Targets For Fluoropyrimidines

Inhibition of TS by FdUMP is considered to be the main mechanism for the action of 5-FU (Fig. 2). Several mechanisms of resistance to 5-FU have been attributed to alterations in TS (3). Characteristics of the TS enzyme have been described in detail by others (39,40). TS catalyses the conversion of dUMP to dTMP, for which 5,10-methylene-tetrahydrofolate (CH2-THF) serves as a methyl donor. FdUMP acts as a potent competitive inhibitor of TS with dUMP. The inhibition by FdUMP is mediated by the...

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...

Introduction

Fluoropyrimidines occupy a unique niche in the noninvasive studies of drugs. For one, 5-fluorouracil (5-FU), which was introduced by Heidelberger in the late 1950s as an anticancer agent, continues to be used widely for chemotherapy of colorectal and other cancers. And the physical properties of the fluorine atom make fluorinated drugs highly suitable for studies by two of the key imaging technologies. The 2-h 18F isotope allows fluorinated drugs to be studied using positron emission tomography...

Late Phase Ii Clinical Trial Of S1 In Head And Neck Cancer

This clinical trial was conducted to examine the antitumor activity and toxicities of S-1, in which 60 patients with head and neck cancer were enrolled. S-1 was administered at a dose of 40 mg m2d, with at least four courses, each of which consisted of twice-a-day (once each after breakfast and dinner), 28-d consecutive oral administration and of 14-d withdrawal two courses were repeated every 6 wk unless the disease progressed. As shown in Table 9, there were four complete response cases and...

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...

Posttranscriptional Regulation Of Ts

The evidence that the TS gene is regulated posttranscriptionally comes from transcrip-tional studies that demonstrated alterations in the rates of transcription are insufficient to explain changes in the levels of TS mRNA and protein, the need for spliceable introns for S-modulation of the translation of TS mRNA by TS protein. There are three major sites for the posttranscriptional regulation of TS levels. These are TS RNA (pre-mRNA and mRNA) processing and stability, protein stability, and TS...

Folate Polyglutamates In Tumors And Optimal Levels Of Reduced Folates For 5fu Enhancement

Virtually all of the intracellular pool of folate cofactors exist as poly-y-glutamate derivatives, and the normal endogenous substrate used by TS in mammalian tumor cells and normal stem cells is and -hexaglutamates. The chain length of the polyglutamate side chain of the folate cosubstrate available to intracellular TS will change depending on the level of folates available in the mileau in which the tumor cell or normal stem cell finds itself, and the level of folylpolyglutamate synthetase....

Info

Recent reports of this intermittent schedule have suggested that a dose of 2000 mg m2 per day can be administered in patients with breast cancer with less toxicity and no loss of efficacy (30, 31). The third trial with leucovorin established a phase II total daily dose of 1650 mg m2 with 60 mg of leucovorin (28). Hand-foot syndrome is a common toxi-city with this agent and usually occurs within the first two cycles of treatment (32). Phase I studies of capecitabine in...

Conclusions

The therapeutical concept of conventional cancer chemotherapy has been, no adverse reaction, no effect. However, the development of an adverse reaction precludes the conduction of long-term treatment, and cancer chemotherapy would involve great difficulty in contributing to life prolongation. Allowance of long-term treatment which enables the patient to eat through alleviation of adverse reactions which are most unendurable for the patient, e.g., diarrhea, stomatitis, anorexia, and HF syndrome,...

Length Of Time That Ts Must Be Inhibited To Yield Efficient Cell Kill

The question has been debated with little solution as to how long TS must be inhibited in order to irreversibly initiate cell kill. Given the multiple mechanisms possible for 5-FU, the timing of inhibition of TS by this agent needed for induction of cytotoxicity could always be debated, with little hope of a definitive answer. However, two test systems have yielded the answer Cell lines genetically modified to be deficient in TS (97,98) and cell lines inhibited by the pure TS inhibitor tomudex...

Studies On The Modulation Of 5fu

Experimental studies had shown that certain agents would enhance the action of 5-FU, and a number of such drug combinations are used clinically. Methotrexate (MTX) is a drug that has been used widely as a modulator of the action of 5-FU (49). Its putative mode of action as a modulator was to inhibit the formation of purines, thereby making more phos-pho-ribosyl-pyrophosphate available for the conversion of 5-FU into of 5-FUR and 5-FdUR and their nucleotides (50). We had shown in animal studies...

Phase I Studies

Three schedules of eniluracil plus 5-FU have been evaluated in phase I studies daily for 5 d every 28 d, which mimics the Mayo Clinic bolus regimen of 5-FU daily for 28 d every 35 d, which more closely parallels the continuous infusion schedule and weekly for 6 wk every 8 wk, which simulates the weekly 24-h high-dose continuous infusion schedule. As expected, the maximum tolerated dose (MTD) of 5-FU administered with eniluracil is dramatically lower than the MTD of 5-FU as a single agent. The...

Drug Design And Discovery Of Capecitabine

2.1. 5'-DFUR as a Lead Compound of Capecitabine In 1976, Cook et al. synthesized 5'-DFUR (10), which has shown higher antitumor activity at broader dose ranges than 5-FU and other fluoropyrimidines in many tumor models (2-4). 5'-DFUR was identified as a prodrug that generates the active drug 5-FU through enzymatic conversion by pyrimidine nucleoside phosphorylases (PyNPase) (2), which are preferentially located in tumor tissues (6,11). Consequently, 5'-DFUR generates 5-FU efficiently in tumors...

Nsabp Colon Cancer Adjuvant Trials

The NSABP historically has included Stage II and Stage III colon cancer patients in all its adjuvant chemotherapy trials. Four such trials (C-01, C-02, C-03, and C-04) are described below. From November 1977 through February 1983, 1166 patients were entered into the NSABP's first randomized adjuvant clinical trial for patients with resected Stage II and Stage III colon cancer (12). Patients were stratified by stage, gender, and age to receive either MOF (MeCCNU, vincristine, and fluorouracil),...

Biomodulation Of 5fu

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...

Combined Locoregional And Systemic Chemotherapy

The rationale for combining locoregional and systemic chemotherapy in advanced col-orectal cancer with metastases to the liver only is based on the following issues 1. Locoregional chemotherapy has a well-defined activity in these patients and is possibly superior, as reported above, to systemic treatment (at least when traditional agents are administered intravenously). 2. The two therapeutic modalities have nonoverlapping side-effects (liver toxicity for intraarterial therapy, chiefly when...

References

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Clinical Pharmacology Trials

UFT in a dose range of 100-400 mg results in linear plasma exposures of tegafur, uracil, and 5-FU. In order to assess the pharmacokinetics of single- and continuous-dose UFT, patients with metastatic colorectal cancer initally received a single dose of UFT at either 100, 200, or 400 mg, accompanied by LV 25 mg orally, followed, after 7 d of rest, by treatment with UFT 300 mg m2 plus LV 75 mg d. After single-dosing, the plasma concentrations of tegafur, 5-FU, and uracil rose rapidly, reaching...

Clinical Chronopharmacology

Rhythm in 5-FU Pharmacokinetics 5-FU 15 mg kg, e.g., approx 600 mg m2 was injected intravenously bolus at 01 00, 07 00, 13 00 or 19 00 h to 28 patients with metastatic gastrointestinal cancer in a randomized sequence, each injection being separated by 96 h from the next one. Both plasma pharmacokinetics and hematologic toxicity were assessed. 5-FU dosing at 01 00 h resulted in the longest half-life, in the largest VdSS and AUC, and in the lowest clearance CIB , as well as in the least...