Folinic acid modulation of fluorouracil: tissue kinetics of bolus administration

Spears, C. P.; Gustavsson, Bengt; Frösing, Roland

doi:10.1007/bf00178189

Cited by 28 publications

(12 citation statements)

References 30 publications

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“…Since reports on the intraperitoneal administration of 5-fluorouracil are encouraging, we used this route to administer 5-fluorouracil plus folinic acid. A scheduledependent synergism is achieved by injecting 5-fluorouracil plus folinic acid [1,19]. The adverse effect of postoperative administration of 5-fluorouracil on wound healing has been reported in various studies [1,10,[14][15][16][20][21][22][23][24].…”

Section: Resultsmentioning

confidence: 99%

Healing of Colonic Anastomoses after Immediate and Delayed Administration of 5-Fluorouracil plus Folinic Acid

Kanellos

Kazantzidou²,

Evangelou³

et al. 1998

Eur Surg Res

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The purpose of this experimental study was to investigate whether the delayed, postoperative, intraperitoneal administration of 5-fluorouracil plus folinic acid had adverse effects on wound healing, as did their early administration. Seventy male Wistar rats underwent colonic resection followed by anastomosis of the colon. The animals were randomized into four groups. The rats in control group 1 received a 0.9% NaCl solution intraperitoneally and those in group 2 received 5-fluorouracil (20 mg/kg) plus folinic acid (2 mg/kg) immediately after surgery and for the next 3 days. The rats in control group 3 and those in group 4 received intraperitoneally a 0.9% NaCl solution or 5-fluorouracil plus folinic acid, respectively, from postoperative day 4 to day 7. The rats were sacrificed on the 8th postoperative day. The rupture rate of the anastomoses was statistically significantly higher in group 2 with early treatment compared to control group 1 (p < 0.05); no differences were observed between control group 3 and group 4 with delayed treatment (p > 0.05). Adhesion and abscess formation were more marked in group 2 compared to control group 1; no differences were recorded between groups 3 and 4. The anastomotic bursting pressure was statistically significantly lower in group 2 compared to control group 1 (p < 0.05); no differences were measured between groups 3 and 4. Histologic evaluation showed a more profound inflammatory response and less marked fibroblastic activity in group 2 compared to control group 1; new collagen production was more evident in group 1. No such differences were observed between groups 3 and 4. In conclusion, the immediate, postoperative, intraperitoneal administration of 5-fluorouracil plus folinic acid inhibited wound healing, but delaying chemotherapy (beginning on the 4th postoperative day) had no adverse effects on the healing of colonic anastomoses and can be considered safe.

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Section: Resultsmentioning

confidence: 99%

Healing of Colonic Anastomoses after Immediate and Delayed Administration of 5-Fluorouracil plus Folinic Acid

Kanellos

Kazantzidou²,

Evangelou³

et al. 1998

Eur Surg Res

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“…It has been shown that the degree of TS inhibition after fluorouracil treatment correlates well with response (Spears et al 1990). The folate concentration in tumour tissue has been shown to be important for the inhibitory effect of the drug on TS (Spears et al 1989). This data will be useful in the development of methods to improve and individualise the treatment of solid tumours with fluorouracil.…”

Section: Fluorouracilmentioning

confidence: 96%

“…The studies of cellular pharmacokinetics and pharmacodynamics meet considerable practical difficulties as surgical biopsies need to be taken before and after administration of the drug (Spears et al 1984). Recently, however, methods for determination ofTS activity and FdUMP and dUMP concentrations from tissue samples have improved since fine needle aspiration techniques have come into use (Spears et al 1989). It has been shown that the degree of TS inhibition after fluorouracil treatment correlates well with response (Spears et al 1990).…”

Section: Fluorouracilmentioning

confidence: 98%

Pharmacokinetic Optimisation of Anticancer Therapy

Liliemark

Peterson

1991

Clinical Pharmacokinetics

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It is obvious that there are great problems with pharmacokinetic individualization of anticancer therapy. The strong relationship between dose intensity (total dose/unit time) and response revealed in clinical trials with some tumours provides a strong support for studies seeking relationships between the individual plasma pharmacokinetic profile and response to treatment. Unfortunately, studies that define a therapeutic window are sparse, and trials that prospectively test such models are even rarer. Thus, for most cancer drugs, it is not possible to give any definite advice on how to use pharmacokinetic determinations to establish individualised therapy, and there is therefore a definite need for such studies. It is important, however, that attempts to establish relationships between drug concentrations and therapeutic effects be founded on a sound theoretical base. When drugs, mainly antimetabolites, are extensively metabolised intracellularly and interact with intracellular processes about which there are data showing a strong interindividual heterogeneity, such data must be considered when designing pharmacokinetic investigations. Cytarabine and fluorouracil are good examples of this. The monitoring of intracellular drug/metabolite concentrations or of the direct biochemical events in the tumour cells seems to be a promising approach with such drugs. It also needs to be emphasised that pharmacokinetically guided individualization cannot be achieved before a therapeutic window is established, i.e. a knowledge of the relationship between drug concentration and clinical effects. The investigators in this field accept a great responsibility when clinical studies are undertaken: a poorly designed study showing no benefit from pharmacokinetically guided individualization can impair the possibilities of performing more adequate studies in the future.

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“…infusion of leucovorin (LV) (60 mg m À2 ) was administered. The pharmacokinetical rationale for this sequential treatment is to obtain simultaneous tissue peak concentration of 5-FU and LV (Spears et al, 1989). The 5-FU dose was selected after a pilot study, showing that an i.p.…”

Section: Intraperitoneal Chemotherapymentioning

confidence: 99%

Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study

et al. 2004

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Patients with peritoneal or local metastases from colorectal cancer have a poor prognosis. However, aggressive treatments by debulking surgery and infusional intraperitoneal (i.p.) chemotherapy have been tried and appear to benefit selected patients. We assayed the effects of debulking surgery and i.p. chemotherapy with respect to survival and compared the results with matched control patients treated by intravenous (i.v.) chemotherapy. In all, 18 patients with peritoneal and/or local metastases from colorectal adenocarcinoma underwent debulking surgery followed by 5-fluorouracil (5-FU) 550 mg m À2 day À1 i.p. and leucovorin (LV) 60 mg m À2 day À1 i.v. The chemotherapy was started the day after surgery and was given daily for 6 days and repeated monthly for totally eight courses. The control patients, matched for age, gender, performance status and metastatic site, were randomly selected from controlled clinical chemotherapy trials and treated with i.v. 5-FU þ LV or i.v. methotrexate þ 5-FU þ LV. There was no treatment-related mortality. The median survival among i.p. patients was 32 months compared to 14 months in the control group. In all, 11 patients who underwent macroscopically radical surgery had a longer survival than those who were not radically operated (P ¼ 0.02). These results indicate that patients with peritoneal metastases and/or locally advanced cancers but without distant metastases may benefit from cytoreductive surgery combined with i.p. chemotherapy.

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Folinic acid modulation of fluorouracil: tissue kinetics of bolus administration

Cited by 28 publications

References 30 publications

Healing of Colonic Anastomoses after Immediate and Delayed Administration of 5-Fluorouracil plus Folinic Acid

Healing of Colonic Anastomoses after Immediate and Delayed Administration of 5-Fluorouracil plus Folinic Acid

Pharmacokinetic Optimisation of Anticancer Therapy

Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study

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