5- Fluorouracil, development

Fluoro-2 -deoxyuridine has been extensively used in studies of the mechanism of action of thymidylate synthase, and 5-fluorouracil is an anticancer drug that has provided a lead to the development of others. The metabolism of 5-fluorouracil by the ascomycete fungus Nectria haematococca has been studied using F NMR (Parisot et al. 1991). a-Fluoro-P-alanine (2-fluoro-3-aminopropionate) was produced (Figure 10.27), while 5-fluorouridine-5 -mono-, di-, and triphosphate were found in acid extracts of the mycelia, and the 2 - and 3 -monophosphates were recovered from RNA. 

Since many essential nutrients (e.g., monosaccharides, amino acids, and vitamins) are water-soluble, they have low oil/water partition coefficients, which would suggest poor absorption from the GIT. However, to ensure adequate uptake of these materials from food, the intestine has developed specialized absorption mechanisms that depend on membrane participation and require the compound to have a specific chemical structure. Since these processes are discussed in Chapter 4, we will not dwell on them here. This carrier transport mechanism is illustrated in Fig. 9C. Absorption by a specialized carrier mechanism (from the rat intestine) has been shown to exist for several agents used in cancer chemotherapy (5-fluorouracil and 5-bromouracil) [37,38], which may be considered false nutrients in that their chemical structures are very similar to essential nutrients for which the intestine has a specialized transport mechanism. It would be instructive to examine some studies concerned with riboflavin and ascorbic acid absorption in humans, as these illustrate how one may treat urine data to explore the mechanism of absorption. If a compound is... 

Oxaliplatin (trans-L-diaminocyclohexane oxalate platinum II) was selected for development based on preclinical antitumor activity in murine leukemia lines and in colon cancer models (151,152). The clinical development of oxaliplatin has been primarily in colorectal cancer alone and in combination with 5-fluorouracil. 

Malerba, I., Casati, S., Diodovich, C., Parent-Massin, D. and Gribaldo, L. (2004) Inhibition of CFU-E/BFU-E and CFU-GM colony growth by cyclophosphamide, 5-fluorouracil and taxol development of high-throughput in vitro method. Toxicol in vitro, 18, 293-300. 

Flucytosine is an oral antifungal pro-drug. It has to be enzymatically deaminated by the fungi to the active metabolite, fluorouracil. Fluorouracil inhibits thymidylate synthetase and DNA synthesis. Its indications are treatment of cryptococcal meningitis and serious systemic candidiasis. Resistance develops rapidly, due to altered drug-permeability. For this reason Amphotericin B and flucytosine are often given in combination as they have synergistic effects. 

Fluorouracil and its derivatives are still important dmgs in the chemotherapy of numerous cancers (doxifluridine, tegafur, carmofur) (cf. Chapter 8). Studies on the mechanism of action of 5-FU had great influence on the development of other antitumor drugs that are derived from pyrimidine and purine. 5-FU is industrially prepared by fluorination of uracil with elemental fluorine (cf. Figure 2.6, Chapter 2). 

Actually, it was in the early 1950s that the organic chemistry of fluorine really emerged. Within only two or three years, some major applications were developed such as fluorinated general anesthetics and the antitumor properties of fluorouracil. 

The observed CEPH population mean IC50 for both docetaxel and 5-fluorouracil was similar to IC50 values observed across the NCI60 panel of human tumor cell lines (http //dtp.nci.nih.gov) (17). In addition, docetaxel- and 5-fluorouracil-induced cell death is mediated by caspase-3 cleavage, similar to that observed in tumor cells (17). These data are encouraging for the use of CEPH pedigrees as a discovery tool. However, the ultimate proof of the value of the cell-based models will be the human validation of markers derived from this process. These studies he ahead and will help position cell-based models in their correct place in the drug development process. 

Flucytosine is converted into the anti metabolite 5-fluorouracil that inhibits thymidilate synthetase, thereby disrupting DNA synthesis. It also interferes with protein synthesis by incorporation of fluorouracil into RNA in place of uracil. Although active against most Candida species, its spectrum of antifungal activity, overall, is narrow. Since resistance can develop rapidly it is usually coadministered with another agent and its main value is that it facilitates a reduction in the dose (and, presumably, the toxic effect) of amphotericin when co-prescribed in this way. The main adverse effects are marrow aplasia and hepatotoxicity. 

Shuey DL, Lau C, Logsdon RR, Zucker RM, Elstein KH, Narotsky MG, Setzer RW, Kavlock RJ, Rogers JM (1994) Biologically-based dose-response modeling in developmental toxicology biochemical and cellular sequelae of 5-fluorouracil exposure in the developing rat. Toxicol Appl Pharmacol, 126 129-144. 

Many drugs have been developed to intervene in the synthesis of TMP (Figure 6.24). For example, methotrexate (6.66) inhibits DHFR by blocking the binding site of DHF. Another antimetabolite, 5-fluorouracil (5-FU, 6.67), is converted in the body to 5-fluoro-2 -deoxyuridine 5 -monophosphate (F-dUMP, 6.68), a potent inhibitor of TS.26... 

Hydromorphone Hydrochloride Formulations containing hydromorphone with either minocycline hydrochloride or tetracycline hydrochloride were found incompatible and manifest as a color change from pale yellow to light green. Concentration-dependent incompatibilities are reported in formulations containing hydromorphone hydrochloride with dexamethasone sodium or phosphate,59 and fluorouracil.60 Visual incompatibility, such as haziness or precipitation, developed 4 hours after mixing thiopentone sodium and hydromorphone hydrochloride.61 Dependence, withdrawal, and interactions are similar to those of opioid analgesics. 

---