Enhanced therapeutic efficacy of 5'deoxy-5-fluorouridine in 5-fluorouracil resistant head and neck tumours in relation to 5-fluorouracil metabolising enzymes

Peters, Godefridus J.; Braakhuis, Boudewijn J.M.; Bruijn, E. A. de; Laurensse, E.; Walsum, Marijke van; Pinedo, H.M.

doi:10.1038/bjc.1989.65

Cited by 35 publications

(17 citation statements)

References 21 publications

(18 reference statements)

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“…In colon cancer cell lines with naturally occurring TP activity, the contribution as concluded by TPI inhibition is Thymidine phosphorylase and fluoropyrimidine sensitivity M de Bruin et al relatively low. Uptake and other activation pathways such as UP and OPRT (Peters et al, 1989) seem much more important. Thymidine phosphorylase may play a more important role when an additional source for the substrate for the activation reaction dR-1-P is provided.…”

Section: Discussionmentioning

confidence: 99%

“…Wild-type Colo320 was, despite lacking measurable TP activity, sensitive to 5 0 DFUR, with an IC 50 of 61.7 mM, comparable to WiDR, 90.1 mM. This might indicate that there is another route of 5 0 DFUR activation in Colo320 cells, such as another phosphorylase (Peters et al, 1989). There was no effect of TPI on the IC 50 's for 5 0 DFUR in SW948 and SW1398 cell lines, corresponding with the low and lack of inhibition of phosphorolytic activity by TPI.…”

Section: Fluoropyrimidine Sensitivity In Relation To Tp Levelsmentioning

confidence: 94%

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Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity

et al. 2003

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Platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (TP) catalyses the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose-1-phosphate and is involved in the metabolism of fluoropyrimidines. It can also activate 5 0 -deoxyfluorouridine (5 0 DFUR) and possibly 5-fluorouracil (5FU) and Ftorafur (Ft), but inactivates trifluorothymidine (TFT). We studied the contribution of TP activity to the sensitivity for these fluoropyrimidines by modulating its activity and/or expression level in colon and lung cancer cells using a specific inhibitor of TP (TPI) or by overproduction of TP via stable transfection of human TP. Expression was analysed using competitive template-RT -PCR (CT-RT -PCR), Western blot and an activity assay. TP activity ranged from nondetectable to 70678 pmol h À1 10 À6 cells, in Colo320 and a TP overexpressing clone Colo320TP1, respectively. We found a good correlation between TP activity and mRNA expression (r ¼ 0.964, Po0.01) in our cell panel. To determine the role of TP in the sensitivity to 5FU, 5 0 DFUR, Ft and TFT, cells were cultured with the various fluoropyrimidines with or without TPI and differences in IC 50 's were established. TPI modified 5 0 DFUR, increasing the IC 50 's 2.5-to 1396-fold in WiDR and Colo320TP1, respectively. 5-Fluorouracil could be modified by inhibiting TP but to a lesser extent than 5 0 DFUR: IC 50 's increased 1.9-to 14.7-fold for WiDR and Colo320TP1, respectively. There was no effect on TFT or Ft. There appears to be a threshold level of TP activity to influence the 5 0 DFUR and 5FU sensitivity, which is higher for 5FU. Even high levels of TP overexpression only had a moderate effect on 5FU sensitivity.

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Section: Discussionmentioning

confidence: 99%

Section: Fluoropyrimidine Sensitivity In Relation To Tp Levelsmentioning

confidence: 94%

Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity

et al. 2003

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“…If the conversion of 5-FC and 5-FU is efficient, the action by the immune system of the host is masked and the tumor cell killing appears to be mediated by the direct cytotoxic action of the metabolites. In that sense, the endogenous activity of orotate phosphoribosyltransferase in Colon 26 cells is relatively high compared with that of other cells; 8,24 consequently, the UPRT/5-FU system is less efficient in Colon 26 cells. However, when the cytotoxic effect caused by active drug(s) can kill a part of tumors, the immune system of the host, stimulated by successful Ag presentation of putative tumor Ag(s), will effectively attack tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…7 These enzymes can also mediate the conversion of 5-fluorouracil (5-FU), a widely used chemotherapeutic agent for various solid tumors such as breast and colon tumors, to 5-fluorouridine-5Ј-monophosphate (FUMP). 8 This conversion is one of the requisite pathways to achieve the cytotoxic effect of 5-FU, because FUMP is further metabolized into two major cytotoxic substances, 5-fluoro-2Ј-deoxyuridine-5Ј-monophosphate, which inhibits thymidylate synthase, and 5-fluorouridine-5Ј-triphosphate, which is incorporated into RNA. The UPRT gene that is absent in mammalian cells, when expressed in tumor cells, can be expected to contribute to the enhanced cytotoxic effect of 5-FU in the transduced cells.…”

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confidence: 99%

Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity

et al. 2000

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Uracil phosphoribosyltransferase (UPRT) of Escherichia coli origin can convert 5-fluorouracil (5-FU), a chemotherapeutic agent widely used for solid tumors, to an active intermediate, 5-fluorouridine-5Ј-monophosphate, as mammalian orotate phosphoribosyltransferase does. To examine whether the E. coli UPRT gene expressed in tumor cells can confer increased sensitivity to 5-FU, we retrovirally transduced Colon 26 cells, a murine colon carcinoma cell line, with the UPRT gene (Colon 26/UPRT cells) and tested the in vivo antitumoral effect of 5-FU in syngeneic immunocompetent mice. After 5-FU administration, tumors of Colon 26/UPRT cells regressed, whereas those of wild-type cells were unaffected. The mice that once eliminated Colon 26/UPRT tumors after 5-FU treatment rejected wild-type cells that were subsequently inoculated but not irrelevant syngeneic tumor cells. This suicide gene/prodrug system was less efficient in nude mice, suggesting that mature ␣␤ T cells play a role in the antitumoral effect. The cytotoxicity mediated by the bystander effect was marginal in this system, contrary to the herpes simplex virus-thymidine kinase gene/ganciclovir system. Therefore, expression of the UPRT gene in tumor cells followed by 5-FU administration is a possible strategy for cancer gene therapy, but potentiation of the bystander effect is required for its therapeutic application. Cancer Gene Therapy (2000) 7, 637-643

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“…At present, 1-hexyl carbamoyl-5-fluorouracil (HCFU, carmofur) has been clinically used (7,8). It is said that 5'-deoxy-5-fluorouridine (5'-DFUR, doxi fluridine), a recently developed derivative of 5-FU, is metabolized into 5-FU by pyrimidine nucleoside phosphorylase which shows higher activity in tumors than in normal tissues, re sulting in a high concentration of 5-FU in tumor cells and less side-effects (9)(10)(11). Up till now, development of 5-FU derivatives has focused on enhancing the anticancer potency and lowering the side-effects.…”

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confidence: 99%

Novel Derivatives of 5-Fluorouridine and 5-Fluorouracil Having Potent Antitumor and Lower Immunosuppressive Activities.

et al. 1992

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ABSTRACT-We studied the biological activities of several 5-fluorouridine (5-FUR) and 5-fluorouracil (5-FU) derivatives to find novel antitumor drugs with lower im munosuppressive effects. We examined 5-FUR and 5-FU derivatives acylated with (2 n-propyl-n-pentanoyl)glycine (KN-539). Among the examined compounds, we found satisfactory activities in a derivative of 5-FUR, 2',3',5'-tris-O-[N-(2-n-propyl-n pentanoyl)glycyl]-5-fluorouridine (UK-21), and a derivative of 5-FU, 1-36-[N-(2-n propyl-n-pent anoyl)glycyl]amino-n-hexylcarbamoyl 1-5 -fluorouracil (UK-25). UK-21 (0.05 -0.2 mmole/kg, p.o., 10 days) and UK-25 (0.1-0.4 mmole/kg, p.o., 10 days) suppressed Meth A and E. L.4 tumor growths in the corresponding syngeneic hosts (BALB/c mice and C57BL/6 mice, respectively) without decreasing body weight and blood leukocyte count. UK-21 and UK-25 suppressed the proliferation of KB tumor cells in vitro (ICSO: 3.0 X 10-11 M and 4.4 X 10-7 M, respectively) at concentrations almost equivalent to those of 5-FUR and 5-FU, respectively. These results suggest that UK-21 and UK-25 express their antitumor activity as 5-FUR and 5-FU, respec tively. Neither UK-21 nor UK-25 suppressed thymus weight and humoral antibody production against sheep red blood cells (SRBC) in ddY mice, although 1-(2 tetrahydrofuryl)-5-fluorouracil (FT-207) and 5-FU suppressed them in their respective therapeutic dose ranges for tumors. Thus, UK-21 and UK-25 are expected to develop into anticancer drugs with lower immunotoxicological effects.5-Fluorouracil (5-FU) is an anticancer agent that was first synthesized in 1957 (1). 5-FU is widely used for many types of cancer because it has a suppressive effect on a wide spectrum of cancers; and it is even effective against car cinomas of the stomach, intestine, breast and other adenocarcinomas, which are relatively resistant to chemotherapy.It is well-known that a metabolite of 5-FU, 5-fluorodeoxyuridine monophosphate (5 FdUMP), exerts its antitumor activity mainly through competitive antimetabolic action against thymidylate synthetase in DNA synth esis (2), although another metabolite, 5 fluorouridine triphosphate (5-FUTP), exerts its cytotoxic action by being incorporated into RNA or inhibiting the synthesis of uridine (3 5). It is also known that tumor cells are most sensitive to 5-FU from the G1 phase to the S phase of the cell proliferation cycle, because the main mode of action of 5-FU is as an anti metabolite as mentioned above. Thus, a better

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Enhanced therapeutic efficacy of 5'deoxy-5-fluorouridine in 5-fluorouracil resistant head and neck tumours in relation to 5-fluorouracil metabolising enzymes

Cited by 35 publications

References 21 publications

Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity

Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity

Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity

Novel Derivatives of 5-Fluorouridine and 5-Fluorouracil Having Potent Antitumor and Lower Immunosuppressive Activities.

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