inhibitor of thymidylate synthase
-FUdR-t inhibitor of thymidylate synthase
1 uridine phosphorylase
2 thymidine phosphorylase
3 phosphoribosyl transferase
4 thymidine kinase
5 uridine kinase
6 ribonucleotide reductase dlhydropyrimidlne dehydrogenase
FIGURE 51-5 Activation pathways for 5-fluorouracil (5-FU) and 5-floxurMine (FUR). FUDP, floxuridine diphosphate; FUMP, floxuridine monophosphate; FUTP, floxuridine triphosphate; FUdR, fluorodeoxyuridine; FdUDP, fluo-rodeoxyuridine diphosphate; FdUMP, fluorodeoxyuridine monophosphate; FdUTP, fluorodeoxyuridine triphosphate; PRPP, 5-phosphoribosyl-1-pyrophosphate.
A number of biochemical mechanisms are associated with resistance to the cytotoxic effects of 5-FU or FUdR. These mechanisms include loss or decreased activity of the enzymes necessary for activation of 5-FU, amplification of TS, and mutation of TS to a form that is not inhibited by FdUMP.
The response to 5-FU correlates significantly with low levels of the degradative enzymes dihydrouracil dehydrogenase and thymidine phosphorylase, and a low level of expression of TS. TS levels are finely controlled by an autoregulatory feedback mechanism wherein unbound TS inhibits the translational efficiency of its own mRNA. When TS is bound to FdUMP, inhibition of translation is relieved, and levels of free TS are restored. Thus, TS autoregulation may be an important mechanism by which malignant cells become insensitive to the effects of 5-FU.
Some malignant cells appear to have insufficient concentrations of 5,10-methylene tetrahy-drofolate, and thus cannot form maximal levels of the inhibited TS-FdUMP-folate ternary complex. Addition of exogenous folate in the form of leucovorin increases formation of the complex and has enhanced responses to 5-FU.
In addition to leucovorin, a number of other agents have been combined with 5-FU in attempts to enhance the cytotoxic activity through biochemical modulation. Methotrexate, by inhibiting purine synthesis and increasing cellular pools of PRPP, enhances 5-FU activation and increases antitumor activity of 5-FU when given before but not after 5-FU. The combination of cisplatin and 5-FU has yielded impressive responses in tumors of the upper aerodigestive tract, but the molecular basis of their interaction is not well understood. Oxaliplatin is commonly used with 5-FU and leucovorin for treating metastatic colorectal cancer, but the mechanism responsible for the syner-gistic clinical effect has not been fully elucidated. Oxaliplatin may inhibit catabolism of 5-FU, perhaps by inhibiting DPD, and may inhibit expression of TS. 5-FU with simultaneous irradiation is curative therapy for anal cancer and enhances local tumor control in head and neck, cervical, rectal, gastroesophageal, and pancreatic cancer; the mechanism for this synergism is unclear.
5-FU is administered parenterally, since oral absorption is unpredictable and incomplete. Metabolic degradation occurs in many tissues, particularly the liver. 5-FU is inactivated by reduction of the pyrimidine ring; this reaction is carried out by DPD, which is found in liver, intestinal mucosa, tumor cells, and other tissues. Although rare, inherited deficiency of DPD leads to greatly increased sensitivity to the drug and profound drug toxicity following conventional doses. DPD deficiency can be detected either by enzymatic or molecular assays using peripheral white blood cells, or by determining the plasma ratio of 5-FU to its metabolite, 5-fluoro-5,6-dihydrouracil.
After intravenous administration of 5-FU, plasma clearance is rapid (t1/2, 10—20 minutes). Urinary excretion of a single intravenous dose of 5-FU amounts to only 5—10% in 24 hours. Although the liver contains high concentrations of DPD, dosage does not have to be modified in patients with hepatic dysfunction, presumably because of degradation of the drug at extrahepatic sites or by vast excess of this enzyme in the liver. 5-FU enters the CSF in minimal amounts.
Capecitabine is well absorbed orally. It is rapidly de-esterified and deaminated, yielding high plasma concentrations of 5 -deoxy-fluorodeoxyuridine (5 -dFdU), which disappears with a t1/2 of ~1 hour. 5-FU levels are <10% of those of 5'-dFdU. The conversion of 5'-dFdU to 5-FU by thymidine phosphorylase occurs in liver, peripheral tissues, and tumors. Liver dysfunction delays the conversion of the parent compound to 5 -dFdU and 5-FU, but there is no consistent effect on toxicity.
5-Fluorouracil 5-Fluorouracil produces partial responses in 10-20% of patients with metastatic colon carcinomas, upper GI carcinomas, and breast carcinomas. The administration of 5-FU in combination with leucovorin in the adjuvant setting is associated with a survival advantage for patients with colorectal cancers and gastric cancers.
For average-risk patients in good nutritional status with adequate hematopoietic function, the weekly dosage regimen is 500-600 mg/m2 with leucovorin once each week for 6 of 8 weeks. Other regimens use daily doses of 500 mg/m2 for 5 days, repeated in monthly cycles. When used with leucovorin, doses of daily 5-FU for 5 days must be reduced to 375-425 mg/m2 because of mucositis and diarrhea. 5-FU is increasingly used as a biweekly loading dose followed by a 48-hour continuous infusion, a schedule that has less overall toxicity as well as superior response rates and progression-free survival for patients with metastatic colon cancer.
FUdR (fluorodeoxyuridine; FUDR) is used primarily by continuous infusion into the hepatic artery for treatment of metastatic carcinoma of the colon or following resection of hepatic metastases; the response rate to such infusion is 40—50%, or double that observed with intravenous administration. Intrahepatic arterial infusion for 14—21 days may be used with minimal systemic toxicity. However, there is a significant risk of biliary sclerosis if this route is used for multiple cycles of therapy. Treatment should be discontinued at the earliest manifestation of toxicity (usually stomatitis or diarrhea) because the maximal effects of bone marrow suppression and gut toxicity will not be evident until days 7—14.
Capecitabine is FDA-approved for the treatment of (1) metastatic breast cancer in patients who have not responded to a regimen of paclitaxel and an anthracycline antibiotic; (2) metastatic breast cancer when used in combination with docetaxel in patients who have had a prior anthra-cycline-containing regimen; and (3) metastatic colorectal cancer for patients in whom fluoropy-rimidine monotherapy is preferred. The recommended dose is 2500 mg/m2 daily, given orally in two divided doses with food, for 2 weeks followed by a rest period of 1 week. This cycle is then repeated two more times.
combination therapy Higher response rates are seen when 5-FU is used in combination with other agents, such as cyclophosphamide and methotrexate (breast cancer), cisplatin (head and neck cancer), and with oxaliplatin or irinotecan in colon cancer. The combination of 5-FU and oxaliplatin or irinotecan has become the standard first-Line treatment for patients with metastatic colorectal cancer. The use of 5-FU in combination regimens has improved survival in the adjuvant treatment for breast cancer, and with oxaliplatin and leucovorin, for colorectal cancer. 5-FU also is a potent radiation sensitizer. Beneficial effects also have been reported when combined with irradiation for cancers of the esophagus, stomach, pancreas, cervix, anus, and head and neck. 5-FU is used widely with very favorable results for the topical treatment of premalignant keratoses of the skin and multiple superficial basal cell carcinomas.
The clinical manifestations of toxicity caused by 5-FU and floxuridine are similar and may be difficult to anticipate because of their delayed appearance. The earliest untoward symptoms are anorexia and nausea; these are followed by stomatitis and diarrhea, which are reliable warning signs that a sufficient dose has been administered. Mucosal ulcerations occur throughout the GI tract and may lead to fulminant diarrhea, shock, and death, particularly in patients who are DPD deficient. The major toxic effects of bolus-dose regimens result from the myelosuppressive action of 5-FU. The nadir of leukopenia usually is between days 9 and 14 after the first injection of drug. Thrombocytopenia and anemia also may occur. Loss of hair, occasionally progressing to total alopecia, nail changes, dermatitis, and increased pigmentation and atrophy of the skin may be encountered. Hand-foot syndrome consisting of erythema, desquamation, pain, and sensitivity to touch of the palms and soles also can occur. Neurological manifestations, including an acute cere-bellar syndrome, have been reported, and myelopathy has been observed after the intrathecal administration of 5-FU. Cardiac toxicity, particularly acute chest pain with evidence of ischemia in the electrocardiogram, also may occur. In general, myelosuppression, mucositis, and diarrhea occur less often with infusion than bolus regimens, while hand-foot syndrome occurs more often with infusion than bolus regimens. The low therapeutic indices of these agents emphasize the need for very skillful supervision by physicians familiar with the action of the fluorinated pyrimidines and the possible hazards of chemotherapy. Capecitabine causes much the same spectrum of toxi-cities as 5-FU (diarrhea, myelosuppression), but the hand-foot syndrome occurs more frequently and may require dose reduction or cessation of therapy.
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