides observed.
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UR - http://www.scopus.com/inward/citedby.url?scp=0020563004&partnerID=8YFLogxK
U2 - 10.1016/0277-5379(83)90013-5
DO - 10.1016/0277-5379(83)90013-5
M3 - Article
C2 - 6191988
AN - SCOPUS:0020563004
VL - 19
SP - 807
EP - 815
JO - European Journal of Cancer and Clinical Oncology
JF - European Journal of Cancer and Clinical Oncology
SN - 0277-5379
IS - 6
ER -