TY - JOUR
T1 - Tumor 5-fluorodeoxyuridylate concentration as a determinant of 5-fluorouracil response
AU - Ardalan, Bach
AU - Buscaglia, M. Denice
AU - Schein, Philip S.
N1 - Funding Information:
Since its synthesis in 1958 the antimetabolite 5-fluorouracil (5FU)f has played a major role in-the treatment ofgastrointestinal cancer [l]. However, it is recognized that only 20 per cent of the patients with colonic cancer treated with this agent will achieve an objective response [2]. The selection of patients for therapy with 5-FU remains an exercise in clinical empiricism; there is no simple test that has been accepted as a predictive index for response. It has been demonstrated that FdUMP is the active metabolite of 5-FU, and forms a covalent complex with thymidylate synthetase in the presence of 5,10-CH, H, folate [S]. Thymidylate synthetase catalyzes the methylation of the natural substrate, dUMP, to dTMP for DNA synthesis. The present study was conducted to correlate the kinetics of intracellular 5-FdUMP concentration with the extent and duration of inhibition of DNA synthesis, and with antitdmor *This work was supported by NC1 Grant NOl-CM-67110. tTo whom reprint requests should be. sent. SAbbreviations used in the text are as follows: S-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyridlyate; dUMP, deoxyuridine monophosphate; UdR, deoxyuridine; and 5,10-CH,H, folate, 5,10-methylenetetrahydrofolate.
PY - 1978
Y1 - 1978
N2 - The antitumor activity of 5-fluoruoracil (5-FU) for two murine colonie adenocarcinomas was correlated with the concentration and the clearance of the active antimetabolite, 5-fluorodeoxyuridylate (FdUMP). Mice inoculated with a cell suspension of murine colonic adenocarcinomas 38 and 51 were treated with 5-FU (100 mg/kg i.p.) on 3 day post-transplantation. For mice bearing adenocarconoma 38, treatment with 5-FU was associated with a 97 per cent reduction in mean tumor weight a day 30 and a 77 per cent reduction at day 37 of tumor growth. In contrast, mice bearing colonic adenocarcinoma 51, treated with the same dose schedule of 5-FU did not demonstrate a reduction in the rate of tumor growth in vivo. Two hr after i.p. injection of 5-FU (100 mg/kg) the intracellular concentration of free FdUMP in the sensitive tumor 38 was 560 fmoles/μg of DNA. The active antimetabolite was maintained at a concentration in excess of 100 fmoles/μg of DNA for 72 hr. In contrast, the 2-hr free FdUMP concentration in the resistant tumor line 51 was 240 fmoles μg of DNA(P < 0.005), and a concentration in excess of 100 fmoles/μg of DNA was maintained for only 24 hr. There was no difference in the rate of progressive accumulation of the competitive metabolite, deoxyuridine monophosphate (dUMP), during the first 24 hr of the study. Two hr after i.p. injection of 5-FU (100 mh/kg), [3H] deoxyuridine ([3H]Udr) incorporation into DNA was reduced in both tumor lines to below 3 per cent of control. However, in the sensitive tumor, adeno-carcinoma 38, DNA synthesis was maximally inhibited for 72 hr, compared to 24 hr in the resistant adenocarcinoma 51. The reinitiation of DNA synthesis corresponded to the reduction of free FdUMP concentration to less than 100 fmoles/μg of DNA. There was no linear relationship between the FdUMP/ dUMP ratio and [3H]UdR incorporation into DNA in either tumor line. These data demonstrate that the peak tumor FdUMP concentration and the kinetics of its clearance correlated with the responsiveness of the two specific murine tumors to 5-FU. The measure of peak FdUMP level should be tested for its potential clinical application as a means of selecting patients with gastrointestinal and breast cancer to be treated with this agent.
AB - The antitumor activity of 5-fluoruoracil (5-FU) for two murine colonie adenocarcinomas was correlated with the concentration and the clearance of the active antimetabolite, 5-fluorodeoxyuridylate (FdUMP). Mice inoculated with a cell suspension of murine colonic adenocarcinomas 38 and 51 were treated with 5-FU (100 mg/kg i.p.) on 3 day post-transplantation. For mice bearing adenocarconoma 38, treatment with 5-FU was associated with a 97 per cent reduction in mean tumor weight a day 30 and a 77 per cent reduction at day 37 of tumor growth. In contrast, mice bearing colonic adenocarcinoma 51, treated with the same dose schedule of 5-FU did not demonstrate a reduction in the rate of tumor growth in vivo. Two hr after i.p. injection of 5-FU (100 mg/kg) the intracellular concentration of free FdUMP in the sensitive tumor 38 was 560 fmoles/μg of DNA. The active antimetabolite was maintained at a concentration in excess of 100 fmoles/μg of DNA for 72 hr. In contrast, the 2-hr free FdUMP concentration in the resistant tumor line 51 was 240 fmoles μg of DNA(P < 0.005), and a concentration in excess of 100 fmoles/μg of DNA was maintained for only 24 hr. There was no difference in the rate of progressive accumulation of the competitive metabolite, deoxyuridine monophosphate (dUMP), during the first 24 hr of the study. Two hr after i.p. injection of 5-FU (100 mh/kg), [3H] deoxyuridine ([3H]Udr) incorporation into DNA was reduced in both tumor lines to below 3 per cent of control. However, in the sensitive tumor, adeno-carcinoma 38, DNA synthesis was maximally inhibited for 72 hr, compared to 24 hr in the resistant adenocarcinoma 51. The reinitiation of DNA synthesis corresponded to the reduction of free FdUMP concentration to less than 100 fmoles/μg of DNA. There was no linear relationship between the FdUMP/ dUMP ratio and [3H]UdR incorporation into DNA in either tumor line. These data demonstrate that the peak tumor FdUMP concentration and the kinetics of its clearance correlated with the responsiveness of the two specific murine tumors to 5-FU. The measure of peak FdUMP level should be tested for its potential clinical application as a means of selecting patients with gastrointestinal and breast cancer to be treated with this agent.
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U2 - 10.1016/0006-2952(78)90059-X
DO - 10.1016/0006-2952(78)90059-X
M3 - Article
C2 - 718724
AN - SCOPUS:0018083698
VL - 27
SP - 2009
EP - 2013
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 16
ER -
