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PubMed2004

Adjuvant chemotherapy in curative resected colon carcinoma: 5-fluorouracil/leucovorin versus high-dose 5-fluorouracil 24-h infusion/leucovorin versus high-dose 5-fluorouracil 24-h infusion.

BACKGROUND: Adjuvant postoperative treatment with 5-fluorouracil (5-FU) and leucovorin in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. The impact of continuous 5-FU with and without leucovorin on survival and tumor recurrence was analyzed in this study compared with the effects of bolus 5-FU/leucovorin. PATIENTS AND METHODS: Patients with a curatively resected UICC stage III colon cancer were stratified according to T, N and G category and randomly assigned to receive one of the three adjuvant treatment schemes: 5-FU 450 mg/m2 and leucovorin 100 mg/m2 x 5 days every 4 weeks; six cycles, arm A; 24-h infusion of high-dose 5-FU/leucovorin 2,600 mg/m2 and 500 mg/m2, two cycles of six applications, arm B; 24-h infusion of high-dose 5-FU 2,600 mg/m2, two cycles of six applications, arm C. RESULTS: One hundred and forty-five patients enrolled into this study were eligible. To date, 28 patients have died; 9 on arm A, 11 on arm B, and 8 on arm C (P was nonsignificant). After a median follow-up time of 45 months, there was no statistical difference in survival and tumor recurrence between the three treatment arms. Adjuvant treatment in all arms was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSION: There is no statistical difference in efficacy and toxicity in patients receiving either high-dose 5-FU with or without leucovorin or the standard 5-FU bolus regime after a curative resection of a stage III colon cancer.

Adenocarcinoma↗
PubMed1998

5-Fluorouracil plus interferon alpha-2a compared to 5-fluorouracil alone in the treatment of advanced colon carcinoma: a multicentric randomized study.

Biochemical modulation is one of the most interesting fields in cancer chemotherapy. Interferon-alpha (IFNalpha) is a cytokine that is able to influence the pharmacodynamics of 5-fluorouracil (5FU) through a number of mechanisms. With the aim of confirming some data emerging from the literature, we initiated a multicentric randomized study comparing the combination of 5FU and IFNalpha-2a with 5FU alone in the treatment of advanced or metastatic colon cancer. A group of 205 colon cancer patients (104 in the 5FU arm and 101 in the 5FU + IFNapha-2a arm) were included in the final intention-to-treat analysis. Rectal cancers were not considered eligible. All patients had measurable disease, were aged 75 years or less, had a Karnofsky index of at least 60 and had good bone marrow, renal, liver and cardiac functions. No previous chemo-immunotherapy was allowed. The treatment was 750 mg/m2 5FU (4 h i.v. infusion) on days 1 5 and then i.v. bolus weekly, starting from day 12, with or without IFNalpha-2a given s.c. three times weekly (starting dose 3 x 10(6) IU rising to 9 x 10(6) IU, if tolerated). Patients were treated until progression or, if responsive, for a maximum of 48 weeks and then observed for a period of 2 years. The primary end-point of the study was objective clinical response (OR); secondary parameters were time to progression, overall survival, and time to death after progression. WHO criteria were used for both clinical response and toxicity measurements. Dose reduction was planned a priori in the event of significant toxicity due to 5FU, IFNalpha-2a or both. Association between primary and secondary end-points and treatment was studied by univariate and multivariate analysis. Altogether, 47 patients achieved a documented response. A 25% OR was observed in the combination arm while a 21% OR was seen in the 5FU arm; this difference is not statistically significant (P = 0.6). Patients with a small tumour burden (below 5 cm2) showed a higher probability of response in both arms. Patients in the experimental arm had a higher but not statistically significant cumulative progression-free probability. Median survival was 47.1 weeks overall, while it was 43.7 and 48.5 weeks in the control and experimental arms, respectively. The combination was clearly more toxic than 5FU alone, leukopenia being the most frequent side-effect in the experimental arm and nausea and vomiting in the control arm. In conclusion these results are quite disappointing and 5FU + IFNalpha-2a can not be considered a standard treatment for advanced colon cancer.

Aged↗
PubMed1986

The increased cytotoxicity in colon adenocarcinoma of methotrexate-5-fluorouracil is not associated with increased induction of lesions in DNA by 5-fluorouracil.

Sequential methotrexate-5-fluorouracil (Mtx-5-Fu) reduces proliferation of human colon adenocarcinoma cells. The DNA of treated cells was examined by cell lysis in dilute alkali in order to detect if there is any release of single-stranded DNA fragments, which occurs in cells treated with 5-Fu. The results showed that in spite of increased cytotoxicity of Mtx-5-Fu there is reduced release of DNA fragments. The findings are paralleled by a reduced incorporation of 5-Fu into DNA. Hypoxanthine reduces the growth inhibitory effect of Mtx-5-Fu. In treated cells grown in the presence of hypoxanthine, alkaline lysis causes release of DNA fragments from bulk DNA, in contrast to cells grown without hypoxanthine. Hence, the increased cytotoxicity of Mtx-5-Fu in human colon adenocarcinoma is not associated with enhanced lesions in DNA by 5-Fu.

Adenocarcinoma↗
PubMed1988

Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5-fluorouracil against adenocarcinoma 755 in mice. Increased therapeutic index and correlation with increased plasma 5-fluorouracil levels.

A marked inhibition of the growth of solid tumor adenocarcinoma 755 was achieved by the combination of 5-fluorouracil (5-FU) with bromovinyldeoxyuridine (BVDU). The therapeutic index (LD50/ED50) for the combination of BVDU plus 5-FU was 8.1 and 3.9 upon intraperitoneal (i.p.) or oral (p.o.) administration, respectively. The therapeutic index of i.p. 5-FU given alone was 2.3, whereas for p.o. 5-FU given alone no therapeutic index could be established because of insufficient activity of the compound. Thus, the therapeutic index of 5-FU increased significantly when combined with BVDU. Pharmacokinetic studies revealed that upon i.p. or p.o. 5-FU administration plasma 5-FU levels rapidly declined, but that, in the combination with BVDU, the plasma clearance of 5-FU, especially following p.o. administration, was slowed down considerably. Antitumor activity of 5-FU correlated with AUC (area under the concentration x time curve), within the plasma 5-FU concentration range from 0.02 to 0.4 microgram/ml.

Adenocarcinoma↗
PubMed1984

Separation of several 5-fluorouracil metabolites in various melanoma cell lines. Evidence for the synthesis of 5-fluorouracil-nucleotide sugars.

5-Fluorouracil (5FU) metabolism was studied in intact cancer cells kept in suspension by incubation with tritiated 5FU. Metabolites were analyzed using various chromatographic procedures, including a one-directional separation on PEI-cellulose sheets, which separated 5FU from the mono-, di- and triphosphate forms and from nucleotide sugars. The monophosphate ester was present as FdUMP, as could be demonstrated with another chromatographic procedure. In the human melanoma cell lines IGR3 and M5 the main metabolite of 5FU was 5-fluorouridine, while in the murine B16 melanoma only a small amount of 5-fluorouridine was formed. In B16 cells more 5FU label was present as the triphosphate ester while in M5 cells more FdUMP was formed. With all three cell lines 5FU was incorporated into RNA; this incorporation was stimulated by 1 mM N-(phosphonacetyl)-L-aspartate (PALA). PALA did not significantly affect the conversion of 5FU into other metabolites, nor did it affect the incorporation of 5FU into DNA. A 5FU-nucleotide sugar, present as the diphosphate-glucose, was a predominant 5FU-metabolite in M5 cells but not in the other cell lines. Its identity was confirmed by thin-layer chromatography and high-performance liquid chromatography. Its possible function is discussed.

Animals↗
PubMed1989

Lack of effectiveness of combined 5-fluorouracil and leucovorin in patients with 5-fluorouracil-resistant advanced colorectal cancer.

Favorable results have been reported for the treatment of advanced colorectal cancer with the combination of 5-fluorouracil (5-FU) and leucovorin (LV). In these investigations the highest response rates were obtained in non-pretreated patients. In the present study, 22 patients with primary or acquired resistance to single-agent 5-FU and documented progressive disease on 5-FU were given a bolus injection of LV at a dose of 200 mg/m2, 1 h prior to a 2 h infusion of 5-FU at a dose of 370-770 mg/m2 on 5 consecutive days, and this was repeated every 3 weeks. Whenever possible the dose of 5-FU was escalated to find the maximum tolerable dose. No objective response was observed. Five patients had short-lasting stable disease. Despite 5-FU dose escalation, toxicity was acceptable. One patient developed 5-FU-related angina pectoris with EKG changes. It is concluded that in the schedule used, combined LV/5-FU treatment is ineffective for patients with 5-FU-resistant advanced colorectal cancer.

Adult↗
PubMed1996

18F-radiopharmacokinetics of [18F]-5-fluorouracil in a mouse bearing two colon tumors with a different 5-fluorouracil sensitivity: a study for a correlation with oncological results.

The tissue distribution and biodynamics of 18F-labelled 5-fluorouracil (FU) are described and studied for correlation with its in vivo antitumor activity. The in vivo model consisted of Balb/c mice bearing a FU sensitive (Colon 26-10 carcinoma) tumor in the left and a less responsive (Colon 26 carcinoma) tumor in the right abdominal side of the animal. Distribution and efflux of 18F-label from tumor, blood, and other tissues were determined by obduction at 0.5, 1, 2, 4, and 6 h postintravenous injection. For a comparison, the 18F-labeled 5-fluoro-6-hydroxy and cis-5-fluoro-6-ethoxy uracil adducts were studied in the same in vivo model. For 18F-FU it was found that the 18F-label tumor kinetics rapidly fell into a biphasic mode: a relatively short 18F beta phase (18F t1/2 beta 21 +/- 3 min), linked with the total body metabolic capacity and clearance of the animal, and a longer 18F gamma phase, linked with the intrinsic intratumoral FU metabolism (Colon 26-10: 18F t1/2 gamma 10.3 h; Colon 26: 18F t1/2 gamma 5.6 h). It is proposed that the observed faster 18F efflux of the less responsive Colon 26 corresponds to an enhanced breakdown of 5-fluoronucleotides to 5-fluoronucleosides and subsequent elimination from the tumor cells. It is concluded that on PET scanning, measurement of the dynamic 18F t1/2 gamma and 18F t1/2 beta parameter is of prime importance for an insight in the in vivo tumor biology of a patient.

Animals↗
PubMed1984

Effects of 5-fluorouracil and the combination of 5-fluorouracil and human leukocyte interferon on human salivary gland adenocarcinoma cell line in culture.

The growth inhibitory effects of 5-fluorouracil (5-Fu) and the combination of 5-Fu and human leukocyte interferon (HuIFN-alpha) on the human salivary gland adenocarcinoma cell line HSG in culture were examined by measuring colony formation in the semi-solid agar medium and cell proliferation in the monolayer culture. As a consequence, the colony-forming ability of HSG cells in the agar medium containing 5-Fu was found to be markedly inhibited as compared with the untreated control. The concentration of 5-Fu yielding 50% inhibition of colony-forming ability of HSG cells under the presence of 5-Fu was 0.08 micrograms/ml. When the growth inhibitory effects of the combination of 5-Fu and HuIFN-alpha on HSG cells were examined, the colony forming ability of HSG cells was synergistically inhibited, whereas effects of the combined treatment on HSG cells in the monolayer culture were less sensitive than those on the colony formation. These findings strongly suggest that the combination of 5-Fu and HuIFN-alpha or 5-Fu alone is selectively effective on the neoplastic cells of HSG cell population but not on the non-neoplastic cells.

Adenocarcinoma↗
PubMed1997

Nocturnal 5-fluorouracil infusion to patients with breast cancer prior to surgery: appearance of 5-fluorouracil-induced AgNORs aggregation (FAA).

Between 1994 and 1995, 1 day nocturnal infusion of 5-fluorouracil (5-FU) was performed prior to surgery in 13 primary breast cancer patients; 300 mg/m2 of 5-FU was infused constantly from 2100 h to 0700 h via peripheral vein with a volumetric pump. 5-FU concentration in tissues was measured within surgical specimens by HPLC. The concentrations of 5-FU in tumor tissues ranged from 6 to 49 ng/g (average +/- SEM 25.0 +/- 4.1 ng/g), while in normal breast tissues and adipose tissues 5-FU was below the detection limit (<3 ng/g). The 5-FU concentration was lower in estrogen-receptor-positive tumors (14.4 +/- 4.5 ng/g) than in estrogen-receptor-negative tumors (31.8 +/- 5.0 ng/g). Typical FAA was observed in the tumor tissues of three patients. In these three cases, AgNORs were aggregated to one large spheroidal figure in more than 39% of tumor cells. Appearance of FAA could not be predicted by other clinical features. Nocturnal 5-FU infusion caused FAA changes in certain types of primary breast cancer.

Aged↗
PubMed2001

In vivo evaluation of a novel antitumor prodrug, 1-(2'-oxopropyl)-5-fluorouracil (OFU001), which releases 5-fluorouracil upon hypoxic irradiation.

PURPOSE: We previously proposed that a prodrug of 5-fluorouracil (5-FU), OFU001, is activated through capturing of hydrated electrons produced by hypoxic irradiation. Because hydrated electrons are readily deactivated by oxygen, the 5-FU release occurs specifically upon hypoxic irradiation. In this study, we investigated the in vivo efficacy, pharmacokinetics, and toxicity of OFU001. METHODS AND MATERIALS: Female 10-week-old C3H/He mice bearing SCCVII tumors were used. To measure release of 5-FU from OFU001 in vivo, the mice were given 100 mg/kg of OFU001 intraperitoneally and irradiated. Thereafter, 5-FU levels in the tumor and serum were measured by high-performance liquid chromatography. To evaluate in vivo efficacy, OFU001 was administered 30 min before irradiation, and radiation-potentiating effects were investigated by means of a tumor growth delay assay and a 50% tumor control dose (TCD-50) assay. The lethal dose of OFU001 was evaluated in the same mice. RESULTS: Following administration of OFU001 and irradiation at 30 Gy, the average 5-FU levels in the tumor and serum were 179 ng/g and 83 ng/mL, respectively. Administration of OFU001 (100-200 mg/kg) to the tumor-bearing mice before a single dose of 15-Gy irradiation produced a mean tumor growth delay of 1-5 days as compared to radiation alone (although the delay was not significant). However, no additional growth delay was observed when OFU001 was combined with 5 radiation fractions of 4 Gy each. The enhancement ratio of OFU001 in the TCD-50 assay was 1.2. No mice died after administration of 0.6-1.2 g/kg of OFU001. CONCLUSIONS: OFU001 appears to work in vivo via the proposed mechanism of activation. Although the in vivo effect of this compound was not strong enough for clinical efficacy, these results should encourage further research on the development of prodrugs of more potent anticancer agents activated through the same mechanism.

Animals↗
PubMed2002

Results of a randomised phase II study of cisplatin plus 5-fluorouracil versus cisplatin plus 5-fluorouracil with alpha-interferon in metastatic pancreatic cancer: an EORTC gastrointestinal tract cancer group trial.

A randomised phase II study of 5-fluorouracil (5-FU) plus cisplatin (CDDP) with or without alpha-interferon 2b was performed in patients with pancreatic cancer with measurable metastatic disease outside the pancreas. The treatment in arm A consisted of cisplatin (100 mg/m(2)) on day 1, followed by a continuous infusion of 5-FU 1000 mg/m(2) for 4 days and in arm B the same treatment was given plus alpha-interferon 2b in a dose of 3 million Units/day subcutaneously (s.c.) from day 1 for 5 days. 36 patients were entered in the trial, 18 in each arm. In arm B only 15 patients were eligible. No responses were observed in the 5-FU/CDDP arm and only 2 partial responses were achieved in the interferon-arm, lasting 27 and 32 weeks, respectively. Both treatment arms showed considerable toxicity. It has to be concluded that both treatment regimens have little activity and cannot be recommended.

Adenocarcinoma↗
PubMed1999

Phase III trial of cyclophosphamide, epirubicin, fluorouracil (CEF) versus cyclophosphamide, mitoxantrone, fluorouracil (CNF) in women with metastatic breast cancer.

BACKGROUND: The mitoxantrone combination CNF and the epirubicin combination CEF have shown similar activity and less toxicity than the standard CAF combination in metastatic breast cancer (MBC). A prospective randomised study was started to compare safety and activity between CEF and CNF administered using a classical chemotherapeutic schedule in MBC. PATIENTS AND METHODS: From December 1987 to June 1993, 151 patients were randomised to receive cyclophosphamide (C) 100 mg m(-2) p.o. days 1-14, fluorouracil (F) 500 mg m(-2) i.v. days 1 and 8, and epirubicin (E) 30 mg m(-2) i.v. days 1 and 8, or mitoxantrone (N) 6 mg m(-2) i.v. days 1 and 8, every 4 weeks. Seventy-three patients were eligible for CEF and 72 for CNF. RESULTS: Objective responses were observed in 61.6% of the CEF group and 44.4% in CNF group (p = 0.004). The median duration of response was 64 weeks in CEF and 50 weeks in CNF group (p = 0.02) and median time to progression was 51 and 33 weeks, respectively (p = 0.0004). At the time of analysis, all except six patients (one in CNF and five in CEF) had died and the median survival time in the CEF group was longer than in CNF (74.4 weeks vs 51.4 weeks; log-rank chi2 test p = 0.015). CNF produced more hematologic toxicity than CEF (WHO scale; grades 2-4); leucopenia 84% vs 68% (p = 0.03) and thrombocytopenia 17% vs 4.5% (p = 0.01); CEF caused more grade 2 and 3 alopecia: 93% vs 70% (p = 0.001). CONCLUSION: The combination CEF using this schedule and dosage in metastatic breast cancer is more effective with less toxicity than CNF, except for alopecia, and was associated with longer survival.

Aged↗
PubMed1998

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study.

PURPOSE: The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 306 patients were randomized to receive either 5-FU 425 mg/m2 given by bolus injection on days 1-5 plus intravenous (i.v.) LV 20 mg/m2 every four to five weeks or 5-FU 3.5 g/m2/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms. RESULTS: The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3-4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm. CONCLUSIONS: In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3-4 toxicity.

Adult↗
PubMed1999

Postoperative radiation and concomitant bolus fluorouracil with or without additional chemotherapy with fluorouracil and high-dose leucovorin in patients with high-risk rectal cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group.

BACKGROUND: Randomized studies have shown that postoperative chemotherapy with or without radiation therapy (RT) improved local control and survival of patients with stages II or III rectal cancer. However, the optimal sequence of treatments and the optimal chemotherapeutic regimen have not been defined. Modulation of fluorouracil (FU) by leucovorin (LV) has yielded a highly significant difference in response rate from that of FU monotherapy, as suggested by an overview of randomized trials in patients with advanced colorectal cancer. However, this difference in response rate did not translate into a survival benefit. PURPOSE: To evaluate the impact on the disease-free survival (DFS) and overall survival (OS) of patients with stages II or III rectal cancer of postoperative RT and concomitant bolus FU administration alone or with additional chemotherapy using FU and high-dose LV. PATIENTS AND METHODS: From October 1989 until February 1997, 220 patients were randomized postoperatively to receive either one cycle of chemotherapy with FU (600 mg/m2/week x 6 followed by a two-week rest) and leucovorin (LV, 500 mg/m2/week x 6 as a two-hour infusion) followed by pelvic RT with concomitant FU (400 mg/m2) as a rapid intravenous injection during the first three and last three days of RT, and three more cycles of the same chemotherapy with FU and LV (standard, group A, 111 patients) or pelvic RT with concomitant FU only (experimental, group B, 109 patients). RESULTS: As of August 1998, after a median follow-up of 4.9 years, there was no significant difference in either three-year DFS (Group A, 70.3%; group B, 68.2%, P = 0.53) or OS (group A, 77%; group B, 73.3%. P = 0.75). Cox multivariate analysis revealed stage of disease, number of infiltrated nodes, tumor grade, presence of regional implants and perforation to be significant prognostic factors. The incidence of severe side effects was significantly higher in the patients in group A than in those in group B (32.4% vs. 4.6%, P < 0.0001). CONCLUSIONS: The incorporation of additional chemotherapy with FU and LV into postoperative concomitant RT and bolus infusion of FU does not offer a > or = 10% three-year survival benefit over that of concomitant RT and bolus infusion of FU, and significantly increases toxicity in patients with stages II or III rectal cancer.

Adult↗
PubMed1998

Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen.

BACKGROUND: FOLFOX2, a bimonthly regimen of high-dose leucovorin (LV), 48-hour continuous infusion of 5-fluorouracil (5-FU) (LV-5-FU) and oxaliplatin (100 mg/m2) produced a high response rate (46%; 95% confidence interval (95% CI): 31%-60%) in 5-FU pre-treated patients with metastatic colorectal cancer. In this phase II study, pre-treated patients were given a lower dose of oxaliplatin to reduce the toxic effects of the regimen. PATIENTS AND METHODS: Thirty patients with advanced colorectal adenocarcinoma and progression while receiving bimonthly LV-5-FU (LV: 500 mg/m2, 5-FU: 1.5-2 g/m2/22 hours, days 1-2, every two weeks), were given the same LV-5-FU schedule with the addition of oxaliplatin (85 mg/m2) every two weeks (FOLFOX3). RESULTS: The main toxic effects were peripheral neuropathy (90%) with four severe sensitive neuropathies (WHO grade 2: 13%). The response rate was 20% (95% CI: 8%-39%). Median progression-free survival was 26 weeks, median survival was 57 weeks from the start of FOLFOX3 and median duration of the response was 37 weeks. CONCLUSIONS: Results obtained with FOLFOX3 confirmed the synergy between oxaliplatin and 5-FU in 5-FU-resistant metastatic colorectal cancer. However, the response rate seems to be lower than that obtained with FOLFOX2. Further studies to determine the best oxaliplatin dose intensity are in progress.

Adenocarcinoma↗
PubMed1977

In vivo cell synchrony in the L1210 mouse leukaemia studied with 5-fluorouracil or 5-fluorouracil followed by cold thymidine infusion.

[3H]-TdR and [3]-udR labelling indices and mitotic indices were followed in tumour-bearing mice after application of either 5-fluorouracil (FU) alone or of FU followed by cold TdR infusion. With FU alone, accumulation of cells at the beginning of S was found, but there was no indication of a synchronous passage of the accumulated cells further round the cycle. When FU injection was followed by cold TdR infusion, a synchronous passage of the accumulated cells through the cycle was observed. However, there was a large variation in the response of individual mice to this treatment.

Animals↗
PubMed1989

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

Four human head and neck xenograft (HNX) tumour lines grown in nude mice and two murine colon carcinomas (Colon 26 and 38) were tested for their sensitivity to 5-fluorouracil (5-FU) and its prodrug 5'deoxy-5-fluorouridine (Doxifluridine, 5'd-FUR). 5-FU sensitivity at the maximum tolerated dose (MTD) showed the following pattern; HNX-DU less than HNX-KE = HNX-E = HNX-G less than Colon 26 much less than Colon 38. The sensitivity pattern to 5'd-FUR was: HNX-DU less than HNX-G less than HNX-E less than HNX-KE less than Colon 38 less than Colon 26. For HNX-KE, HNX-E and Colon 26 an increase in therapeutic efficacy was observed with 5'd-FUR as compared to 5-FU; Colon 38 was as sensitive to 5'd-FUR as to 5-FU. Plasma pharmacokinetics of 5'd-FUR and 5-FU were comparable in normal and nude mice. Metabolism of 5-FU and 5'd-FUR was studied in the tumours. Conversion of 5'd-FUR to 5-FU was highest in Colon 26 and 15-20 times lower in HNX-DU, HNX-KE and Colon 38. The Km for 5'd-FUR in all tumours was 1-2 mM. Further anabolism of 5-FU to fluorouridine (FUR) was 5-10 times higher than that of 5-FU to FUR in HNX tumours and 3 times in the colon tumours. 5-FU conversion to FUMP via FUR had the following pattern: Colon 26 much greater than HNX-DU greater than HNX-G greater than HNX-E greater than HNX-KE much greater than Colon 38; of 5-FU to FdUMP via FUdR: Colon 26 greater than HNX-DU = HNX-KE greater than HNX-E greater than HNX-G = Colon 38; and that of 5-FU to FUMP catalysed by orotate phosphoribosyl transferase (OPRT); Colon 26 greater than or equal to Colon 38 greater than HNX-KE greater than HNX-E = HNX-DU = HNX-G. Only those tumours with a relatively high activity of OPRT were sensitive to 5'd-FUR. Colon 26, which has a very high rate of pyrimidine nucleoside phosphorylase, showed a relatively high increase in the therapeutic efficacy. It is concluded that a low rate of pyrimidine nucleoside phosphorylase is enough to convert 5'd-FUR to 5-FU; further anabolism of 5-FU catalysed by OPRT may be limiting and explain the differential sensitivity.

Animals↗
PubMed1994

The effect of 5-fluorouracil and alpha interferon and 5-fluorouracil and leucovorin on cellular anti-tumour immune responses in patients with advanced colorectal cancer.

Interferon alpha (IFN-alpha) enhances the activity of 5-fluorouracil (5-FU) in the treatment of advanced colorectal cancer although the mechanism is not understood. We have investigated the effect of this combination on cellular immunity and compared this with standard therapy of 5-FU/L-leucovorin, in 24 patients with advanced colorectal cancer. This study has demonstrated an enhancement of the cellular immune response in patients given 5-FU/IFN-alpha with augmentation of natural killer (NK) cell function and abrogation of 5-FU-induced suppression of lymphokine-activated killer (LAK) cell activity.

Adult↗