5-fluorouracil Toxicity Research Articles

Prevention of indigenous infection of mice with Escherichia coli by nonspecific immunostimulation.

We have previously reported that the lethal toxicity of 5-fluorouracil (5-FU) in specific-pathogen-free mice is due to an intestinal infection with indigenous Escherichia coli induced by the drug (K. Nomoto, T. Yokokura, Y. Yoshikai, M. Mitsuyama, and K. Nomoto, Can J. Microbiol. 37:244-247, 1991). In the present study we demonstrate that nonspecific immunostimulation is effective in the protection of mice from the lethal indigenous infection induced by 5-FU. Intravenous or subcutaneous injection of a preparation of heat-killed Lactobacillus casei YIT 9018, a potent nonspecific immunostimulant, into BALB/c mice reduced the lethal toxicity of 5-FU at doses ranging from 338 to 800 mg/kg of body weight if YIT 9018 was injected 7 to 40 days before administration of 5-FU. Systemic infection with E. coli developed in all of the 5-FU-treated control mice 7 days or more after administration of 5-FU in large doses and was accompanied by overgrowth of the bacteria in the intestinal tract. Pretreatment of mice with YIT 9018 resulted in a decreased occurrence of systemic infection with E. coli to levels of 0 to 20% and no significant changes in the population levels of E. coli in the intestinal tract during the 14 days after administration of 5-FU. The levels of leukopenia in the spleen and peripheral blood were lower, and recovery of granulocyte-macrophage precursor cells in the spleen and femur began earlier in the treated animals than in the 5-FU-treated controls. Intravenous transfusion of syngeneic normal bone marrow cells or spleen cells into the mice at an early period after administration of 5-FU diminished markedly the occurrence of the lethal indigenous infection, suggestion that an earlier recovery from chemotherapy-induced myelosuppression is important in the mechanisms of protection of the host from the infection.

A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma.

Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon alpha-2a (rIFN alpha-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN alpha-2a at 5 x 10(6) or 10 x 10(6) U/m2/d on days 1 to 7, or with 3 x 10(6) U/m2/d on days 1 to 14. In 26 matched cycles, rIFN alpha-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN alpha-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 10(6) U/m2/d rIFN alpha-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 10(6) and 5 x 10(6) U/m2/d rIFN alpha-2a had acceptable toxicity. Administration of rIFN alpha-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 10(6) and 10 x 10(6) U/m2/d rIFN alpha-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN alpha-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 10(6) U/m2/d dose of rIFN alpha-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

Reducing corneal toxicity of 5-fluorouracil in the early postoperative period following glaucoma filtering surgery

To gain a better understanding of the relationship between postoperative 5-fluorouracil administration and corneal complications associated with its use, we analysed 43 consecutive filtering procedures in which it had been employed. Nine of the 43 eyes had corneal complications during that period. At the end of the three-month period, these corneal complications had all resolved. There was no correlation between postoperative intraocular pressure lowering and incidence of corneal complications. A low dose of 5-fluorouracil, and early recognition and treatment of corneal toxicity associated with its use may reduce corneal complications while maintaining filtration in eyes with poor surgical prognosis.

Clinical and Pharmacologic Study of Orally Administrated Uridine

Effects of oral administrations of uridine were investigated in a study of six healthy volunteer control subjects and nine patients with metastatic colorectal cancer. Oral uridine was studied as single-dose administrations at doses escalating from 0.3 to 12 g/m2 and as multiple-dose administrations every 6 hours for 3 days at doses from 5 to 10 g/m2. The maximum tolerated dose (MTD) was 10 to 12 g/m2 for a single dose of uridine and 5 g/m2 for the multiple-dose regimen. Diarrhea was the dose-limiting toxic effect. Single-dose oral uridine resulted in an increase in plasma uridine concentrations in the range of 60 to 80 microM after doses of 8 to 12 g/m2. At these doses, bioavailability of oral uridine ranged from 5.8% to 9.9%. At the MTD of 5 g/m2 in the multiple-dose uridine schedule, steady-state plasma uridine levels of approximately 50 microM were achieved. Further studies should explore the role of oral uridine in the modulation of the toxicity of fluorouracil.

A phase II trial of cisplatin and 5-fluorouracil with allopurinol for recurrent or metastatic carcinoma of the uterine cervix: A Southwest Oncology Group trial

Abstract On the strength of recent evidence of the activity of the combination of cisplatin and 5-fluorouracil against squamous malignancies of the esophagus and head and neck, this regimen was evaluated in a phase II trial against metastatic or recurrent squamous carcinoma of the uterine cervix. Cisplatin was administered at a dosage of 100 mg/m 2 iv bolus and 5-fluorouracil was cotinuously infused iv at a dosage of 1000 mg/m 2 /day for 4 days. In an effort to determine whether the toxicities of 5-fluorouracil could be ameliorated by coadministration of allopurinol, patients were randomized to receive allopurinol, 900 mg orally, an odd or even courses of therapy beginning 5 days before 5-fluorouracil administration and continuing until conclusion of the infusion. Fifty-two eligible patients received 177 evaluable courses of treatment. The overall response rate was 28% (8 complete responses and 6 partial responses). Toxicity was confined to nausea and vomiting (81% of courses), anemia (47%), leukopenia (37%), oral mucositis (15%), diarrhea (6%), and thrombocytopenia (4%). Allopurinol produced no improvement in treatment-related toxicities. Allopurinol did not permit substantial increases in 5-fluorouracil dosage.

Protein intake and 5-fluorouracil toxicity in tumor-bearing animals

The administration of chemotherapy is limited in clinical situations by lack of selective antineoplastic activity resulting in significant host toxicity. Although it has been suggested that nutrition support can reduce chemotherapy-related toxicity, few controlled studies exist to document this clinical impression. This study was performed to determine the effect of enteral protein intake on 5-fluorouracil toxicity in tumor-bearing animals. Seventy-nine female Lewis/Wistar rats with subcutaneous mammary tumor implants (AC-33) were randomized to receive either standard protein (22.0% protein; 4.27 kcal/g) or an isocaloric, protein-depleted diet (0.03% protein; 4.20 kcal/g). One-half of the animals in each group received daily injections of 5-fluorouracil (15- or 25 mg/kg ip) or placebo (saline) for 4 or 5 days. Standard protein intake significantly increased host body weight and decreased leukopenia at low (15 mg/kg) and high (25 mg/kg) 5-fluorouracil therapy. At high-dose 5-Fluorouracil (25 mg/kg), the incidence and duration of diarrhea were decreased in animals receiving standard protein intake. Thus, enteral protein intake significantly reduced clinical and objective 5-fluorouracil toxicity and improved body weight in this tumor-bearing animal model.

A phase II trial of cisplatin and 5-fluorouracil with allopurinol for recurrent or metastatic carcinoma of the uterine cervix: A southwest oncology group trial

On the strength of recent evidence of the activity of the combination of cisplatin and 5-fluorouracil against squamous malignancies of the esophagus and head and neck, this regimen was evaluated in a phase II trial against metastatic or recurrent squamous carcinoma of the uterine cervix. Cisplatin was administered at a dosage of 100 mg/m 2 iv bolus and 5-fluorouracil was cotinuously infused iv at a dosage of 1000 mg/m 2/day for 4 days. In an effort to determine whether the toxicities of 5-fluorouracil could be ameliorated by coadministration of allopurinol, patients were randomized to receive allopurinol, 900 mg orally, an odd or even courses of therapy beginning 5 days before 5-fluorouracil administration and continuing until conclusion of the infusion. Fifty-two eligible patients received 177 evaluable courses of treatment. The overall response rate was 28% (8 complete responses and 6 partial responses). Toxicity was confined to nausea and vomiting (81% of courses), anemia (47%), leukopenia (37%), oral mucositis (15%), diarrhea (6%), and thrombocytopenia (4%). Allopurinol produced no improvement in treatment-related toxicities. Allopurinol did not permit substantial increases in 5-fluorouracil dosage.

Efficacy and Toxicity of 5-Fluorouracil and Folates in Advanced Colon Cancer

From February 1987 to December 1988, 34 patients with histologically confirmed advanced colorectal carcinoma were entered in a phase II trial with 5-fluorouracil (5-FU) and folinic acid, for evaluation of treatment effectiveness and toxicity. Our data confirmed that the association 5-FU and folates represents an effective and moderately tolerated palliative treatment, with diarrhea being the only dose-limiting toxicity.

Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion

The limiting toxicity of low dose continuous infusion 5-fluorouracil (200-300 mg/m2/day) is often palmar-plantar erythrodysesthesia (PPE). PPE developed in 16/25 patients (exact 95% confidence interval of 42%-82%) with metastatic colon cancer enrolled in a phase II trial. In this trial, 5-FU was given continuously at a dose of 200 mg/m2/day until toxicity or progressive disease forced discontinuation. The first signs of the syndrome developed at a median of 2 months following infusion initiation and, unless treatment was interrupted, became progressively worse. The incidence of moderate to severe PPE was 71% in the 14 previously untreated patients (exact 95% confidence intervals of 42-92%). Seventy-eight percent of the responders in the no prior treatment group developed PPE. The incidence of moderate to severe PPE was only 27% in the 11 previously treated patients (exact 95% confidence intervals of 6-61%). The higher incidence of PPE in the previously untreated patients probably resulted from a longer total infusion time (median = 7.3 months) than the previously treated (median = 4.5 months). The longer infusion time in turn was a result of the higher response rates (64 vs 18%) in the previously untreated versus treated groups. Five previously untreated patients who developed PPE received 50 or 150 mg of pyridoxine/day when moderate PPE changes were noted. Reversal of PPE without interruption of the 5-FU was seen in 4/5 patients. Four of these patients who received pyridoxine had responded to 5-FU treatment. No adverse affect of pyridoxine on clinical response was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

A Phase I–II Study on the Toxicity and Therapeutic Efficacy of 5-Fluorouracil in Combination with Leucovorin and Cisplatinum in Patients with Advanced Colorectal Carcinoma

5-Fluorouracil (5-FU) has been the treatment of choice for colorectal carcinoma with an overall response rate of about 20%. Recent studies have shown that folate (LV) can increase 5-FU therapeutic efficacy, achieving about a 40% response rate without a clear impact on survival. Cisplatinum (CDDP) is usually inactive in colorectal carcinoma, but the association with 5-FU results in a synergistic antineoplastic effect. A phase I-II study was done to assess the maximally tolerated dose (MTD) of CDDP in association with 5-FU + LV. The MTD for CDDP was 20 mg/m2/wk in association with 5-FU 400-500 mg/m2/wk and LV 500 mg/m2/wk. WHO criteria were used for evaluation of both toxicity and response. In the phase I part we found that the main side-effect in 27 evaluable patients (pts) was gastrointestinal toxicity, mainly in the form of nausea/vomiting (92%) and diarrhea (70%) which caused one therapy-related death. Renal (26%) and marrow (59%) toxicity were acceptable. In the phase II part of the study 1 out of 19 evaluable pts (5%) had a complete response of 309 days, 3 pts achieved a partial response (16%) with a median duration od 410 days, 2 pts had a minimal response (10%) with a median duration of 261 days, and 8 pts experienced no change (42%) with a mean duration of 196 + days. In our opinion the 21% response rate obtained in this series is not satisfactory. Nevertheless the very high number of minimal response + no change patients together with the interesting impact on survival in responders may suggest further phase II-III studies.

Concomitant Administration of 4-Hydroxypyrazolopyrimidine (Allopurinol) and High-Dose Continuous Infusion 5-Fluorouracil

We tried to study the protection of allopurinol (HPP) from the toxicity of 5-fluorouracil (5-FU). A total of 29 patients received 74 cycles of chemotherapy (16 colon adenocarcinomas, 7 head and neck, 3 breast cancers and 3 cancers of pancreas). HPP was given 900 mg/day p.o. 4 days prior to treatment, and continued with same dose throughout the course of 5-FU and for 12 days after completion of the treatment. 5-FU was administered in 24 hour intravenous infusions on days 1-5 (dose range 900-1,200 mg/m2/day). 5-FU was given alone or in combination with mitomycin-C 10 mg/m2/day (1st day), epirubicin 40 mg/m2/day (1st, 2nd day), cis-platinum 120 mg/m2/day (1st day). In comparison with other studies the toxicity was limited. We conclude that HPP can diminish the side effects, especially myelosuppression, allowing an increase in the maximum tolerated dose of 5-FU; even if combined with other cytostatic drugs. Control studies must be done to confirm our observations.

Phase I Trial of Pala, Methotrexate, Fluorouracil, Lcucovorin, and Uridine Rescue in Patients with Advanced Cancer. The Use of Uridine to Decrease Fluorouracil Toxicity

Phase I Trial of Pala, Methotrexate, Fluorouracil, Lcucovorin, and Uridine Rescue in Patients with Advanced Cancer. The Use of Uridine to Decrease Fluorouracil Toxicity

Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma.

The effect of leucovorin (LV) given in various doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil (5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous administration of 5FU and LV nor 5FU combined with delayed administration of LV potentiated the antitumor activity of 5FU. LV given twice - 1 hr before (50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) - gave significantly better delay of tumor growth of both tumor lines than 5FU did alone (100 mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg. Delayed administration of uridine (3500 mg/kg) allowed the use of higher 5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity led to moderate weight loss in treated mice, but was comparable for mice treated with 5FU alone or combined with LV. Hematological toxicity consisted of moderate leukopenia (nadir 40%), which was observed with the most active schedule and was less severe than with 5FU alone. This schedule did not cause thrombocytopenia, but after discontinuation the thrombocyte count showed an overshoot. Addition of uridine to this schedule reduced hematological toxicity only slightly. It is concluded that LV potentiated the antitumor activity of 5FU against two solid tumor lines, i.e., a relatively resistant and a sensitive murine colon carcinoma, and that toxicity was moderate.

Use of oral uridine as a substitute for parenteral uridine rescue of 5-fluorouracil therapy, with and without the uridine phosphorylase inhibitor 5-benzylacyclouridine.

Initial clinical trials have demonstrated that uridine (Urd) rescue given i.v. over at least 3 days can ameliorate 5-fluorouracil (FUra) toxicity; to avoid Urd-induced phlebitis in the peripheral veins of patients, a central vein is used. The latter necessity, along with the need for 3 days of i.v. administration, makes Urd rescue by parenteral means a cumbersome and complicated clinical procedure. It would appear preferable to use oral Urd; however, the oral Urd dose in the clinic is limited, as high doses cause diarrhea. Therefore, using a tumor-bearing murine model we investigated as to whether low doses of oral Urd coupled with a Urd phosphorylase inhibitor benzylacyclouridine (BAU), would effect safe rescue of FUra toxicity with preservation of antitumor activity. A high-dose FUra-containing drug combination that included parenteral Urd rescue was used as a control; other groups of tumor-bearing mice received the same drug combination, except that p.o. Urd was substituted for i.p. Urd. In the absence of BAU, p.o. Urd could effect rescue while maintaining an antitumor effect comparable to that obtained with i.p. Urd. When given concomitantly with BAU, a 50% reduction in the oral Urd dose (i.e., from 4,000 to 2,000 mg/kg) enabled the achievement of a comparable therapeutic index. Intraperitoneal Urd produces very high (6-8 mM) plasma and tissue Urd levels, which remain above 100 microM for at least 6 h. In contrast, neither oral Urd nor oral BAU alone raised plasma Urd concentrations above about 50 microM. However, the combination of oral Urd plus oral BAU gave a peak plasma Urd level of about 300 microM, and the level was maintained above 100 microM for 6 h. Following oral Urd administration, gut tissue levels of Urd were in the mM range and those of BAU were in the range of 10-20 micrograms/g tissue, a level sufficient to result in substantial inhibition of Urd phosphorylase. Oral Urd plus oral BAU appears to be a promising clinical alternative to parenteral administration of Urd for selective rescue of FUra toxicity.

Toxicity and antitumor activity of 5-fluorouracil in combination with leucovorin. Role of dose schedule and route of administration of leucovorin.

Clinically, 5-formyltetrahydrofolate (leucovorin, folinic acid, LV) in combination with 5-fluorouracil (5-FU) has been used at various doses, schedules, and routes of administration with therapeutic benefit to patients with advanced colorectal carcinoma and breast carcinoma. Clinical experiences have been primarily with LV doses of 25, 200, and 500 mg/m2 administered by either short-term intravenous infusion, daily continuous infusion, or orally. In patients with lung carcinoma, oral administration of dl-LV at 125 mg/m2 hourly for 4 hours (total dose of 500 mg/m2) gave the following peak plasma folate concentrations: dl-LV, 4.6 + 1.9 microM; 5-methyltetrahydrofolate, 4.3 + 2.1 microM; and no detectable l-LV in most cases. The d-LV/5-methyltetrahydrofolate ratios, however, were lower for the oral route than for the same dl-LV dose administered by 2-hour intravenous infusion in the same patient. To determine if there is a relationship between the dose, schedule, or route of administration and the therapeutic efficacy of LV combined with 5-FU, studies were carried out in rats with transplantable colon carcinoma. 5-Formyltetrahydrofolate was administered at various doses by either 2-hour infusion, 2-day continuous intravenous infusion, or by divided hourly oral doses for 4 hours. In all cases, the total doses of dl-LV administered were 100, 200, and 400 mg/kg. Data obtained to date indicate: (1) plasma folate concentrations by intravenous administration were dose dependent, but lower and saturable concentrations of folates were observed by oral administration; and (2) while the concentrations of 5-methyltetrahydrofolate achieved by the 2-hour infusion schedule were relatively constant and independent of the dose of dl-LV administered, conversion of dl-LV to 5-methyltetrahydrofolate with the 2-day infusion of 100, 200, and 400 mg/kg was dose dependent. In humans, however, conversion was independent of the route of administration of dl-LV (19% for the 2-hour infusion and 23% for the 5-day infusion of 500 mg/m2 dose). Preliminary results for antitumor activity of 5-FU in combination with dl-LV, administered by either 2-hour intravenous infusion (400 mg/kg/day for 5 days) or orally (100 mg/kg/hour for 4 hours), yielded similar inhibition of in vivo tumor growth, each being greater than what was achieved with 5-FU alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Interaction of deoxyuridine with fluorouracil and dipyridamole in a human colon cancer cell line

We have reported previously that dipyridamole increases the toxicity of 5-fluorouracil and alters fluorouracil metabolism in HCT 116 cells, producing a selective increase in fluorodeoxyuridine monophosphate (FdUMP) levels by blocking the efflux of fluorodeoxyuridine. Dipyridamole also blocks deoxyuridine efflux and prolongs the intracellular half-life of deoxyuridine monophosphate (dUMP). The significance of the effect of dipyridamole on FdUMP and dUMP levels was explored further. In cell growth experiments, 1–50 μM deoxyuridine enhanced the cytotoxicity of 5 μM fluorouracil in a dose-dependent manner, and ≥10 μM deoxyuridine increased the augmentation of fluorouracil toxicity produced by 0.5 μM dipyridamole. The effect of deoxyuridine on [6- 3H]fluorouracil metabolism was studied. After 4 hr, 25 μM deoxyuridine increased the amount of [ 3H]FdUMP formed 2- to 4-fold relative to that of fluorouracil ± dipyridamole alone. The mechanism by which deoxyuridine increased FdUMP was examined by measuring the distribution of [2′- 3H]deoxyuridine metabolites following exposure of 25 μM deoxyuridine ±5 μM fluorouracil. Tritium appeared in the FdUMP peak at 4 and 24 hr in cells exposed to fluorouracil and deoxyuridine, indicating that [ 3H]deoxyribose was transferred to fluorouracil. A large buildup of [ 3H]dUMP was seen in cells exposed to fluorouracil plus deoxyuridine for 4 and 24 hr compared to exposure to [ 3H]deoxyuridine alone, suggesting that dUMP may also inhibit catabolism of FdUMP. Since the increased FdUMP levels produced by dipyridamole did not appear to correlate with further depletion of thymidine triphosphate pools, the incorporation of [ 3H]fluorouracil metabolites into nucleic acids was monitored by cesium sulfate density centrifugation. Fluorouracil-RNA increased as a function of time (1, 2 and 13 pmol 10 6 cells after 4, 8 and 24 hr), but fluorouracil-DNA was detected only after 24 hr (0.5 pmoI 10 6 cells). Dipyridamole however, did not appear to alter the pattern of incorporation of fluorouracil into either RNA or DNA. Perturbations of endogenous dUMP levels by fluorouracil and dipyridamole were then studied. In cells exposed to fluorouracil alone, dUMP pools were unchanged from control at 2 hr, but they had increased 9-fold by 4hr (3362 pmol 10 6 cells). Simultaneous exposure to fluorouracil and dipyridamole resulted in a 1.5-fold (566 pmol 10 6 cells) and 13.6-fold (5049 pmol 10 6 cells) increase over control dUMP levels after 2 and 4hr respectively. The dUMP pools continued to enlarge through 24 hr. The effect of fluorouracil on DNA fragility was examined. In cells prelabeled with [ 14C]thymidine, there was no evidence of single-strand breaks in high molecular weight DNA after 4 or 24 hr of exposure to fluorouracil alone or with dipyridamole as measured by alkaline elution. In contrast, fluorouracil produced alkaline labile sites in newly synthesized DNA. Alkaline labile sites were also produced by exposure to dipyridamole. Concomitant exposure to FUra with dipyridamole and/or deoxyuridine resulted in a striking increase in the alkaline labile sites in DNA. These results suggest that effects on deoxyuridine metabolism may be important components of the interaction between fluorouracil and dipyridamole.

The effect of fluorouracil on the corneal endothelium.

The utility of the antiproliferative agent fluorouracil has been demonstrated recently in glaucoma-filtering surgery and in the management of proliferative vitreoretinopathy after vitrectomy. Because of the potential for contact with the corneal endothelium, its toxicity to the endothelium is an important consideration. The effect of fluorouracil on corneal endothelial integrity in an in vitro animal model was studied. Freshly excised sheep corneal buttons were exposed to increasing concentrations of fluorouracil for four hours and were subsequently evaluated microscopically using vital staining with alizarin red and trypan blue. Exposure to normal saline and chlorhexidine gluconate was used to establish negative- and positive-staining controls. Corneal buttons exposed to normal saline or to 1.0 mg/mL or less of fluorouracil had intact endothelial monolayers that completely excluded trypan blue. Corneal buttons exposed to chlorhexidine gluconate or to 10 mg/mL of fluorouracil, however, had severely or totally disrupted endothelial monolayers in which the remaining cells, if any, all had blue-staining nuclei. These results suggest that the threshold concentration for fluorouracil toxicity to corneal endothelium lies between 1 and 10 mg/mL when exposure time is four hours.

Improvement of therapeutic index in gastrointestinal cancer

There are several methods to reduce toxicity that apply in the chemotherapy of all cancers. Most of these topics are being covered by other authors in this Symposium volume of Cancer Treatment Reviews. Circadian timing of chemotherapeutic drugs may be an additional way to reduce chemotherapy related toxicities (6). To my knowledge there have been no clinical trials to investigate this possibility in gastrointestinal cancer. Regional chemotherapy to the liver has drawn a lot of attention in the last few years especially in colorectal cancer and the most recent results were presented at this Symposium. This approach has documented the difficulty of comparing treatments with different toxicity profiles. In addition, regional chemotherapy is applied to the peritoneal cavity and to the iliac arteries. The NCI group has recently published their preliminary results on the toxicity of adjuvant 5-fluorouracil (5-FU) given either by the intravenous (i.v.) or intraperitoneal (i.p.) routes in colorectal cancer (15). Patients receiving i.p. 5-FU tolerated higher total drug doses and still had significantly less myelotoxicity. This may be a worthwhile approach for situations requiring the highest drug concentration in the peritoneal cavity and its draining sites. Results of such treatment results have not yet been reported. Locoregional recurrence of rectal cancer presents a major problem for patients as well as physicians. While radiotherapy is the treatment of choice, intraarterial (i.a.) chemotherapy to the internal iliac artery may be helpful in palliation of pain and obstructions. With this method Patt (13) has reported significant improvement in a number of patients treated with 5-FU and mitomycin C (Table 1), It is unlikely to achieve similar effects and patterns of toxicity with systemic i.v. chemotherapy. Despite some rather optimistic reports (14), results of chemotherapy of pancreatic cancer are very poor. Recently the Cancer and Leukemia Group B reported a 14% response rate for FAM (5FU, adriamycin and mitomycin C) and a 4% response rate for FSM (5-FU, streptozotocin

Locoregional application of 5-fluorouracil to the liver: Alteration of pharmacokinetics and bone marrow toxicity in rats with thioacetamide-induced cirrhosis

Pharmacokinetics and toxicity of 5-fluorouracil (5-FU) applied intra-arterially into the liver were studied in control and cirrhotic rats. Cirrhosis was induced by administering thioacetamide (4.5 mg/rat × day) over 6 months. 5-FU was administered into the hepatic artery at 30 mg/kg b.w. by bolus injection followed by infusion of 0.63 mg/kg × min for 40 min. Pharmacokinetics of 5-FU in plasma was studied by HPLC analysis. 5-FU induced toxicity was examined in a second group of control and cirrhotic rats at 48 and 168 hours after treatment with 5-FU (31.4 mg/kg b.w.) infused into the liver artery for 1 h. Analysis of toxicity was carried out by determining liver enzymes in plasma, bone marrow cellularity and colony forming units in vitro (CFU-C) and in vivo (CFU-S). The results indicate that during the period investigated (85 min) 5-FU was not eliminated from the plasma of cirrhotic rats in contrast to controls. The constant level of 5-FU in the plasma of cirrhotic rats induced a considerably higher myelosuppression in these animals, than the short-lived 5-FU peak in controls.

Oral Ftorafur Versus Intravenous 5-Fluorouracil: A comparative study in patients with colorectal cancer

The toxicities of oral Ftorafur (1 g/m2/day 1-21) and intravenous 5-fluorouracil (5-FU) (500 mg/m2/day 1-5) were compared in a prospective randomized study in patients with colorectal cancer. The treatment courses were repeated every 6th week. Leucopenia was more common after 5-FU. Leucocyte nadir in connection with first treatment cycle was on average seen on day 15 in patients receiving 5-FU and on day 28 in patients receiving Ftorafur. Significantly more patients on 5-FU developed stomatitis. There was no difference in the number of patients with diarrhea or nausea/vomiting. Median survival and response rates were not significantly different after the two treatment schedules.