Dihydropyrimidine dehydrogenase activity: prognostic partner of 5-fluorouracil?

5-FU is one of the most commonly prescribed anticancer agents having notable activity in the treatment of cancers arising from the breast, gastrointestinal tract, and head and neck. The metabolism, mechanisms of action and resistance, and pharmacokinetics of 5-FU have been extensively investigated since its synthesis over 4 decades ago. Despite a longstanding knowledge of the metabolic pathways governing the fate of 5-FU, it is only recently that cellular activities of particular metabolic steps critical in the metabolism of 5-FU have been used as a potential means for defining populations of patients at increased risk for the toxic side effects of the drug, as well as those who may derive the greatest clinical benefit from its use. DPD is the critical rate-limiting step in the catabolism of 5-FU and accounts for 80–90% of the drug’s clearance. Thus, the level of this enzyme may be an important determinant in predicting toxicity associated with the use of 5-FU and potentially for predicting patients whose tumors are most likely to respond to treatment with 5-FU. In this issue of Clinical Cancer Research, Johnson et al. (1) describe severe multiorgan toxicity associated with the topical application of 5% 5-FU cream to the scalp of a 76-yearold male patient with basal cell carcinoma (1). This unusual and heretofore unreported example of severe toxicity associated with the topical use of 5-FU was shown by the authors to be the result of virtually undetectable DPD enzymatic activity in the PBMCs of the patient. Given the generally accepted safety of topical 5-FU use, this case represents a striking example of the severity of toxicities that may be associated with even minor exposure to 5-FU in patients with severe DPD deficiency. It has been estimated that ;3–5% of patients have PBMC DPD activity less than the 95% of the lower limit for the normal population (150 pmol/min/mg protein) and are considered to be at a high risk for the development of severe or life-threatening toxicities with the use of 5-FU (2–5). The risk of lethal toxicities is even greater for those patients with DPD activity #100 pmol/min/mg protein (#99% of normal population). Tuchman et al. (6) were the first to describe severe toxicity, including semi-coma associated with the use of 5-FU in a 27-year old woman undergoing adjuvant therapy for the treatment of breast cancer. Although these investigators did not directly measure DPD activity, the association of pyrimidinemia and pyrimidinuria in the patient, as well as in a sibling, suggested that the toxicity associated with 5-FU was the result of a genetic defect in the degradation of uracil and thymidine, most likely due to a deficiency of DPD. Subsequent investigations by Diasio et al. (7), in a second reported case of severe toxicity associated with the use of 5-FU, identified a complete lack of DPD enzymatic activity (7). Additional investigations in family members suggested an autosomal recessive pattern of inheritance. Although patients with severe or complete DPD deficiency have a high incidence of toxicity associated with the use of 5-FU, there does not seem to be a significant correlation between DPD levels within the normal range and 5-FU-associated toxicity (8). Thus, the potential role for DPD quantitation in normal tissues (PBMCs) may be limited to the identification of patients with DPD levels 2 or 3 SDs lower than the population mean and are, thus, at the highest risk for toxicity, particularly neurotoxicity, associated with the use of 5-FU. It is important to note that although the greatest site for 5-FU catabolism is in the liver, the PBMC DPD levels have been shown to closely correlate with DPD activity in normal liver, thus supporting the use of PBMCs as surrogate for total body DPD activity (9). However, recent investigations have identified monocytes as containing 3-fold more DPD activity than lymphocytes, thus the relative ratios of various mononuclear cell fractions needs to be accounted for particularly in those patients whose levels of DPD approach the 95th percentile (10). For those patients who develop severe neurological toxicity associated with the use of 5-FU in the setting of DPD deficiency, infusional thymidine may be considered a potential rescue agent. A report by Takimoto and colleagues demonstrated the value of such an approach in a patient who developed severe encephalopathy associated with the use of 5-FU and who was subsequently found to be severely DPD deficient (11). In addition to its role as a predictor of toxicity associated with 5-FU use, DPD levels may also aid in the prognostication of patient populations whose tumors are likely to respond to 5-FU. Low levels of DPD activity in normal tissues may predict for a greater fluorouracil exposure and, thus, the possibility of enhanced tumor response. Perhaps more critical are intratumoral levels of DPD that regulate intracellular 5-FU levels and, thus, may be an important determinant of clinical outcome. Preclinical work using cancer cell lines found DPD levels to be, at best, only poorly correlated with 5-FU responsiveness (12, 13). Nonetheless, several groups have investigated the predictive value of DPD as an indicator of sensitivity to 5-FU in patients. These results, albeit in relative small numbers of patients, suggest that low levels of intratumoral DPD expression are associated with 5-FU responsiveness (14–16). Given the ease with which PBMCs may be obtained, it has been suggested that this tissue may serve as a surrogate for DPD activity in tumor tissue. However, a recent investigation of colorectal tumors taken from 57 patients found only a poor correlation of DPD levels in tumor tissue with that in the PBMCs, thus supporting the need for Received 4/29/99; accepted 5/7/99. 1 To whom requests for reprints should be addressed, at Medicine Branch, National Cancer Institute, Building 10, Room 12N226, 10 Center Drive, MSC 1906, Bethesda, MD 20892-1906. 2 The abbreviations used are: 5-FU, 5-fluorouracil; DPD, dihydropyrimidine dehydrogenase; PBMC, peripheral blood mononuclear cell. 1947 Vol. 5, 1947–1949, August 1999 Clinical Cancer Research