Effect of uridine coadministration on 5′-deoxy-5-fluorouridine disposition in rats

Summary Uridine (UR) inhibits the metabolic activation of 5-deoxy-5-fluorouridine (dFUR) to 5-fluorouracil (FU) by the intestinal pyrimidine nucleoside phosphorylases and could potentially reduce its intestinal toxicity. This study examined the effect of UR coadministration on the absorption and disposition of an oral dose of dFUR. Rats were given dFUR alone (500 mg kg^-1) and dFUR (300 mg kg^-1) plus UR (4.5 g kg^-1) in a random crossover experiment. Simultaneous injection of a tracer dose of [6-³H]dFUR was used to asses the total body clearance (Cl) of dFUR. The absorption of UR was rapid and variable. The UR dose produced a maximal blood concentration of 80 g/ml for UR and 100 g/ml for its metabolite uracil (U). The absorption of dFUR was slower than UR, as indicated by its later time of maximal concentration. UR did not alter the Cl of dFUR, but reduced the absorption rate of dFUR from the gastrointestinal tract and significantly reduced the absolute oral bioavailability of dFUR from 55.2% to 33.4%. The effects of UR coadministration on the dFUR metabolite FU were opposite to those on dFUR; the FU availability was increased sixfold, and the elimination of FU was reduced. Based on the known competition between pyrimidine bases for their saturable metabolic enzymes, the increase in FU availability by UR coadministration was likely due to a competitive inhibition of FU metabolism by U. This study established the complex pharmacokinetic interactions between dFUR and UR and between their metabolites, which may be important in the modulation of dFUR activity by UR.Supported in part by research grants CA-37110, CA-43365 and P30CA16058-12 from the National Cancer Institute, USPHS     

Comparative antitumor activity of ruthenium derivatives with 5′-deoxy-5-fluorouridine in chemically induced colorectal tumors in SD rats

Summary The activity of the newly synthesized ruthenium derivative imidazolium-bis(imidazole)tetrachlororuthenate (III) [ImH(RuIm₂Cl₄)] was compared with that of 5-deoxy-5-fluorouridine (5dFUR) in autochthonous acetoxymethyl-methylnitrosamine (AMMN)-induced colorectal cancer in SD rats. Following coloscopic diagnosis of colorectal tumors treatment was administered twice weekly for a 10-week period. ImH(RuIm₂Cl₄) exhibited considerable antitumoral efficacy compared with 5dFUR (20 T/C % and 60 T/C %, respectively) against the growth of AMMN-induced colorectal adenocarcinoma in SD rats. The mortality rates with ImH(RuIm₂Cl₄) were dose-related, but its efficacy did not vary in all doses administered.     

New approach to metabolism of 5′-deoxy-5-fluorouridine in humans with fluorine-19 NMR

Summary The metabolism of 5-deoxy-5-fluorouridine (5dFUrd), an antitumor fluoropyrimidine, has been investigated in human biofluids (blood, plasma, urine) using a new method: fluorine-19 NMR spectrometry. This method allows direct study of the biological sample and simultaneous identification of all the fluorinated metabolites. In the blood of a patient treated with 5dFUrd during a 6-h continuous perfusion, we observed unmetabolized 5dFUrd, 5-fluorouracil, 5,6-dihydrofluorouracil, and another metabolite which has not previously been reported -fluoro--alanine. The two major metabolites in urine are unmetabolized 5dFUrd and -fluoro-alanine.     

Concurrent allopurinol and 5-fluorouracil: 5-fluoro-2′-deoxyuridylate formation and thymidylate synthase inhibition in rat colon carcinoma and in regenerating rat liver

Summary The formation of FdUMP and the inhibition of TS were studied in a subcutaneously growing transplantable rat colon carcinoma and in regenerating rat liver following bolus administration of 5-FU, with or without HPP pretreatment.In tumor, peak levels of FdUMP at 30 min following bolus 5-FU, 100 mg/kg, averaged 4931±587 pmol/g. Pretreatment with HPP, 50 mg/kg, 24 h and 1 h before 5-FU, reduced the peak FdUMP level to 2085±387 pmol/g. The inhibition of TS by 5-FU treatment was greater than 95% by 30 min, and after 48 h residual enzyme inhibition averaged 40%. No effect on TS inhibition by 5-FU treatment could be observed as a result of HPP pretreatment. The levels of TS_tot increased linearly after 5-FU treatment and doubled within 48 h.In regenerating rat liver, neither FdUMP levels nor TS inhibition, studied at 1 h after bolus 5-FU, were affected by HPP pretreatment.Abbreviations BSA bovine serum albumin - DMH dimethylhydrazine - 5-FU 5-fluorouracil - HPP allopurinol (4-hydroxypyrazolopyrimidine) - CH₂FH₄ 5, 10-methylenepteroylmonoglutamic acid - FUMP 5-fluorouridine-5-monophosphate - FUTP 5-fluorouridine-5-triphosphate - FdUMP 5-fluoro-2-deoxyuridylate - TS thymidylate synthase (EC 2.1.1.45, dTMP synthase) - TS_f free, non-FdUMP-bound TS - TS_b ternary complex-bound TS - TS_tot total TS TS_f+TS_b - PRPP phosphoribosylpyrophosphate This study was supported by grants from the Swedish Cancer Society, The Medical Society of Göteborg, the University of Göteborg, the Wellcome Foundation, and NCI Grant 39629.     

Fibulin-5 inhibits Wnt/β-catenin signaling in lung cancer

Metastatic lung cancer is incurable and a leading cause of cancer death in the United States. However, the molecular mechanism by which lung cancer cells invade other tissues has remained unclear. We previously identified fibulin-5, an extracellular matrix protein, as a frequently silenced gene in lung cancer and a suppressor of cell invasion. In this study, we found fibulin-5 functions by inhibiting the Wnt/β-catenin pathway. The Cancer Genome Atlas (TCGA) datasets show a strong association between loss of fibulin-5 expression and poor outcomes of lung cancer patients, and also activation of the Wnt target genes MMP-7 and c-Myc. Fibulin-5 impedes Wnt/β-catenin signaling by inhibiting extracellular signal-regulated kinase (ERK) to activate glycogen synthase kinase-3 β (GSK3β), which downregulates β-catenin and prevents its nuclear accumulation, leading to suppression of MMP-7 and c-Myc expression. These effects of fibulin-5 are mediated by its amino-terminal integrin-binding RGD motif. Fibulin-5 also blocks Wnt/β-catenin signaling in vivo in H460 metastasis and H1299 tumor models. Furthermore, knockdown of β-catenin suppresses metastasis of H460 tumors, while knockdown of GSK3β promotes metastasis of fibulin-5-expressing H1752 tumors. Together, our results suggest that fibulin-5 functions as a metastasis suppressor in lung cancer by modulating tumor microenvironment to suppress Wnt/β-catenin signaling.     

Combination of interferon-α and 5-fluorouracil induces apoptosis through mitochondrial pathway in hepatocellular carcinoma in vitro

Many clinical reports have proven that the combination therapy of interferon-alpha plus 5-fluorouracil is remarkably effective for advanced hepatocellular carcinoma (HCC). However, the mechanism of this therapy is not well understood. Here, we demonstrated that the combination therapy synergistically inhibited the growth of Fas-negative HCC cells, arrested cell-cycle progression and induced apoptosis. Moreover, the combination therapy significantly increased the protein expression of caspase-8, activated Bid and cytochrome c. Meanwhile, the expression of anti-apoptotic gene Bcl-xL was reduced and intracellular calcium elevated obviously during the early stage of treatment. Therefore, mitochondrial pathway was involved in the apoptosis of Fas-negative HCC cells induced by IFN-α/5-FU and Ca(2+) partially promoted the beneficial effect against HCC.     

Potentiation of the chemotherapeutic action of 5′-deoxy-5-fluorouridine in combination with guanosine and related compounds

Summary The effect of inosine, guanosine, and guanosine 5-monophosphate (GMP) on the antitumor activity of 5-deoxy-5-fluorouridine (5-DFUR) was investigated using P388 leukemia and P815 mastocytoma.The antitumor activity of 5-DFUR was markedly enhanced by coadministration of inosine or guanosine. The increase in lifespan (ILS) of mice treated with 5-DFUR was augmented by the combination with guanosine or inosine in a dose-dependent fashion, and the maximum ILS was about 160% with the combination, while that in the case of 5-DFUR alone was only 48% in the P388 leukemia system. The therapeutic ratio (dose at ILS_max/dose at ILS₃₀) of the combination with guanosine or inosine was 333 and 136, respectively, whereas that of 5-DFUR alone was 3.6. GMP also markedly potentiated the antitumor activity of 5-DFUR in both P388 leukemia and P815 mastocytoma systems, just as it potentiated the activity of 5-fluorouracil in the latter system.The uric acid level in the serum was elevated after IP injection of guanosine or inosine but the value was much lower in the case of guanosine than in inosine.     

A pivotal role of Krüppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma

In hepatocellular carcinoma (HCC), there exists a highly tumorigenic subset of cells defined by high expression of CD44 and CD133 that has been reported to contain cancer stem-like cells (CSCs). Krüppel-like factor 5 (KLF5) regulates many factors involved in cell cycle, migration, inflammation, angiogenesis and stemness and has cancer-promoting effects in some cancers. While some reports have indicated that KLF5 may have important roles in regulation of CSCs, what role, if any, KLF5 plays in regulation of CSCs in HCC remains to be elucidated. Flow cytometric analysis of CD44 and CD133 in HCC cell lines revealed subpopulations of CD44^High/CD133^High and CD44^Low/CD133^Low cells. We subsequently sorted these subpopulations and identified KLF5 as a gene that is significantly upregulated in CD44^High/CD44^High cells via RNA sequencing using next generation sequencing technology. Moreover, KLF5 overexpression enriched the CD44^High/CD133^High subpopulation and, consistent with the up-regulation of CD44^High/CD133^High cells, KLF5 overexpressing cells were more resistant to anti-cancer drugs and displayed enhanced colony-formation capacity. By contrast, knock-down of KLF5 by siRNA diminished the CD44^High/CD133^High subpopulation. When KLF5 was acetylated by TGF-β1, the KLF5-mediated CD44^High/CD133^High subpopulation enrichment was abrogated. Oppositely, ectopic expression of an acetylation-deficient KLF5 mutant further increased CD44^High/CD133^High subpopulations as compared to cell expressing wild-type KLF5. These findings provide novel mechanistic insight into a pivotal role for KLF5 in the regulation of CSCs in HCC.     

Doxifluridine (5′-dFUrd) in patients with advanced colorectal carcinoma

Summary Infusion of 5-dFUrd (2.0–3.0 g/m² over 1 h on days 1–5 every 3rd week) resulted in one partial response in 21 patients with advanced and progressing colorectal cancer. No patient had received chemotherapy before the 5-dFUrd trial. Hematological and gastrointestinal toxicity were generally mild. In 4 patients peripheral neurotoxicity was diagnosed during treatment, whereas transient cerebellopathy was observed in one. Cardiac side effects (repeated angina pectoris following 5-dFUrd infusion) led to discontinuation of treatment after two courses in ont superior to conventional 5-FU treatment in colorectal cancer. Neurological and cardiac side effects are rare but may be a problem in individual patients.     

5-Aminosalicylic acid inhibits TGF-β1 signalling in colorectal cancer cells

The transforming growth factor-β (TGF-β) pathway is an important pathway in the initiation and progression of colorectal cancer. We aimed to determine the effects of 5-aminosalicylic acid (5-ASA) on TGF-β signalling in colorectal cancer cells in vitro. 5-ASA inhibited TGF-β1 signalling in HCT116 cells and colonic fibroblasts, as judged by a TGF-β-specific reporter gene assay, plasminogen activator inhibitor-1 mRNA and protein levels, fibroblast trans-differentiation, Smad3 phosphorylation and nuclear translocation. We conclude that 5-ASA inhibits TGF-β1 signalling in colorectal cancer cells, and might be a potent adjuvant therapeutic drug, interfering with aberrant TGF-β signalling in colorectal cancer.     

Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer

Purpose

Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer and is the most common cause of cancer death in industrialized countries. Epigenetic modifications are observed universally during the tumorigenesis of lung cancer. The development of epigenetic-modulating agents utilizing the synergism between hypomethylating agents and histone deacetylase (HDAC) inhibitors provides a novel therapeutic approach in treating NSCLC.

Methods

We performed a phase I trial combining 5-aza-2′-deoxycytidine (decitabine) and valproic acid (VPA), in patients with advanced stage NSCLC. Patients were treated with escalating doses of decitabine (5–15 mg/m²) IV for 10 days in combination with VPA (10–20 mg/kg/day) PO on days 5–21 of a 28-day cycle. Pharmacokinetic and pharmacodynamic analysis included decitabine pharmacokinetics and fetal hemoglobin expression.

Results

Eight patients were accrued to this phase I study. All patients had advanced NSCLC and had received prior chemotherapy. Eastern Cooperative Oncology Group performance status was 0–2. Major toxicities included myelosuppression and neurotoxicity. Dose-limiting toxicity was seen in two patients suffering grade 3 neurotoxicity during cycle one including disorientation, lethargy, memory loss, and ataxia at dose level 1. One patient had grade 3 neutropenia at the de-escalated dose. No objective response was observed, and stable disease was seen in one patient. Fetal hemoglobin levels increased after cycle one in all seven patients with evaluable results.

Conclusions

We observed that decitabine and valproic acid are an effective combination in reactivating hypermethylated genes as demonstrated by re-expressing fetal hemoglobin. This combination in patients with advanced stage IV NSCLC, however, is limited by unacceptable neurological toxicity at a relatively low dosage. Combining hypomethylating agents with alternative HDAC inhibitors that lack the toxicity of VPA should be explored further.     

Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients?

5-HT₃-receptor antagonists are the current antiemetic gold standard for chemotherapy- and radiotherapy-induced nausea and vomiting. Interestingly, studies have shown that patients experiencing poor control of acute chemotherapy-induced nausea and vomiting with one antiemetic therapy may respond well to another agent, including a drug of the same class. This review examines pharmacological differences between the 5-HT₃-receptor antagonists in order to determine potential reasons for their differing efficacy, particularly in relation to refractory emesis. Differences in drug metabolism by the cytochrome P450 system, inadequate dosing of the respective agents, differences in onset and duration of action, and effects on serotonin release and reuptake are discussed.     

Prognostic Significance of α5β1-integrin Expression in Cervical Cancer

The purpose of this study was to evaluate the association of expression of α5β1-integrin with clinicopathologicfeatures and prognosis in cervical cancer. Levels of α5β1-integrin in normal cervical mucosa and cervicalcancer tissue were detected with immunohistochemistry. Survival analysis by the Kaplan-Meier method wasperformed to assess prognostic significance. α5β1-integrin expression was detected in 84.6% (143/169) cervicalcancer samples, significantly different from that in normal cervical mucosa (P < 0.05). Positive expressionrates of α5β1-integrin in patients with poor histologic differentiation, lymph node metastasis, and recurrencewere elevated. Using Kaplan–Meier analysis, a comparison of survival curves of low versus high expression ofα5β1-integrin revealed a highly significant difference in human cervical cancer cases (P < 0.05), suggesting thatoverexpression of α5β1-integrin is associated with a worse prognosis.The α5β1-integrin promotes angiogenesisand associates with lymph node metastasis, vascular invasion and poor prognosis of cervical cancer. The currentstudy indicated that α5β1-integrin may be an independent prognostic factor for cervical cancer patients.     

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL. However, 5 years later, some issues relating to this disorder still remain including the fact that with ibrutinib only a relatively small proportion of patients achieve complete remission and that ibrutinib-resistant CLL clones can develop in about 20% of patients. In addition, therapy must still be given continuously, and toxicities leading to drug discontinuation occur in about 30% of patients. In the meantime second-generation BTK inhibitors have already aroused considerable interest and gathered momentum. A possible strategy to overcome some of these obstacles is to combine ibrutinib with other targeted agents especially in high-risk disease, such as previously treated refractory patients or those with TP53 aberrations or complex karyotypes, in whom rapid eradication of disease is most desirable. Therapy with single agent ibrutinib should be part of a sequential approach for patients with low risk disease, especially in older patients (aged >70 years) with a higher burden of comorbidities. Long-term results of ongoing studies combining Ibrutinib with (chemo)-immunotherapy or other targeted agents are eagerly awaited. Future clinical trials are indeed still needed to provide answers to these open questions.     

Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5′-deoxy-5-fluorouridine

The present study shows that various cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interferon- (IFN) make tumor cells much more susceptible to the cytostatic 5-deoxy-5-fluorouridine (5-dFUrd) than to 5-fluorouracil (5-FUra) and other cytostaties. These three cytokines increased the susceptibility of human cancer cell lines (COLO201, MKN45 and WiDr) but did not affect that of normal fibroblast WI38 cells. The cytokine mixture induced a 50-fold increase in the susceptibility of COLO201 to 5-dFUrd, whereas a 12-fold increase and a less than 5-fold enhancement in the susceptibility to 5-FUra and other cytostatics, respectively, were observed. The increased susceptibility would be a result of the induction of thymidine phosphorylase (TdR Pase), which is the essential enzyme for the conversion of 5-dFUrd to 5-FUra. The cytokine mixture increased TdR Pase activity by up to 47 times and greatly induced its mRNA expression in the cancer cell lines. These results suggest that the therapeutic benefit of 5-dFUrd would be improved by its use in combination with the cytokines.     

Survival patterns in lung and pleural cancer in Europe 1999–2007: Results from the EUROCARE-5 study

BackgroundSurvival of patients diagnosed with lung and pleura cancer is a relevant health care indicator which is related to the availability and access to early diagnosis and treatment facilities. Aim of this paper is to update lung and pleural cancer survival patterns and time trends in Europe using the EUROCARE-5 database.MethodsData on adults diagnosed with lung and pleural cancer from 87 European cancer registries in 28 countries were analysed. Relative survival (RS) in 2000–2007 by country/region, age and gender, and over time trends in 1999–2007 were estimated.ResultsLung cancer survival is poor everywhere in Europe, with a RS of 39% and 13% at 1 and 5 years since diagnosis, respectively. A geographical variability is present across European areas with a maximum regional difference of 12 and 5 percentage points in 1-year and 5-year RS respectively. Pleural cancer represents 4% of cases included in the present study with 7% 5-year RS overall in Europe. Most pleural cancers (83%) are microscopically verified mesotheliomas. Survival for both cancers decreases with advancing age at diagnosis for both cancers. Slight increasing trends are described for lung cancer. Survival over time is higher for squamous cell carcinoma and adenocarcinomas than for small and large cell carcinoma; and better among women than men.ConclusionsDespite the generalised although slight increase, survival of lung and pleural cancer patients still remains poor in European countries.Priority should be given to prevention, with tobacco control policies across Europe for lung cancer and banning asbestos exposure for pleural cancer, and in early diagnosis and better treatment. The management of mesothelioma needs a multidisciplinary team and standardised health care strategies.     

Expression of laminin 5-γ2 chain in cutaneous squamous cell carcinoma and its role in tumour invasion

Background:

Laminin-5 (Ln5), a heterotrimer composed of three chains (α3, β3, and γ2), is a major component of the basement membrane in most adult tissues. One of the chains, Ln5-γ2, is a marker of invasive tumours because it is frequently expressed as a monomer in malignant tumours. Recent studies from our laboratories detected higher levels of Ln5-γ2 expression in basal cell carcinoma (BCC) than in trichoblastoma. Furthermore, Ln5-γ2 overexpression tended to correlate with aggressiveness in BCC.

Methods:

In this study, we compared the expression of Ln5-γ2 in invasive squamous cell carcinoma (SCC, n=62) of the skin to that in preinvasive Bowen''s disease (BD, n=51), followed by analysis of the role of Ln5-γ2 in cancer invasion in vitro.

Results:

Immunohistochemically, the proportion of SCC cases (86%) strongly positive for Ln5-γ2 expression was higher than that of BD (16%). Real-time RT–PCR showed Ln5-γ2 overexpression in SCC cell line, A431, compared with normal keratinocyte cell line, HaCaT. Ln5-γ2 monomer and proteolytically cleaved, biologically active fragments of Ln5-γ2 were identified in SCC tumour extracts. In in vitro raft cultures, which simulate in vivo conditions, Ln5-γ2 siRNA significantly suppressed epidermal growth factor (EGF)-stimulated A431 cell invasion.

Conclusion:

Our results indicate that Ln5-γ2 has a role in cutaneous SCC invasion.     

Single-nucleotide polymorphism in the 5-α-reductase gene (SRD5A2) is associated with increased prevalence of metabolic syndrome in chemotherapy-treated testicular cancer survivors

PurposeChemotherapy-treated testicular cancer survivors are at risk for development of the metabolic syndrome, especially in case of decreased androgen levels. Polymorphisms in the gene encoding steroid 5-α-reductase type II (SRD5A2) are involved in altered androgen metabolism. We investigated whether single-nucleotide polymorphisms (SNPs) rs523349 (V89L) and rs9282858 (A49T) in SRD5A2 are associated with cardiometabolic status in testicular cancer survivors.MethodsIn 173 chemotherapy-treated testicular cancer survivors, hormone levels and cardiometabolic status were evaluated cross-sectionally (median 5 years [range 3–20] after chemotherapy) and correlated with SNPs in SRD5A2.ResultsThe metabolic syndrome was more prevalent in survivors who were homozygous or heterozygous variant for SRD5A2 rs523349 compared to wild type (33% versus 19%, P = 0.032). In particular, patients with lower testosterone levels (<15 nmol/l) and a variant genotype showed a high prevalence of the metabolic syndrome (66.7%). Mean intima-media thickness of the carotid artery and urinary albumin excretion, both markers of vascular damage, were higher in the group of survivors homozygous or heterozygous variant for rs523349 (0.62 versus 0.57 mm, P = 0.026; 5.6 versus 3.1 mg/24 h, P = 0.017, respectively). No association was found between cardiometabolic status and SNP rs9282858 in SRD5A2.ConclusionMetabolic syndrome develops more frequently in testicular cancer survivors homozygous or heterozygous variant for SNP rs523349 in SRD5A2. Altered androgen sensitivity appears to be involved in the development of adverse metabolic and vascular changes in testicular cancer survivors and is a target for intervention.     

Hepatic arterial 5-fluorouracil in patients with liver metastases of colorectal?cancer: Single-centre experience in 145 patients

Background:Hepatic arterial chemotherapy for liver metastases ofcolorectal cancer is still under discussion. Mainly because of the technicalcomplications of this mode of treatment and the lack of a survival benefit inrandomized studies. We performed an analysis of hepatic arterial5-fluorouracil (5-FU) chemotherapy in 145 consecutive patients treated at asingle institution. Patients and methods:One hundred forty-five patients withinoperable liver metastases from colorectal cancer were included. 5-FU, 1000mg/m²/day continuous infusion for five days every three weeks, wasdelivered in the hepatic artery by percutaneous catheter or arterial accessdevice. Results:The response rate was 34% for all patients,40% in patients with extrahepatic disease, and 15% in patientswith i.v. 5-FU-based pretreatment. TTP and OS for all patients were 7.5 and14.3 months, respectively. In patients with extrahepatic disease or i.v.5-FU-based pretreatment, OS was significantly shorter compared to patientswithout extrahepatic disease or 5-FU-based pretreatment (9.7 vs. 19.3 monthsand 10.1 vs. 17.4 months, respectively). forty-seven percent of patientsstopped treatment because of a complication. Complications most often seen inpatients with arterial ports were hepatic artery thrombosis (48%) anddislocation of the catheter (22%). Conclusions:The results of our analysis are in line with previousphase III studies. Extrahepatic disease and i.v. 5-FU-based pretreatment wereprognostic for reduced OS. The complication rate of hepatic arterial deliverywas worrisome, although, no negative impact on survival could be established.There is a strong need for improvement of hepatic arterial delivery methodsbefore further evaluation of hepatic arterial 5-FU will be worthwhile.     

Should continuous infusion 5-fluorouracil become the standard of care in the USA as it is in Europe?

The mechanism of action of 5-fluorouracil (5-FU) and its pharmacologic behavior are influenced by its mode of administration. Several clinical studies have been conducted with the purpose of evaluating the difference between the continuous (CI 5-FU) and the bolus infusion of 5-FU (BI 5-FU). We focus our review on the studies relevant to the treatment of colorectal cancer, both in the adjuvant and metastatic setting. While individual trials fail to show a survival benefit for CI 5-FU, a meta-analyses of 7 trials shows an improvement in overall survival (OS) over BI 5-FU in metastatic colorectal cancer treatment. All trials in the same setting reveal a different toxicity profile for CI 5-FU that is generally more favorable than BI 5-FU. In the adjuvant setting, CI 5-FU allows the duration of therapy to be shortened by half without compromising the efficacy. CI 5-FU is the regimen of choice when given concurrently with radiation. When given in combination with other cytotoxic agents, CI 5-FU seems to be associated with less toxicity and potentially higher efficacy. Oral fluoropyrimidines, especially capecitabine, appear to behave in similar manner to CI 5-FU and may offer a convenient alternative to the usage of infusion pumps and indwelling catheters. While clinical trials are ongoing to compare capecitabine to CI 5-FU, we believe that CI 5-FU should be offered to patients in the United States given its favorable toxicity profile and higher efficacy in several settings.