Opiate effects on 5-fluorouracil disposition in mice

 Purpose: This study was performed to investigate the effects of morphine on the disposition of 5-fluorouracil (5-FU). Methods: Mice were injected subcutaneously (s.c.) with saline or morphine, 20 mg/kg. 5-FU was administered intravenously (i.v.) 30 min later as a single bolus or by constant infusion. Blood samples were obtained by orbital sinus puncture. Urine samples were obtained from the bladder after ligation of the external urethra. 5-FU concentrations in plasma and urine were determined by HPLC. Results: Morphine markedly elevated plasma levels of 5-FU given at doses of 100 to 860 mg/kg. The plasma clearance rate of a bolus dose of 100 mg/kg 5-FU was significantly reduced from 54 to 28 ml/min per kg and the elimination half-life was increased from 6.9 to 12.2 min by prior administration of morphine. When 5-FU was infused at 0.5 mg/kg per min, morphine reduced its plasma clearance rate from 145 to 94 ml/min per kg. Mice made tolerant by prior morphine administration required higher doses of this opiate to raise 5-FU levels as well as to cause analgesia. The effects of morphine on 5-FU disposition were antagonized by naltrexone. Excretion of 5-FU in urine was not affected by morphine treatment. Conclusions: The plasma clearance rate of 5-FU in mice is significantly reduced by concomitant use of morphine. This effect of morphine is due to reduced hepatic elimination of 5-FU rather than to a decrease in its renal excretion. Received: 22 December 1995 / Accepted: 25 May 1996     

Phase II study of the combination of carboplatin and 5-fluorouracil in metastatic nasopharyngeal carcinoma

 A carboplatin and 5-fluorouracil (CF) chemotherapy protocol was designed to evaluate tumor response and toxicity in patients with metastatic nasopharyngeal carcinoma (NPC). Patients with metastatic NPC were treated with a maximum of eight courses of CF. Carboplatin was given at 300 mg/m² by intravenous bolus on day 1 and 5-fluorouracil at 1 g/m² per day by continuous infusion on days 1 – 3; cycles were repeated once every 3 weeks. A total of 42 patients were evaluable for response and toxicity. They received a median of 6 courses (range 2 – 8) of chemotherapy. The overall response rate was 38% (16/42), comprising 7 complete responses (CR, 17%) and 9 partial responses (PR, 21%). The median survival was 12.1 months (range 6 – 54.2 months). The treatment was well tolerated. Toxicity was mainly bone marrow suppression. There were four episodes of neutropenic fever, but no renal toxicity or treatment-related death was documented. The combination of carboplatin given at a fixed dose of 300 mg/m² for 1 day and 5-fluorouracil given at 1 g/m² per day for 3 days produced an objective response rate of 38% and tolerable side effects. Received: 21 October 1995 / Recepted: 1 March 1996     

Multimodal biochemical modulation of 5-fluorouracil by leucovorin,methotrexate, and interferon alpha in patients with advanced colorectal cancer

 A total of 26 patients with advanced colorectal cancer received 60 mg/m² methotrexate i. v. on days 1 – 4; 400 mg/m² 5-fluorouracil i. v. on days 2, 3, 5, and 6; and 100 mg/m² 6S-leucovorin i. v. on days 2, 3, 5, and 6. Interferon-α2b at a dose of 3 million U was given i. m. daily for the 6 days of chemotherapy. Courses were repeated every 3 weeks. There were four partial responses for a response rate of 15% (95% confidence interval 2 – 28%). In all, 14 patients expressed grade 3 toxicity; 9 patients had diarrhea, 3 had stomatitis, and 2 developed leukopenia. In conclusion, multimodal biochemical modulation of 5-fluorouracil, at least on this schedule, does not seem to be effective, as it results in severe toxicity. Received: 5 November 1995 / Accepted: 17 January 1996     

5-Fluorouracil and low-dose leucovorin in metastatic colorectal cancer: a pilot study

 A total of 56 consecutive patients with metastatic colorectal cancer received treatment with 5-fluorouracil (5-FU) given at 425 mg/m² by rapid intravenous infusion, immediately preceded by leucovorin (LV) given at 20 mg/m², with cycles being repeated every 4 weeks. Of 48 evaluable patients undergoing this treatment, a tumor response was observed in 16 (33%); a complete response, in 2 (4%); and a partial response, in 14 (29%). The median survival was 8.5 months for all patients and 16.5 months for responders. An improvement in symptoms was seen in 9 (26%) of 34 symptomatic patients. In all 15 (27%) of 44 evaluable patients showed an improvement in performance status. The most significant toxicity attributable to the treatment was mucositis of grade 3 or 4, seen in 27% of the patients. Altogether, 2 patients (3.5%) were hospitalized for treatment-related toxicity. We conclude that the combination of 5-FU and low-dose LV is active in advanced colorectal cancer and is associated with acceptable toxicity. Received: 9 May 1994/Accepted: 15 July 1994     

A clinical and pharmacological study of 5-fluorouracil,leucovorin and interferon alfa in advanced colorectal caner

Modulation of 5-fluorouracil (FUra) using leucovorin (LV) is a standard treatment approach in patients with metastatic colorectal cancer. Modulation of FUra with interferon alfa has also shown some promise. Laboratory data have demonstrated increased cytotoxicity when FUra is combined with both LV and interferon. The current study examined the effects of double modulation of FUra using LV and interferon. Patients with measurable advanced colorectal cancer received bolus FUra 375 mg/m² plus LV 20 mg/m² daily for 5 days, repeated every 28 days. Recombinant human interferon alfa-2a, 3 million IU/m² subcutaneously, was given daily on the days of chemotherapy then three times weekly. There was one complete response and nine partial responses (10/41) seen for an overall response rate of 24% (95% CI 12.0–40.0%). Overall, 70% of patients experienced one or more episodes of nonhematologic toxicity of grade 3 or more. Weight loss was common, with a mean decrease of 2.9 kg over the first two months (P<0.0001). Improvements in tumor-related symptoms were balanced by increased fatigue and a deterioration in body weight and performance status. There was no evidence of progressive changes in FUra metabolism from interferon usage.This work was supported in part by a grant from Hoffman LaRoche Canada     

Effects on DNA and RNA after the administration of two different schedules of 5-fluorouracil in colorectal cancer patients

Purpose 5-Fluorouracil (5-FU) has two major mechanisms by which it exerts its anticancer activity. One mechanism operates through the inhibition of thymidylate synthetase (TS) by the active metabolite 5-fluorodeoxyuridine 5-monophosphate. The other mechanism is the incorporation of 5-FU into RNA. Using tumor tissue specimens from colon carcinoma patients given 5-FU by two different modes of administration, we investigated the effects of 5-FU on DNA and RNA.Experimental design Group A patients received 200 mg/day of 5-FU as a rapid infusion for 5 days preoperatively, and group B patients received 200 mg/day of 5-FU as a continuous infusion for 5 days preoperatively. Postoperatively, we analyzed the 5-FU concentration, 5-FU incorporation into RNA (F-RNA), and TS inhibition rate (TSIR) in normal tissue, cancerous tissue, and lymph nodes.Results The F-RNA concentration in tumor tissue from group A patients was higher than in tissue from group B patients. The TS concentrations in tumor tissue were significantly higher than in non-tumor tissue in both groups. In lymph nodes, the TSIR of group A was 78.5% and that of group B was 55.2%, a significant difference.Conclusion Bolus injection can be considered to be more effective with respect to RNA damage in tumor tissue. Especially in cases involving lymph node metastasis, bolus injection was effective with respect to DNA damage as well as RNA damage.     

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus ± LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m² per day and the l-LV dose being 5 mg/m² per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3–4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8–25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus ± LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin. Received: 22 September 1998 / Accepted: 5 January 1999     

A phase II study of sequential methotrexate and 5-fluorouracil in colorectal carcinoma

Nineteen patients with locally recurrent or metastatic colorectal carcinomas were treated with 3-weekly cycles of methotrexate (MTX) given as a loading dose of 100 mg m⁻² and a subsequent 12 h infusion of 400 mg m⁻², followed by 5-fluorouracil (5-FU) 900 mg m⁻² as a bolus injection on completion of infusion. No objective responses were seen in 14 evaluable patients. One early death was treatment related, and four patients were withdrawn from the study after a single course as toxicity was considered unacceptable. The results suggest that in this regimen of sequential MTX and 5-FU, any synergism may be restricted to drug toxicity as no therapeutic benefit was evident.     

Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer

Purpose: The purpose of this work was to estimate the population pharmacokinetic parameters of 5-fluorouracil (5-FU) in patients with advanced colorectal cancer using circadian change kinetics. Methods: Eighty-five patients (32 females, 53 males) were enrolled onto this study. All patients received folinic acid (200 mg/m²) by intravenous infusion over 2 h followed by a 5-FU loading dose (400 mg/m²) and then continuous infusion (600 mg/m²) for 22 h. This whole regimen was repeated on day 2 and was given on a 14-day cycle. Plasma 5-FU determinations were performed by high-performance liquid chromatography with ultraviolet absorbance detection. Pharmacokinetic analyses were performed using the NONMEM computer program through the Visual-NM graphical interface. An open one-compartment pharmacokinetic model with zero-order input rate was used to describe the kinetics of 5-FU; moreover, circadian time-dependent changes in 5-FU concentrations were taken into account in the model. The circadian model was defined as the sum of two cyclic components; the amplitude of the first cyclic component (over 24 h) was about 30% of the average clearance and the amplitude of the second cyclic component (over 12 h) was about 50% of the amplitude of the first component. The acrophase (peak) times of the first and the second periodic component were 04 h 12 m and 00 h 25 m, respectively. The potential sources of variability on the population parameters (65 patients) were investigated using patient's sex, body area, age, body weight, height, liver enzymes and serum creatinine as covariables. Results: Only the estimated clearance circadian changes were different for the two sexes. The population parameter estimates of mean clearance (CL _mean ) and initial volume of distribution (V), were as follows: the male subgroup showed a CL _mean value twice larger (125 l/h) than the value observed in the female subgroup (65 l/h), and V = 21 l. A validation group of 20 additional patients was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic parameters were computed by means of a Bayesian fitting procedure. From the resulting individualized parameter values, concentrations of 5-FU in the plasma were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. Conclusion: In conclusion, a chronomodulated delivery schedule of 5-FU should be performed, using a perfusion rate inversely proportional to the circadian variations of clearance in order to maintain stable 5-FU plasma levels. Such a treatment schedule may result in increased effectiveness of the treatment and decreased occurrence of drug-associated side-effects. The present study develops a complete procedure to efficiently estimate 5-FU clearance in order to optimize dosage regimens in individual patients. Received: 21 September 1998 / Accepted: 20 January 1999     

Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells: synergism with 5-fluorouracil

Cannabinoids (CBs) have been found to exert antiproliferative effects upon a variety of cancer cells, including colorectal carcinoma cells. However, little is known about the signalling mechanisms behind the antitumoural effect in these cells, whether the effects are shared by endogenous lipids related to endocannabinoids, or whether such effects are synergistic with treatment paradigms currently used in the clinic. The aim of this preclinical study was to investigate the effect of synthetic and endogenous CBs and their related fatty acids on the viability of human colorectal carcinoma Caco-2 cells, and to determine whether CB effects are synergistic with those seen with the pyrimidine antagonist 5-fluorouracil (5-FU). The synthetic CB HU 210, the endogenous CB anandamide, the endogenous structural analogue of anandamide, N-arachidonoyl glycine (NAGly), as well as the related polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid showed antiproliferative and cytotoxic effects in the Caco-2 cells, as measured by using [³H]-thymidine incorporation assay, the CyQUANT proliferation assay and calcein-AM fluorescence. HU 210 was the most potent compound examined, followed by anandamide, whereas NAGly showed equal potency and efficacy as the polyunsaturated fatty acids. Furthermore, HU 210 and 5-FU produced synergistic effects in the Caco-2 cells, but not in the human colorectal carcinoma cell lines HCT116 or HT29. The compounds examined produced cytotoxic, rather than antiproliferative effects, by a mechanism not involving CB receptors, since the CB receptor antagonists AM251 and AM630 did not attenuate the effects, nor did pertussis toxin. However, α-tocopherol and the nitric oxide synthase inhibitor L-NAME attenuated the CB toxicity, suggesting involvement of oxidative stress. It is concluded that the CB system may provide new targets for the development of drugs to treat colorectal cancer. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Synergistic antitumor effect of 5-fluorouracil in combination with parthenolide in human colorectal cancer

Parthenolide (PT), a NF-κB inhibitor, has recently been demonstrated as a promising anticancer agent that promotes apoptosis of cancer cells. 5-fluorouracil (5-FU) has been a drug of choice for treatment of colorectal cancer (CRC). Unfortunately, many of the therapies that use 5-FU alone or in combination with other agents are likely to become ineffective due to drug resistance. In the present study, we investigated the antitumor effect of PT combined with 5-FU on a human CRC cell line, SW620. The results demonstrated that combination of PT and 5-FU induced apoptosis which was determined using MTT, cell cycle analysis, annexin-V assay, and Hoechst 33258 staining. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, cytochrome C release, and activation of caspase 3 and 9. Moreover, intra-peritoneal injection of PT and 5-FU showed significant inhibition of tumor growth in the xenograft model. These results demonstrate that PT exhibits anticancer activity in human colorectal cancer in vitro and in vivo. These findings provide an efficacious strategy to overcome 5-FU resistance in certain CRC.     

Dihydropyrimidine dehydrogenase inactivation and 5-fluorouracil pharmacokinetics: allometric scaling of animal data,pharmacokinetics and toxicodynamics of 5-fluorouracil in humans

 The pharmacokinetics of 5-fluorouracil (5-FU) in different animal species treated with the dihy-dropyrimidine dehydrogenase (DPD) inactivator, 5-ethynyluracil (776C85) were related through allometric scaling. Estimates of 5-FU dose in combination with 776C85 were determined from pharmacokinetic and toxicodynamic analysis. Method: The pharmacokinetics of 5-FU in the DPD-deficient state were obtained from mice, rats and dogs treated with 776C85 followed by 5-FU. The pharmacokinetics of 5-FU in humans were then estimated using interspecies allometric scaling. Data related to the clinical toxicity for 5-FU were obtained from the literature. The predicted pharmacokinetics of 5-FU and the clinical toxicity data were then used to estimate the appropriate dose of 5-FU in combination with 776C85 in clinical trials. Results: The allometric equation relating total body clearance (CL) of 5-FU to the body weight (B) (CL=0.47B^0.74) indicates that clearance increased disproportionately with body weight. In contrast, the apparent volume of distribution (V_c) increased proportionately with body weight (V_c=0.58 B^0.99). Based on allometric analysis, the estimated clearance of 5-FU (10.9 l/h) in humans with DPD deficiency was comparable to the observed values in humans lacking DPD activity due to genetic predisposition (10.1 l/h), or treatment with 776C85 (7.0 l/h) or (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVdUrd, 6.6 l/h). The maximum tolerated dose (MTD) of 5-FU in combination with 776C85 was predicted from literature data relating toxicity and plasma 5-FU area under the concentration-time curve (AUC). Based on allometric analysis, the estimated values for the MTD in humans treated with 776C85 and receiving 5-FU as a single i.v. bolus dose, and 5-day and 12-day continuous infusions were about 110, 50 and 30 mg/m² of 5-FU, respectively. Discussion: The pharmacokinetics of 5-FU in the DPD-deficient state in humans can be predicted from animal data. A much smaller dose of 5-FU is needed in patients treated with 776C85. Received: 6 October 1995/Accepted: 28 May 1996     

Use of the folinic acid/5-fluorouracil/irinotecan (FOLFIRI 1) regimen in elderly patients as a first-line treatment for metastatic colorectal cancer: a Phase II study

Background  The aim of this study was to evaluate the effects of a combination of folinic acid, 5-fluorouracil (5FU) and irinotecan (FOLFIRI 1) administered every 2 weeks in a population of elderly subjects with advanced colorectal cancer. Patients and methods  Patients with metastatic colorectal cancer included in this study were aged at least 70 years, with a performance status of 0/1, without geriatric syndrome and without previous palliative chemotherapy. They received irinotecan [180 mg/m² intravenous (iv) infusion over 90 min] followed by folinic acid (400 mg/m² iv over 2 h), then 5FU (400 mg/m² iv bolus) and 5FU (2,400 mg/m² continuous iv infusion for 46 h) every 2 weeks. Results  Forty eligible patients were included. The median age was 77.3 years (range 70–84.7). The objective response rate was 40% and the stabilisation rate was 45%. Median progression-free survival was 8 months, overall survival was 17.2 months and cancer-related specific survival was 20.2 months. In total, 300 cycles of chemotherapy were administered with a median number of eight cycles per patient (range 1–18). Tolerance was good; grade 3/4 toxicities included diarrhoea (15%), asthenia (15%), nausea/vomiting (7.5%) and neutropenia (7.5%). One toxic death was observed due to grade 4 diarrhoea. Conclusion  The FOLFIRI 1 regimen is a valid therapeutic option for elderly patients in good clinical condition. This study was partly sponsored by Pfizer, Paris, France.     

Pharmacokinetics of levamisole in cancer patients treated with 5-fluorouracil

Purpose: To investigate the pharmacokinetics of levamisole and a metabolite, p-hydroxylevamisole in patients with colorectal cancer treated with 5-fluorouracil (5-FU). Methods: Following an intravenous bolus dose of 5-FU, 20 patients with colorectal cancer received oral doses of 50 mg levamisole every 8 h for 3 days. Immediately after the last dose, blood and urine samples were collected over at least an 8-h period. Samples were assayed for levamisole and p-hydroxylevamisole by GC/MS. The levamisole plasma and urine data were subjected to pharmacokinetic analysis using NONMEM software. Results: Substantial interpatient variability was observed in the levamisole plasma concentration-time curves. Patients with cardiovascular or gastrointestinal complications demonstrated altered absorption of levamisole. Pharmacokinetic parameter values for levamisole were similar to those obtained previously in healthy subjects and other cancer patients. Conclusions: There is no evidence that the pharmacokinetics of levamisole are altered by 5-FU administered immediately prior to levamisole administration. The relationship between the substantial intersubject variability in levamisole plasma concentration-time curves and clinical outcome following 5-FU/levamisole adjuvant chemotherapy should be examined. Received: 19 May 1999 / Accepted: 11 August 1999     

The role of levamisole in the adjuvant treatment of stage III colon cancer patients: a randomized trial of 5-fluorouracil and levamisole versus 5-fluorouracil alone

Adjuvant 5-fluorouracil (5FU) and levamisole (Lev) have been considered standard treatment for stage III colon cancer patients. However, the uncertain contribution of Lev to the efficacy of treatment has led many oncologists to prefer the 5FU/leucovorin combination. To establish the role of Lev, we conducted a randomized trial comparing the 5FU/Lev combination with 5FU alone in patients with Dukes' C colon cancer. Patients with stage III colon cancer were randomized to receive 5FU alone (450 mg/m² IV bolus daily for 5 days and then, beginning at day 28, weekly for 48 weeks) or the same plus Lev (50 mg orally three times/day for 3 days, repeated every 2 weeks for 1 year). From December 1994 to March 1998, 92 patients were assigned to receive 5FU/Lev, and 93 were assigned to receive 5FU alone. Leukopenia and hepatic toxicity were more frequent in patients receiving 5FU/Lev as compared with those receiving 5FU (respectively, p=0.003 and p=0.039), whereas other toxicities were equivalent and mild in both arms. After a median follow-up time of 48 months, 80 patients have had recurrences (40 in each arm) and no advantages in terms of disease-free survival and overall survival could be demonstrated for the combination arm. The addition of Lev to 5FU does not seem to be relevant for the clinical activity of this adjuvant regimen, whereas toxicity related to Lev should be considered when an adjuvant treatment for stage III colon cancer patients is proposed.     

In-vitro effect of a combination of 5-fluorouracil (5-FU) and cisplatin (CDDP) on human gastric cancer cell lines: timing of cisplatin treatment

Abstract. Background: To date, we have few effective chemotherapeutic agents against advanced and recurrent gastric cancer. 5-Fluorouracil (5-FU) and cisplatin (CDDP) are the most widely used drugs, and their combination has demonstrated favorable outcomes. However, the method (especially the timing) of CDDP administration is not well established. Methods: We examined the in-vitro effect of a combination of 5-FU and CDDP on four human gastric cancer cell lines: MKN-1, MKN-28, MKN-45, and MKN-74. The cell lines were exposed to 50% of the inhibitory concentrations of 5-FU and CDDP for 72 h and 8 h, respectively. CDDP was applied before, simultaneously with, and after the start of treatment with 5-FU. Results: When CDDP was applied after 5-FU, the cytotoxic activity against MKN-28, MKN-45, and MKN-74 was significantly potentiated. Against MKN-1, the earlier the initiation of CDDP treatment, the stronger was the cytotoxic effect. Conclusion: Our results suggest that the cytotoxicity of a combination of 5-FU and CDDP against human gastric cancer cells is both cell-line- and schedule-dependent and is especially affected by the timing of the CDDP treatment. Received: August 22, 2001 / Accepted: December 7, 2001     

Biochemical modulation of fluorouracil: comparison of methotrexate,folinic acid,and fluorouracil versus folinic acid and fluorouracil in advanced colorectal cancer: a randomized trial

 Recent advances in biochemical pharmacology have revealed the basis for the biological modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and folinic acid (FA). Sequential use of MTX given 24 h prior to 5-FU has resulted in enhanced cell kill in vitro and in vivo. In addition, administration of FA prior to 5-FU has led to potentiation of 5-FU action by stabilization of the ternary complex of thymidine synthase. In the present randomized study, two groups of patients with advanced colorectal cancer were treated as follows: 43 patients (pts) in group A received 5-FU + FA, whereas 45 pts in group B received 5-FU + FA + MTX. The dosage was as follows: group A received FA i. v. at 300 mg/m² per day, prior to i. v. 5-FU at 500 mg/m² per day on days 1 – 4; group B was given MTX i. v. at 130 mg/m² per day on day 0, followed 24 h later by FA at 15 mg q6h × 6, and 5-FU + FA was started on day 1 and given at the same doses and schedule described for group A. Objective responses were achieved by 8/43 pts in group A (1 complete response and 7 partial responses) and by 18/45 pts in group B (3 complete and 15 partial responses), all occurring in the liver. There was no significant difference in the median time to progression (group A 6.1 months, group B 6.8 months) or the median survival (group A 9.2 months, group B 10.3 months). Toxicity was significantly greater in group B [grade 2 – 3 mucositis 20% versus only 2% in group A (P <0.0001); grade 3 diarrhea in group B 15% versus 3% in group A (P <0.001)]. According to our results, double biological modulation of 5-FU with MTX + FA led to an enhanced response rate with increased toxicity as compared with the 5-FU + FA regimen given at less than its maximally tolerated dose. Received: 8 May 1995 / Accepted: 25 January 1996     

Feasibility study of ambulatory continuous infusion of 5-fluorouracil followed by cisplatin through hepatic artery for metastatic colorectal cancer

Purpose: A great synergy has been reported in a number of preclinical studies when 5-fluorouracil (5-FU) precedes cisplatin (CDDP). The objective of this study was to determine the feasibility of ambulatory continuous infusion of 5-FU followed by CDDP through hepatic artery for metastatic colorectal cancer. Patients and methods: Seventeen patients with unresectable liver metastases, who underwent primary tumor resection, were treated with 5-FU (450 mg/m²/day) for seven consecutive days followed by CDDP (100 mg/body/week) for seven consecutive days, each administered continuously by using a balloon pump via Infuse-A-Port catheter inserted into common hepatic artery. The doses of drugs were reduced 20% in patients older than 70 years. The treatment was repeated every 4–6 weeks until disease progression. Results: Of 17 assessable patients, nine patients showed PR (53%; 95% CI, 29.3–76.7%) and eight patients had SD (47%; 95% CI, 23.3–70.7%), with disease control rate of 100%. The median overall survival was 26 months (95% CI: 17.5–41 months) and TTP 14 months (95% CI: 11–20.3 months). Two patients (11.8%), who showed progression due to collateral feeding arteries, responded to HAI again after occlusion. Grade 3 toxicity included leukopenia (12%) and anemia (24%). Grade 4 toxicity was absent. Four patients (23.5%) progressed at extrahepatic sites. Conclusions: This sequential combination of 5-FU followed by CDDP through hepatic artery is active and safe in an outpatient setting, and warrants further multi-institutional study, although prevention of micrometastasis would be mandatory to further prolong overall survival.     

RNA-Seq profiling of circular RNAs in human colorectal cancer 5-fluorouracil resistance and potential biomarkers

BACKGROUNDColorectal cancer (CRC) is a commonly diagnosed cancer of the digestive system worldwide. Although chemotherapeutic agents and targeted therapeutic drugs are currently available for CRC treatment, drug resistance is a problem that cannot be ignored and needs to be solved. AIMTo explore the relationship between circular RNA (circRNA) and CRC drug resistance. circRNA plays a key role in the occurrence and development of cancers, but its function in the process of drug resistance has not been widely revealed. METHODSTo explore the role of circRNA in 5-fluorouracil (5-Fu) resistance, we performed the circRNA expression profile in two CRC cell lines and their homologous 5-Fu resistant cells by high-throughput sequencing.RESULTSWe validated the differentially expressed circRNAs in other two paired CRC cells, confirmed that circ_0002813 and circ_0000236 could have a potential competitive endogenous RNA mechanism and be involved in the formation of 5-Fu resistance. And we combined the sequencing results of mRNA to construct the regulatory network of circRNA-miRNA-mRNA. CONCLUSIONOur study revealed that circ_0002813 and circ_0000236 may as the biomarkers to predict the occurrence of 5-Fu resistance in CRC.     

5-Methyltetrahydrofolate or 5-formyltetrahydrofolic acid to modulate 5-fluorouracil’s cytotoxic activity in vivo? A phase II study in patients with advanced colon cancer

 The purpose of this study was to test the hypothesis that 5-methyltetrahydrofolate (Me-THF), a source of reduced folates alternative to leucovorin, could effectively modulate 5-fluorouracil’s (5-FU) cytotoxic activity in patients with advanced colon cancer. A total of 23 patients were enrolled in a phase II trial; they received 5-FU as a 30-min infusion at a dose of 370 mg/m² following a rapid i.v. push of 200 mg/m² Me-THF, both drugs being given for 5 consecutive days. Cycles were repeated every 4 weeks until disease progression. No patient achieved a complete response. In all, 4 patients showed a partial response (17.4%), 7 developed stable disease (30.4%), and the remaining 12 (52.2%) progressed. Toxicity was acceptable and never exceeded WHO grade III intensity. According to our experience, the MeTHF/5-FU combination does not appear to be an effective treatment for advanced colon cancer. Despite its low toxic profile, in our opinion its wider use should be discouraged. Received: 9 September 1995 / Accepted: 30 November 1995