References

Iyer L, Ratain MJ 5-fluorouracil pharmacokinetics causes for variability and strategies for modulation in cancer chemotherapy. Cancer Invest 1999 17(7) 494-506. 2. Meta-analysis Group in Cancer Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998 16(1) 301-308. 3. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997 15(1)...

History Of Cancer Chemotherapy And Reflection Thereon

Originally, cancer chemotherapy started with nitrogen mustard, a derivative of poisonous gas yperite, a by-product in World War II. The pharmacological action of nitrogen mustard consists in cytotoxicities (e.g., leukopenia, diarrhea, and stomatitis) to the organism, and attempts were made to utilize these toxicities to obtain anticancer activity. Namely, the modality consisted in cancer therapy using toxicities to the organism that were inherent to nitrogen mustard. From the standpoint of...

Dpd Inhibitors

There were recently four agents under development that interacted with DPD activity (Table 1) 5 ethynyluracil was the only one that is a DPD inactivitor (irreversible inhibition) 5-FU Oral Prodrugs Under Clinical Evaluation that Contain a DPD Inhibitor Eniluracil (Glaxo-Wellcome) UFT (Orzel(R), Bristol-Myers Squibb, contains UFT plus leucovorin) S1 (Bristol-Myers Squibb) tegafur + potassium oxonate 1-Ethoxymethyl-5-fluorouracil + BOF-A2 (Emitefur(R), Otsuka America Pharmaceutical) while the...

Clinical Chronotherapy With 5fu Based Regimens

Chronotherapy Tolerability and Efficacy (Phase I-II studies) 5.1.1. Hypotheses and Overall Strategy A dose-response relationship characterized the antitumor efficacy of 5-FU against colorectal cancer (76). The chronotherapy hypothesis has thus considered that high doses of this drug and proper circadian scheduling of drug delivery were needed to concurrently achieve maximum anticancer efficacy and good treatment tolerability and compliance. 5-FU has been the model drug to test these...

Biomodulation Of 5fu

Folfox Regimen Colorectal Cancer

Biomodulation is a strategy that involves the alteration of tumor cell susceptibility to anticancer drugs through the modification of biochemical pathways to produce an accentuated or selective action on the cancer cells. This approach differs from that of combination chemotherapy because the biomodulator is not a cytotoxic agent. The most widespread use of biomodulation involves the use of leucovorin (LV) to increase intracellular folate cofac-tors and, thus, enhance the binding of...

Transcriptional Regulation

The majority of the initial studies on the regulation of expression of TS focused on cell-cycle-directed events. TS enzyme activity increases maximally at the Gl S-phase boundary of the cell cycle in eukaryotic cells (29). In quiescent cells, the levels of TS mRNA and TS protein are present at relatively low levels. However, when resting cells are stimulated to proliferate upon addition of serum, both TS mRNA and TS protein levels increase by more than 10- to 20-fold as cells progress from the...

Role Of P53 In The Mechanism Of 5fu Action

The relationship between apoptosis, p53, and the sensitivity of cancer cells to chemother-apeutic agents has been the subject of considerable debate reviewed in ref. 67 . The relationship between wtp53 and induction of apoptosis following DNA damage has been well established, particularly in oncogenically transformed normal cells, which appear to have a lower threshold for apoptosis induction following drug treatment, as well as in tissues of lymphoid origin 68 . Loss of wtp53 function is...

Mechanism Of 5fu Action

Following entry within the cell, 5-FU is extensively metabolized. The active metabolite 5-fluorodeoxyuridylate FdUMP binds to the enzyme TS in a covalent ternary complex with the reduced folate cofator 5,10-methylenetetrahydrofolate CH2-H4PteGlu thereby inhibiting enzyme function and the synthesis of deoxythymidine triphosphate dTTP de novo Fig. 1 . The stability of the ternary complex, degree and duration of TS inhibition, and the cyto-toxic action of 5-FU are enhanced when the folate is...

Geert H Blijham MD PhD

Development of UFT Tegafur-Uracil Clinical Application of UFT as Monotherapy Phase I II Trials of UFT Plus LV Clinical Pharmacology Trials Phase Ill Trials of UFT LV in Previously Untreated CRC Future Development of UFT Plus LV Therapy Conclusions References The fluoropyrimidines are among the most active classes of anticancer agents used in the chemotherapy of colorectal cancer. More than 40 yr after its introduction, intravenous 5- flu-orouracil IV 5-FU therapy remains a fundamental treatment...

Dpd In Tumors And Resistance To 5fubased Therapy

DPD activity can be considered as a potential factor for controlling 5-FU responsiveness at the tumoral level. The concept is simple A high level of tumor DPD would metabolize 5-FU to inactive products before cytotoxic nucleotides can be formed. The potential role of DPD for influencing 5-FU activity also concerns new 5-FU prodrugs like UFT or capecitabine, where 5-FU is metabolically produced at the target site. Previous in vitro data revealed that DPD activity in tumor cells was significantly...