During the course of anti-cancer chemotherapy in patients with hematological malignancy, the patients'urate metabolism is supposed to change dynamically. In the early stage of anti-cancer chemotherapy, some patients show overproductive hyperuticemia, and subsequently hyperuricosuric hypouricemia at a later stage. To clarify the mechanism of such change in urate dynamics and the mechanism related to anti-cancer chemotherapy, we retrospectively analyzed the serum urate level and the urate dynamics before and just after CHOP therapy (cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone)in 20 patients with non-Hodgkin's lymphoma. The serum urate level decreased with significant hyper-excretion of uric acid from kidneys one week after chemotherapy. Moreover, the total amount of urine excretion was elevated after chemotherapy, suggesting that increased uricosuria persisted one week after chemotherapy. We also analyzed several parameters in both peripheral blood and urine before and just after CHOP therapy with lowering of the serum urate level. Among the blood parameters, a significant decrease in the serum LDH level and an increase in both the serum GPT level and fasting blood sugar were seen after CHOP therapy. Regarding urine parameters, urine volume, urine sodium excretion and the concentration of NAG were significantly increased after CHOP therapy compared to that before therapy, suggesting that the chemotherapy-induced tubulopathy occurred after CHOP therapy. Thus, as a reason for hyper-excretion of uric acid from kidneys, it was suspected that renal tubular dysfunction occurred secondary to druginduced toxicity. Therefore, to prevent urate nephropathy due to chemotherapy, we conclude that the monitoring and control of both uricosuria and the serum uric acid level are important during anti-cancer chemotherapy.

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Cytosine arabinoside (ara-C), a pyrimidine nucleoside analogue, has been one the key drug for treatment of acute leukemia. The incorporation into DNA of ara-C nucleotide (ara-C/DNA), which induces a kind of DNA damage, is a critical step for inducing apoptosisin leukemic cells. Ara-C/DNA has been shown to correlate negatively with the loss of colonyforming ability of leukemic cells. In HL-60 cells incubated in the presence of 1μ Mara-C for 4.5 h, the ara-C/DNA reached 79.5±11.2fmol/μg DNA, however, the induction of apoptosiswas not observed. In contrast, aphidicolin (APD), an inhibitor of DNA polymerases, induced pronounced apoptosisin cells with ara-C/DNA mealy one thirds of above. c-Jun N-terminal kinase (JNK) was found to be activated by APD treatment in a concentrationdependent manner in cells minimally damaged with ara-C. The activation of JNK was followed by the induction of apoptosis. Since it has been suggested that ara-C/DNA decreased in ara-C-resistant cells, the ability of APD to overcome the ara-C-resistance was determined. HL/AD and HL/AD30, which were 10- and 300-folds resistance to ara-C compared with original HL-60 cells, respectively, have established. In both resistant cells,3μM APD treatment combined with ara-C induced synergistic apoptosis. The isobologram analysis also showed the synergistic interaction of APD and ara-C in both resistant cells. Taken together, APD induces apoptosisin cells tolerating ara-C-mediated DNA damage by activating JNK, and has the ability to circumvent ara-C-resistance in vitro.

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We analyzed the clinical profiles of 22 patients showing formation or disappearance for urolithiasis on ultrasonography during treatment for hyperuricemia. Patients were divided into two groups; the calculi formation group and the calculi disappearance group. Urinary uric acid and calcium excretion, pH of urine, and osmotic pressure of urine were examined retrospectively over one year before the formation or disappearance of urolithiasis. In these parameters, there were no significant differences between the groups. Most patients in both groups demonstrated overproductiontype hyperuricemia. We found that 88 % of the patients had taken allopurinol in the disappearance group, while 43% of the patients were administered benzbromarone in the formation group. In analysis of the type of hyperuricemia in both groups, all 3patients with underexcretion-type hyperuricemia in the formation group were administered benzbromarone, and all 4 patients with overproduction-type in the disappearance group took allopurinol. These findings suggested that there might be close relationships between calculi formation and benzbromarone administration, and between calculi disappearance and allopurinol administration.

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