5-Fluorouracil, first introduced as a rationally synthesized anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metabolic pathways as uracil. Although several potential sites of antitumour activity have been identified, the precise mechanism of action and the extent to which each of these sites contributes to tumour or host cell toxicity remains unclear. Several assay methods are available to quantify 5-fluorouracil in serum, plasma and other biological fluids. Unfortunately, there is no evidence that plasma drug concentrations can predict antitumour effect or host cell toxicity. The recent development of clinically useful pharmacodynamic assays provides an attractive alternative to plasma drug concentrations, since these assays allow the detection of active metabolites of 5-fluorouracil in biopsied tumour or normal tissue. 5-Fluorouracil is poorly absorbed after oral administration, with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). Recently, studies have demonstrated the pharmacokinetic rationale and clinical feasibility of hepatic arterial infusion and intraperitoneal administration of 5-fluorouracil. In addition, 5-fluorouracil continues to be used in topical preparations for the treatment of malignant skin cancers. Following parenteral administration of 5-fluorouracil, there is rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes. The rapid elimination is primarily due to swift catabolism of the liver. As with all drugs, caution should be used in administering 5-fluorouracil in various pathophysiological states. In general, however, there are no set recommendations for dose adjustment in the presence of renal or hepatic dysfunction. Drug interactions continue to be described with other antineoplastic drugs, as well as with other classes of agents.

This study describes the inheritance of a defect in pyrimidine catabolism and its association with drug-induced toxicity in a patient receiving 5-fluorouracil (FUra) as adjuvant chemotherapy for breast carcinoma. The study population included the affected patient (proband), nine of her blood relatives, and seven healthy volunteers. The activity of dihydropyrimidine dehydrogenase (DPD), the initial enzyme of pyrimidine (and FUra) catabolism, in peripheral blood mononuclear cells was measured in each subject by a specific radiometric assay using FUra as the substrate. The proband had no detectable DPD activity. When enzyme levels in the proband and relatives were compared with that in controls, an autosomal recessive pattern of inheritance was demonstrated. This is the third patient with severe FUra toxicity secondary to an alteration in pyrimidine catabolism and the second from our clinic population suggesting that the frequency of this genetic defect may be greater than previously thought. Monitoring DPD activity may be important in the management of patients experiencing severe toxicity secondary to FUra chemotherapy.

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The mechanism of toxicity from 5-fluorocytosine chemotherapy is unclear. However, recent evidence suggests that the generation of 5-fluorouracil by a host may play an important role in the development of this toxicity. Using an in vitro semicontinuous culture system to mimic the intestinal microflora, we examined the capacity of this complex microbial community to convert 5-fluorocytosine to 5-fluorouracil. The system was dosed initially and after 2 weeks of chronic exposure to 5-fluorocytosine with radiolabeled 5-fluorocytosine. No detectable production of 5-fluorouracil was observed up to 8 h after the acute dose; however, at 24 h and at all time points thereafter, increasing levels of 5-fluorouracil were detected for 4 days. The chronic dose resulted in an increased rate of 5-fluorouracil production without the 8-h lag time. These findings suggest that the enzyme or enzymes responsible for the deamination of 5-fluorocytosine to 5-fluorouracil by the intestinal microflora can be induced by chronic exposure to 5-fluorocytosine and that this conversion may provide a mechanism through which 5-fluorocytosine toxicity is manifested.

The sterols of nine mature plant species in seven families ranging from the subphylum Lycopsida through the Filicopsida and the classes Gymnospermae and Angiospermae in the Pteropsida were structurally and stereochemically defined. Two plant categories were found. In the first, comprised by Dryopteris {Thelypteris) noveboracensis, Polystichum acrostichoides, Dennstaedtia punctilobuIa, Osmunda cinnamomea, Ginkgo biloba, Cucurbita pepo, and Kalmia latifolia, 24ot-alkylsterols were dominant and were composed principally of 24~-ethylcholesterol (sitosterol) or (in Cucurbita pepo) 24a-ethyllathosterol and its trans-22-dehydro derivative (spinasterol). Depending on the species, small amounts of 24a-ethyl-trans-22-dehydrocholesterol (stigmasterol), 24a-methylcholesterol (campesterol), 2 4fl-methylcholesterol (dihydrobrassicasterol, always less than campesterol), cholesterol, lathosterol, 2 4a-ethyllathosterol, 24~-methyllathosterol, trans-24-ethylidenelathosterol (AT-avenasterol), and (tentatively identified) 24-ethyl-24(25)-dehydrolathosterol were present. Spinacea oleracea was alsoCucurbitaceae, from Magnoliales through Theales to Ericales, nor from Ranales to Saxifragales. However, they are consonant with a relationship between Cucurbitaceae and Theales and between Rosales and Lamiales. Triterpenoids found in various of the families studied included cycloartenol and friedelin. The spectroscopic properties of the latter are described.