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221.
V. Kurowski T. Cerny A. Küpfer T. Wagner 《Journal of cancer research and clinical oncology》1991,117(Z4):S148-S153
The initial metabolism of ifosfamide (IF) consists of two different pathways: enzymatic hydroxylation at carbon-4 forms the cytostatically active metabolite 4-OH-IF (activated ifosfamide) whereas side-chain oxidation results in the liberation of chloroacetaldehyde, a compound with possible neurotoxic properties. The pharmacokinetics of ifosfamide and its activated form were investigated in 12 cancer patients, who received both oral and i.v. treatment in a randomized sequence on days 1 and 3 at a dose of 1 g/m2 (n=7) or 1.5 g/m2 (n=5). In 3 patients the pharmacokinetics of chloroacetaldehyde were also investigated. After oral application, ifosfamide absorption proceeded rapidly, the oral bioavailability was 0.92. Independent of the route of ifosfamide application on day 1, the terminal half-life on day 3 (when the drug was given by the alternative route) was decreased in 6 out of the 12 patients, thus indicating self-induction of hepatic metabolism. 4-OH-IF was already present 20 min after ifosfamide administration. In the individual patient the concentrations of 4-OH-IF were always higher after oral than after i.v. IF application: the mean p.o.:i.v. ratios forc
max and the area under the concentration/time curve were 2.3 and 1.7 respectively (P<0.05). in=" a=" first=" series=" of=" 3=" patients=" the=" chloroacetaldehyde=" concentrations=" measured=" after=" oral=" ifosfamide=" application=" were=" about=" twice=" as=" high=" as=" those=" when=" the=" drug=" was=" given=" intravenously.=" these=" results=" indicate=" that=" (in=" comparison=" to=" the=" i.v.=" route)=" orally=" administered=" ifosfamide=" may=" be=" more=" cancerotoxic=" but=" also=" leads=" to=" higher=" levels=" of=" chloroacetaldehyde.=" this=" would=" explain=" the=" neurotoxic=" sideeffects=" previously=" seen=" after=" oral=" administration=" of=" comparatively=" low=" ifosfamide=">0.05).>Presented at the Satellite Symposium Ifosfamide in Tumor Therapy: Questions for the Nineties; 15th International Cancer Congress, Hamburg, August 16–22,1990 相似文献
222.
目的探讨奥沙利铂+多柔比星+异环磷酰胺(OXIA)方案治疗耐药性和难治性卵巢上皮癌的临床疗效。方法 2009年7月—2010年3月济南军区总医院肿瘤科收治的复发、进展及耐药的难治性卵巢癌患者26例,均采用OXIA方案(奥沙利铂130mg/m2,多柔比星50~60mg/m2,异环磷酰胺4g/m2,每3周为1个疗程)进行挽救性化疗。其中接受≥2个疗程OXIA方案化疗的22例纳入本研究,并对其疗效及化疗不良反应进行回顾性分析。22例患者共接受81个疗程的OXIA方案化疗,中位疗程数为4个(2~7个)。结果完全缓解5例(22.7%),部分缓解10例(45.4%),有效率达68.2%;病情稳定2例(9.1%),病情进展5例(22.7%)。Ⅲ~Ⅳ度血液学不良反应的发生率为29.6%(24/81),Ⅲ~Ⅳ度中性粒细胞减少症的发生率为24.7%(20/81),Ⅲ~Ⅳ度血小板减少症的发生率为8.6%(7/81),Ⅲ~Ⅳ度贫血的发生率为7.4%(6/81);Ⅲ~Ⅳ度消化道反应的发生率为34.6%(28/81),周围神经毒性反应的发生率为37.0%(30/81),Ⅲ~Ⅳ度心脏毒性的发生率为19.8%(16/81),浅表静脉炎的发生... 相似文献
223.
Use of V79 cells with stably transfected cytochrome P450 cDNAs in studying the metabolism and effects of cytotoxic drugs 总被引:1,自引:0,他引:1
Philip Agop Philip Shadan Ali-Sadat Johannes Doehmer Thomas Kocarek Aftab Akhtar Hong Lu Kenneth K. Chan 《Cancer chemotherapy and pharmacology》1999,43(1):59-67
Purpose: Studying the metabolism of cytotoxic drugs has become increasingly necessary to predict clinically significant drug-drug interactions and to understand the basis of interindividual variations in the pharmacokinetics of anticancer agents. The aim of this study was to determine the feasibility of using V79 Chinese hamster fibroblasts, which are stably transfected with cytochrome P450 (CYP) cDNAs, to study the metabolism of cytotoxic drugs in vitro. Methods: The 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine cell survival after incubation with drugs. Gas chromatography/mass spectroscopy was used for the quantitation of metabolites of cyclophosphamide and ifosfamide in culture medium. The coculture technique was used to study the generation of cytotoxic metabolites in culture medium. Results: After treatment with either cyclophosphamide or ifosfamide (100 μM to 1 mM ) cytotoxicity was demonstrated in only cytochrome CYP2B1- and cytochrome CYP3A4-expressing cells. Treatment of parental nontransfected cells that were cocultured with CYP-expressing cells with cyclophosphamide resulted in increased sensitivity to this drug. All active and inactive metabolites of cyclophosphamide and ifosfamide were detected in the culture medium. Cyclophosphamide-induced cytotoxicity in CYP2B1- and CYP3A4-expressing cells was abrogated by metyrapone and midazolam/ troleandomycin, respectively. Paclitaxel showed greater cytotoxicity against parental V79 cells than against the CYP2B1-, 2E1-, or 3A4-expressing cells, which was also influenced by cotreatment with CYP inhibitors. Conclusions: Stable expression of CYP cDNAs by V79 cells provided an in vitro system to study cytotoxic drug metabolism. Cell viability and metabolite assays were used to determine the differential metabolism and effects in different CYP-transfected cell lines treated with cytotoxic drugs. The potential use of this V79 cell expression system is in studying enzymes involved in the metabolism of cytotoxic drugs, especially early in drug development. In addition, this system may be used to determine drug interactions that may influence the outcome of therapy in patients with cancer. Received: 18 December 1997 / Accepted: 14 May 1998 相似文献
224.
目的 探讨三氧化二砷联合ICE方案(异环磷酰胺、顺铂、依托泊苷)治疗复发难治非霍奇金淋巴瘤(NHL)的疗效和不良反应.方法 15例复发难治性NHL患者采用三氧化二砷联合ICE方案化疗.异环磷酰胺1.2 g/m2,静脉滴注,第1~4天;同时于异环磷酰胺后0 h、4 h和8 h应用美司那预防出血性膀胱炎,每次用量为当日异环磷酰胺的20%,静脉注射;顺铂25 mg/m2,静脉滴注,第1~2天,足叶乙甙50 mg/m2,静脉滴注,第1~3天,亚砷酸10 mg,静脉滴注,第5~18天;21~28 d为一个周期,每例患者至少完成两个周期以上治疗.观察疗效和不良反应.结果 15例患者中完全缓解5例,部分缓解4例,疾病稳定4例,疾病进展2例,临床总有效率为60%.主要不良反应为骨髓抑制,Ⅲ~Ⅳ度白细胞减少为12例(80.0%).结论 三氧化二砷联合ICE方案治疗复发难治性NHL临床效果满意,值得临床推广. 相似文献