Fluorometric determination of 4-hydroxyifosfamide in blood and urine.

Ikeuchi, Isao; Amano, Tameyuki

doi:10.1248/cpb.33.2416

Cited by 13 publications

(3 citation statements)

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“…During the first 2 decades of ifosfamide research, few data concerning identification and quantitative estimation of activated ifosfamide in humans and animals were published (Arndt et al 1988;Ikeuchi & Amano 1985;Kurowski & Wagner 1993;Kurowski et al 1991;Wagner et al 1981;Wiedemann et al 1993). This is probably 443 due to the extreme instability of 4-hydroxyifosfamide in blood (Wagner et al 1981) and to the relatively low peak plasma ifosfamide concentrations (Cmax) [l to 5 tJ,mollL] observed after administration of therapeutic doses of ifosfamide in patients (table II).…”

Section: Activation Ofifosfamide and Side-chain Oxidationmentioning

confidence: 99%

Ifosfamide Clinical Pharmacokinetics

Wagner

1994

Clinical Pharmacokinetics

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This article reviews the metabolism and pharmacokinetics of ifosfamide and their implications for the cytostatic efficacy and toxicity pattern of this alkylating agent. Ifosfamide is a prodrug that requires biotransformation to become cytotoxic. It is a structural isomer of cyclophosphamide from which it differs only in having the chlorethyl functions on different nitrogen atoms. This causes a considerable change in initial metabolism, although overall metabolism remains the same. Beside the formation of 4-hydroxy-ifosfamide ('activated ifosfamide'), a second pathway with liberation of chloroacetaldehyde exists. Therefore, less activated drug is formed than during cyclophosphamide metabolism. This fact may well explain why higher doses of ifosfamide are required during treatment. Chloroacetaldehyde may account for the adverse effects and therapeutic effects of the parent drug. This metabolite has been associated with central nervous system toxicity during ifosfamide treatment and was shown to deplete intracellular glutathione concentrations. Glutathione depletion may support the activity of alkylating metabolites in tumour cells, thus overcoming the relative resistance of the cells to alkylating agents. Possibly, this mechanism explains the lack of complete cross-resistance between ifosfamide and cyclophosphamide as well as the greater antitumour activity of ifosfamide in some tumours. Urotoxicity of ifosfamide, which was the dose-limiting adverse effect, can be successfully attenuated by the use of mesna. Distinct pharmacokinetic properties of mesna are responsible for the fact that in contrast to other sulphydryl compounds the uroprotective activity of mesna does not imply a loss of therapeutic efficacy.

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Section: Activation Ofifosfamide and Side-chain Oxidationmentioning

confidence: 99%

Ifosfamide Clinical Pharmacokinetics

Wagner

1994

Clinical Pharmacokinetics

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“…Cath B also cleaves this substrate. All three assays demonstrate satisfactory data for the within-run and between-days imprecision, which are in the range of other standardized fluorometric assays used in clinical practice (Büttner et al, 1970;Ikeuchi and Amano, 1985;Yamato et al, 1990). To discriminate between cath L-type and cath B activity, the cath L-inhibitor Z-Phe-Phe-CHN 2 was used in assays (Barrett and Kirschke, 1981;Lesser et al, 1989;Lah et al, 1992;Werle et al, 1995).…”

Section: Discussionmentioning

confidence: 70%

Fluorometric Microassays for the Determination of Cathepsin L and Cathepsin S Activities in Tissue Extracts

Werle

Staib²,

Jülke³

et al. 1999

Biological Chemistry

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We established a continuous semi-microassay, and for large-scale studies both a stopped and a continuous microtiter plate assay for the fluorometric determination of cathepsin L and cathepsin S activities in body fluids, tissues or cell extracts in the presence of cathepsin B. For the detection of enzymatic activities we used the synthetic substrate Z-Phe-Arg-AMC, and for discrimination between cathepsin L, S and cathepsin B the specific inhibitor CA-074 for blocking interfering cathepsin B activities was applied. Furthermore, we took advantage of the stability of cathepsin S at pH 7.5 for further differentiation between cathepsin L and cathepsin S activities. The kinetic assays were characterized in terms of imprecision, analytical sensitivity, accuracy and substrate concentration. The within-run coefficients of variation were found to be 4.9%-7.2% for the continuous semi-microassay, 10.3%-11.7% for the stopped, and 4.5%-11.8% for the continuous microtiter plate assay. The between-days coefficients of variation for the continuous semi-microassay were 8.1%-8.9%, while for the stopped and continuous microtiter plate assays the coefficients were 11.2%-13.5% and 5.8%-12.2%, respectively. Compared to the continuous semi-microassay, the stopped and the continuous microtiter plate assays showed 3-fold and 11-fold higher sensitivity, respectively. Comparison between the continuous enzyme activity assays at substrate concentrations of 40 microM and 200 microM demonstrated a significant correlation of r = 0.97 and r = 0.99, respectively. The newly developed microtiter plate assay will allow efficient, sensitive and high precision determination of cathepsin L and cathepsin S activities in large-scale studies of cysteine-cathepsin dependent diseases.

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“…With regard to CPM, the concentration of 4-hydroxycyclophosphamide (4-HCP), an active metabolite of CPM, was determined by means of the fluorometric method as described previously. 25) In vitro cell culture For determination of the in vitro cytotoxic activity of NDP and CPM, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used as described previously. 26) KF-28 cells (3000 cells/well) were plated in a 96-well culture plate (Sumitomo Bakelite Co., Tokyo) in 100 µl of culture medium.…”

Section: In Vivo Therapeutic Experimentsmentioning

confidence: 99%

Combination Chemotherapy with Nedaplatin and Cyclophosphamide in Human Ovarian Cancer Model

Uchida

Yoshida

Yamada

et al. 1999

Japanese Journal of Cancer Research

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The antitumor efficacy of the combination of nedaplatin (NDP) with cyclophosphamide (CPM) was evaluated using human ovarian cancer models. Since NDP has been found to have greater antitumor activity and lower nephrotoxicity than cisplatin (CDDP), we also compared the antitumor activity of NDP plus CPM with that of CDDP plus CPM. Increasing doses of NDP (16.5, 33 and 66 mg/kg as a total dose) and a fixed amount of CPM (174 or 348 mg/kg as a total dose) were injected three times at intervals of 7 days via the tail vein into mice implanted with RMUG-S, OC9-JCK or KF-28 human ovarian cancer. Simultaneous administration of NDP with CPM resulted in markedly enhanced inhibition of tumor growth for all cancers tested. The growth inhibition and survival effect of the combination therapy of NDP with CPM against KF-28 and OC9-JCK were as potent as those of CDDP plus CPM. Neither increased hematotoxicity nor a significant difference in maximum concentration, half time or area under the curve of platinum or CPM in plasma between the single and combined treatment was found. These results suggest that the combination of NDP with CPM may be clinically effective.Key words: Nedaplatin -Cisplatin -Cyclophosphamide -Combination chemotherapy -Ovarian cancer Nedaplatin (NDP) was selected from a series of platinum analogs because of its pronounced antitumor activity against solid tumors including colon carcinoma, lung carcinoma, melanoma and breast cancer, with lower nephrotoxicity than cisplatin (CDDP), in preclinical studies. [1][2][3][4][5] In clinical Phase II studies, NDP showed good efficacy against lung, 6, 7) head and neck, 8) testicular, 9) and gynecological 10) cancers. In previous studies, we have demonstrated that NDP shows synergistic antitumor activity against various cancers in combination with etoposide (ETP) or 5-fluorouracil (5-FU). 11,12) Administration of a platinum complex plus an alkylating agent is standard therapy for advanced epithelial ovarian cancer [13][14][15][16] and the most commonly used combination is CDDP and cyclophosphamide (CPM). [17][18][19] Currently, the combination of CDDP and paclitaxel represents the new standard. 20) We have previously demonstrated that NDP showed synergistic antitumor efficacy in combination with CPM against murine and human lung cancer. 21) In the present study, we evaluated the augmentation of in vivo antitumor efficacy and toxicity in the combination chemotherapy of NDP plus CPM against three human ovarian cancers, including pharmacokinetic studies. We also compared the therapeutic efficacy of NDP plus CPM with that of CDDP plus CPM.

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Fluorometric determination of 4-hydroxyifosfamide in blood and urine.

Cited by 13 publications

References 0 publications

Ifosfamide Clinical Pharmacokinetics

Ifosfamide Clinical Pharmacokinetics

Fluorometric Microassays for the Determination of Cathepsin L and Cathepsin S Activities in Tissue Extracts

Combination Chemotherapy with Nedaplatin and Cyclophosphamide in Human Ovarian Cancer Model

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