The expression of TS is an important independent prognosticator of disease-free survival and survival in patients with rectal cancer. Adjuvant fluorouracil (5-FU)-based chemotherapy demonstrated significant improvement in disease-free and overall survival for patients with high TS levels. Prospective studies measuring TS levels will be needed to understand further the role of TS as a prognosticator of survival and chemotherapeutic benefit.

SummaryTwenty-five patients with advanced metastatic breast cancer were treated with the combination of methotrexate 60 mg/M2 and 5-fluorouracil 700 mg/M2 intravenously on the first and eighth days, and cyclophosphamide 100 mg/M2 and prednisone 40 mg/M2 by mouth daily for the first 14 days of a 28-day cycle. The patients had had no previous chemotherapy or extensive radiotherapy and all but two had not responded to hormonal therapy or endocrine ablation. The major metastatic lesions were: lung (12 patients), liver (four patients), bone (four patients), soft tissue (three patients), nodes (two patients). Seventeen of the 25 patients (68oo) responded to treatment with seven complete remissions; these included patients suffering metastatic lesions in the lung, nodes, and soft tissue. The overall median duration of response was nine months (range 6-26 months). Toxicity was primarily haematological, but the group received an average of at least 75% of their calculated dose for each monthly cycle. Haematological toxicity was most pronounced in patients with liver dysfunction and bone marrow involvement. Out of eight nonresponders seven died, with a median survival of six months. Only six of 17 responders died, and the median survival in this group will exceed thirteen months. There was no correlation between the length of the metastasis-free interval after previous treatment and subsequent response to chemotherapy.

A B S T R A C T Cytidine deaminiase, an enzyme that catalyses the deamination of both cytidine and its nucleoside analogues including the antineoplastic agents cytosine arabinoside (ara-C) and 5-azacytidine (5-azaC), lhas been partially purified from normal and leukemic humiian granulocytes. The purification procedure included lheat precipitation at 700 C, ammoniunm sulfate precipitation, calcium phosphate gel ionl exchange, and Sephadex G-150 gel filtration. The enzymlle has mol xvt 51,000, isoelectric pH of 4.8, and maximlum activity over a broad pH range of 5-9.5. The enzyme is stabilized by the presence of the sulfhydryl reagent, dithiothreitol.Cytidine deaminase from normal human graniulocytes lhas a greater affinity for its physiologic substrate cytidine (Km = 1.1 X 10-5 AM) than for ara-C (8.8 X 10-°MI) or 5-azaC (4.3 X 10' M). Halogenated analogues such as 5-fluorocytidine and 5-bromo-2'-deoxycytidine also exhiibited substrate activity, with maximum velocities greater than that of the physiologic substrates cytidine anid deoxycytidine. No activity was observed witlh nucleotides or (leoxyniucleotides. The relative maximumlii velocity of the enzyme for cytidine and its nucleoside analogues remaiie(l constanit during purification, inidicating that a single enzynme was responsible for deaminiatioln of these substrates.Tetrahydrouridine (THU) was founid to be a strong competitive inhibitor of partially purified deamiiinase with a KT of 5.4 X 10' M.The X 10'/nmg protein) than chronic myelocytic leukemia (CML) cells (1.40±0.70 X 10' U/mg proteini) or acute myelocytic leukemia (AML) cells (0.19+0.17 X 103 U/ mg protein). To explain these differences in enzyme levels in leukemic versus normal cells, the changes in cytidine deaminase levels associated with maturation of nornmal granulocvtes were studied in niormal human bone marrow. Myeloid precursors obtained from bone marrow aspirates were separated into mature and immature fractions by Ficoll density centrifugation. Deaminase activity in lysates of mature granulocytes was 3.55-14.2 times greater than the activity found in the lysates of immature cells. Decreased enzyme activity was also found in immature myeloid cells from a patient with CML as compared to mature granulocytes from the same patient. These observations support the conclusion that the greater specific activity of cytidine deaminase in normal mature granulocytes as compared to leukemic cells is related to the process of granulocyte maturation ratlher than a specific enzymatic defect in leukemic cells.

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