Eniluracil plus 5-fluorouracil and leucovorin: treatment for metastatic breast cancer patients in whom capecitabine treatment rapidly failed.

BACKGROUND: As part of a comparative phase II study of eniluracil/5-FU/Lv vs. capecitabine (Xeloda), an oral 5-FU prodrug for MBC, patients with rapid PD during capecitabine therapy crossed over to take eniluracil/5-FU/Lv. PATIENTS AND METHODS: Ten evaluable patients with radiologically documented PD within 70 days of capecitabine treatment were treated with a modified oral weekly eniluracil/5-FU/Lv regimen. RESULTS: After switching to eniluracil/5-FU/Lv, 3 (30%) patients had PR. Six (60%) had SD, producing a total of 90% with PR or SD. The median PFS was 140 days (vs. 42.5 days for capecitabine). Four (40%) patients had > 7 months PFS. Eniluracil/5-FU/Lv was well tolerated with mild to moderate diarrhea and nausea as the most common side effects. CONCLUSION: These positive efficacy and safety results encourage a larger study in patients with rapid PD during capecitabine treatment. Eniluracil/5-FU/Lv might enable these patients to continue with oral 5-FU rather than switching to the generally less well tolerated intravenous microtubule-interfering agents. In addition, the eniluracil/5-FU/Lv regimen might also provide any overall survival contribution of 5-FU that, for pharmacokinetic reasons, was not provided by capecitabine and would not be provided if these patients progressed directly to the other approved treatments.

Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer.

PURPOSE: This phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy. METHODS: Five cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m² in the first cohort. For subsequent cohorts, dose was increased by 20 g/m² until a maximum tolerated dose was found. RESULTS: Ascorbic acid was eliminated by simple first-order kinetics. Half-life and clearance values were similar for all patients of all cohorts (2.0 ± 0.6 h, 21 ± 5 dL/h m², respectively). C(max) and AUC values increased proportionately with dose between 0 and 70 g/m², but appeared to reach maximal values at 70 g/m² (49 mM and 220 h mM, respectively). Doses of 70, 90, and 110 g/m² maintained levels at or above 10-20 mM for 5-6 h. All doses were well tolerated. No patient demonstrated an objective antitumor response. CONCLUSIONS: Ascorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient's blood and was well tolerated. The recommended dose for future studies is 70-80 g/m².

A possible cause and remedy for the clinical failure of 5-fluorouracil plus eniluracil.

BACKGROUND: Eniluracil is a potent inactivator of dihydropyrimidine dehydrogenase (uracil reductase), the enzyme that rapidly catabolizes 5-fluorouracil (5-FU). Although eniluracil in combination with 5-FU was promising in phase I and II studies, in 2 multicenter phase III colorectal cancer studies, eniluracil dosed in a 10-to-1 ratio to 5-FU produced less antitumor benefit than the standard regimen of 5-FU/leucovorin without eniluracil. The current study tested whether the high eniluracil doses caused the clinical failure. The effect of excess eniluracil versus adequate eniluracil on 5-FU antitumor activity was studied in rats bearing large transplanted colon tumors. MATERIALS AND METHODS: The rats were divided into 3 groups: group A received no treatment, group B was treated with eniluracil 1 mg/kg (adequate) 1 hour before 5 mg/kg 5-FU, and group C was treated identically to group B but also received eniluracil 25 mg/kg (excess) 5 minutes before 5-FU administration. RESULTS: The rate of complete tumor regression (cure) was 0% in group A (no treatment), 88% in group B (adequate eniluracil), and 25% in group C (excess eniluracil). Toxicity was minimal. Only slight weight loss occurred in all groups. CONCLUSION: When the eniluracil dose is in 5-fold excess to 5-FU (as in the phase III clinical trials), the antitumor activity of 5-FU was significantly diminished. Moreover, to maximize the antitumor activity of 5-FU, eniluracil must not be present in excess over 5-FU in rats bearing tumors. Simple strategies to achieve optimal antitumor efficacy are presented.

Superoxide radical production by allopurinol and xanthine oxidase.

Oxypurinol, an inhibitor of xanthine oxidase (XO), is being studied to block XO-catalyzed superoxide radical formation and thereby treat and protect failing heart tissue. Allopurinol, a prodrug that is converted to oxypurinol by xanthine oxidase, is also being studied for similar purposes. Because allopurinol, itself, may be generating superoxide radicals, we currently studied the reaction of allopurinol with xanthine oxidase and confirmed that allopurinol does produce superoxide radicals during its conversion to oxypurinol. At pH 6.8 and 25 degrees C in the presence of 0.02 U/ml of XO, 10 and 20 microM allopurinol both produced 10 microM oxypurinol and 2.8 microM superoxide radical (determined by cytochrome C reduction). The 10 microM allopurinol was completely converted to oxypurinol, while the 20 microM allopurinol required a second addition of xanthine oxidase to complete the conversion. Fourteen percent of the reducing equivalents donated from allopurinol or xanthine reacted with oxygen to form superoxide radicals. Superoxide dismutase prevented the reduction of cytochrome C by these substrates. At higher xanthine oxidase concentrations, or at lower temperatures, more of the 20 microM allopurinol was converted to oxypurinol during the initial reaction. At lower xanthine oxidase concentrations, or higher temperatures, less conversion occurred. At pH 7.8, the amount of superoxide radicals produced from allopurinol and xanthine was nearly doubled. These results indicate that allopurinol is a conventional substrate that generates superoxide radicals during its oxidation by xanthine oxidase. Oxypurinol did not produce superoxide radicals.