ISSN:
1569-8041
Keywords:
chemotherapy
;
colorectal cancer
;
5-fluorouracil
;
folinic acid
;
hydroxyurea
;
modulation
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of 1 mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 – FA 250 mg/m2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1–51+ months). There were eight partial responses (28%, 95% CI: 13%–47%). The median duration of response was 6.5 (range 4–9 months). Grade 3–4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008330302535
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