1,721,019 research outputs found
Comparison of in vitro drug sensitivity by inhibition of tritium release from [5-3H]-2'-deoxyuridine and a clonogenic assay
No full textThymidylate synthase protein expression in primary colorectal cancer compared with the corresponding distant metastases and relationship with the clinical response to 5-fluorouracil
No full textMechanism of action of fluoropyrimidines: relevance to the new developments in colorectal cancer chemotherapy
No full textReply to Letter to the Editor 'Weekly oxaliplatin and pre-operative radiotherapy as a new neoadjuvant therapy for locally advanced rectal cancer', by T. Watanabe et al. (Ann Oncol 2006; 17 : 1173)
No full textResistance to 5-fluorouracil and 5fluoro 2'deoxyuridine: mechanisms and clinical implications
No full textMechanism of action of fluoropyrimidines: Relevance to the new developments in colorectal cancer chemotherapy
No full textAlternating bolus and continuous infusion 5-fluorouracil: A strategy to overcome resistance to this fluoropyrimidine in advanced colorectal cancer patients
No full textFocusing our effort on the importance of FUra scheduling we have tested the hypothesis that pulse and continuous
infusion (CI) of the fluoropyrimidine have different mechanisms of cytotoxicity. Our initial approach was to compare
the mechanism of resistance of a cell line resistant to a short term exposure to FUra (HCT-8/FU4hR) to that of a
cell line resistant to a prolonged exposure to the fluoropyrimidine (HCT-8/FU7dR). Cytotoxicity studies showed
that HCT-8/FU4hR cells were still sensitive to FUra given as a 7-d exposure, suggesting different mech~misms
of resistance. Indeed, rapid recovery of TS activity after drug removal was evident in the HTC-8/FU7dR cell
line while HCT-8/FU4hR cells were similar to the parental cell line with regard to both the degree of in situ TS
inhibition by FUra and duration of inhibition after FUra removal. In contrast, labelling studies with [3H-6] FUra (4
h exposure, 100 # M) showed that the incorporation of the fluoropyrimidine into RNA is significantly decreased in
HCT-8/FU4hR cells as compared to parental HCT-8 cells.
Given the lack of cross resistance between the two schedules in vitro, a pilot trial was done on patients with
colorectal cancer refractory to bolus FUra. On 15 patients failing after FUra+LV or FUra alone 1 PR, 3 MR,, 3 SD
and 8 P were observed, confirming a certain degree of activity of CI FUra in patients clinically resistant to bolus
FUra.
Based on this rationale, a phase II trial of schedule-oriented biochemical modulation of FUra in advanced
colorectal cancer patients was conducted, employing a hybrid regimen of 2 biweekly cycles of FUra bolus (600
mg/sqm), preceeded by (24 h interval) methotrexate, 200 mg/sqm (in order to maximize the RNA effect of the drug)
alternating with FUra continuous infusion, 200 mg/sqm daily for 3 weeks, modulated by leucovorin, 20 mg/sqm
weekly bolus (in order to maximize the DNA effect).
Thirty-three consecutive patients (median ECOG PS 1) with advanced measurable colorectal cancer and no prior
therapy for metastatic disease entered the study, from February 1992 to August 1993. Three complete and 13 partial
responses were obtained among these 33 patients (RR=48%, 95% confidence limis, 31-66%). After a median
follow-up time of 23 months, 16 patients are still alive. The median progression free survival and overall survival
were 9.6 and 20.8 months, respectively. No toxic deaths or grade 4 toxicity occurred. The incidence of grade 3
toxicity per patient in any cycle was: mucositis 6%, diarrhea 3% and vomiting 3% for the bolus part and 21%, 3%
and 6% respectively, for the continuous infusion part of the regimen. Hand-foot syndrome occurred in 27% ,of the
patients treated with the continuous infusion regimen.
In conclusion, this experimental and clinical project has generated a novel regimen of schedule oriented biochemical modulation that is twice as active and half as toxic compared to bolus FU+LV given with either the daily x
5 or the weekly schedule. This high clinical activity is very encouraging, especially considering that 1) consecutive
patients were entered, 2) the responses were independently reviewed, 3) the progression free survival and survival
were much longer than those actually reported for this disease, 4) the toxicity of the program, in particular the bolus
regimen, was relatively low allowing further intensificatio
Fluorouracil in colorectal cancer: a tale of two drugs. Implications for biochemical modulation
No full textPURPOSE To determine if fluorouracil (FUra) has different mechanisms of action as a function of the dose schedule used. DESIGN The preclinical and clinical literature relating toxicity and antitumor effects of FUra as a function of its dose schedule, with and without modulating agents, was reviewed. RESULTS The data support the hypothesis that FUra may be considered to be two different drugs, depending on its dose schedule (bolus v continuous infusion [CI]). CONCLUSION These results suggest that additional therapeutic benefit may be obtained from FUra regimens by (1) appropriate schedule-dependent modulation, (2) the sequential or alternating use of cycles of bolus followed by cycles of CI FUra appropriately modulated, or (3) hybrid regimens, ie, those that contain both pulse and CI schedules. </jats:sec
Novel mechanisms of resistance to 5-fluorouracil in human colon cancer (HCT-8) sublines following exposure to two different clinically relevant dose schedules
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