长程低剂量口服Vp-16治疗晚期肺癌17例近期效疗观察

应用长程低剂量口服足叶乙甙（Ｖｐ－１６）治疗晚期肺癌１７例，ＰＲ为２３．５２％（４／１７），ＮＣ３５．２９％（６／１７）；毒副作用主要为骨髓抑制、恶心、呕吐和脱发，但均为轻度及可逆性反应。长程低剂量口服Ｖｐ－１６对失去手术机会或术后复发、转移而不能耐受正规静脉化疗的晚期肺癌患者是较理想的治疗方法。     

Enhanced in vivo cytotoxicity of recombinant human tumor necrosis factor with etoposide in human renal cell carcinoma

Summary The combination of tumor necrosis factor (TNF) and etoposide (ETP) was evaluated for potential cytotoxic efficacy against a human renal cell carcinoma xenograft using an in vivo assay employing an athymic mouse host with tumor implanted a the subrenal capsule site. Both antitumor efficacy (relative survival or RTS) and toxicity (weight loss) of TNF and ETP alone and in combination were evaluated. While TNF and ETP alone were mildly inhibitory (RTS 90% and 71%, respectively), the combination caused marked tumor inhibition (45% of controls). Host toxicity encountered with the combination did not exceed the toxicity associated with ETP alone, suggesting that the therapeutic index may have been augmented. It is concluded that enhanced antitumor activity without substantial augmentation of toxicity is observed with this combination, providing a rationale for further evaluation of tumor necrosis factor-based regimens for the treatment of advanced renal carcinoma.Supported by a Merit Review grant, VA Medical Research Service, Durham, NC 27710, USA     

Effect of etoposide on experimental testicular teratoma in 129/SvJ mice

To study the effects of etoposide on experimental testicular teratoma in 129/SvJ mouse we analysed the tumour growth, differentiation, apoptosis and the localisation of mdr₁ P-glycoprotein (mdr₁-Pgp). In this model the implanted gonadal ridges developed into testicular teratomas in 17 out of 56 implanted testes (30%) and in 14 out of 28 mice (50%). The tumour-bearing mice were treated with etoposide on 4 successive days either 4 weeks or 6 weeks after implantation, and killed 7 days after the last dose. The mice in the control groups did not receive etoposide. The teratomas consisted mainly of neural tissue. The etoposide-treated 4-week teratomas, but not the 6-week teratomas, were significantly smaller than those in the corresponding control groups. The density of apoptotic cells and the distribution of the mdr₁-Pgp were not altered by etoposide. The decreased proportion of immature neuroectodermal tissue components was observed in all treated teratomas, converting the histology towards that of a mature teratoma. In addition, a low proportion of immature tissue components was frequently combined with a low density of apoptotic cells. In conclusion, etoposide decreased the immature tissue components of teratomas, while mature tissues remained unaffected. These results may have clinical relevance in man, since they confirm that postchemotherapy mature teratomas cannot be treated with chemotherapy. Despite benign histology, the human residual tumours have a significant malignant potential and require complete surgical excision and close surveillance. Received: 20 August 1999 / Accepted: 20 January 2000     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

长期口服VP-16联合顺铂治疗肺癌38例疗效分析

长期低剂量口服ＶＰ－１６（５０ｍｇ／ｍ２／ｄ×２１天）联合静滴ＤＤＰ（２０ｍｇ／ｍ２／ｄ×５天）治疗肺癌病人３８例，其中ＳＣＬＣ２４例，ＣＲ４例，ＰＲ１６例，有效率８３．３％；ＮＳＣＬＣ１４例，ＰＲ５例，有效率３５．７％。平均缓解时间ＳＣＬＣ６个月，ＮＳＣＬＣ６．５个月。毒副作用主要表现为骨髓抑制、脱发和胃肠道反应，其它毒性少见。     

Potentiation of etoposide-induced apoptosis by staurosporine in human tumor cells is associated with events downstream of DNA-protein complex formation

 Protein kinase inhibitors have demonstrated potential for use in the therapy of human cancers, in particular leukemia. Staurosporine, a protein kinase inhibitor with broad specificity, enhances the cytotoxic effects of various antitumor agents with different modes of action. The topoisomerase II inhibitor, etoposide, has shown clinical activity against a wide range of tumor types. Purpose: The purpose of this study was to assess the effects of staurosporine on etoposide-induced cell death processes in a human tumor of epithelial origin. Methods: Modulation of etoposide-induced apoptosis by staurosporine in HeLa cells was assessed by cell morphology, extraction of low molecular weight DNA, quantitation of DNA-protein complexes, and measurements of rates of DNA synthesis. The effects on cellular genes implicated in apoptosis were determined by Northern and Western blotting, along with assays of cyclin-dependent kinase activities. Results: Stauro- sporine exhibited a two- to three-fold potentiation of apoptosis caused by etoposide in HeLa cells when ap- plied concurrently, or immediately following etoposide removal, but did not alter the quantity of DNA-protein complexes produced by etoposide. Etoposide-induced apoptosis, and its potentiation by staurosporine, were associated with reduced c-myc expression, and a moderate increase in p21^WAF1/CIP1 mRNA and protein levels. Inhibitors of cyclic AMP-dependent protein kinase and protein kinase C, which exhibit greater specificity than staurosporine, were without effect on apoptosis caused by etoposide, whereas use of the tyrosine phosphatase inhibitor, vanadate, resulted in its abrogation. The potentiation of etoposide-induced apoptosis by staurosporine was associated with a significant increase in cyclin A-dependent kinase activity. In addition, etoposide caused substantial inhibition of DNA synthesis. Conclusion: These results indicate that staurosporine potentiates apoptosis through events which occur downstream of DNA damage, and implicate unscheduled activation of cyclin A-dependent kinase during inhibition of DNA synthesis as a possible cause. Received: 28 November 1995/Accepted: 8 July 1996     

Stage IV ovarian clear cell adenocarcinoma treated effectively by chemotherapy with etoposide and cisplatin (EP)

We report a case of stage IV ovarian clear cell adenocarcinoma (OCCA) in a 72-year-old woman who was treated postoperatively with etoposide combined with cisplatin (EP). The patient exhibited bulky intrapelvic and para-aortic lymph nodes with metastases to the cervical lymph nodes. The primary lesion was resected and, postoperatively, she received one course of combination chemotherapy consisting of cyclophosphamide, 500 mg/m²; doxorubicin, 50 mg/m²; and cisplatin, 70mg/m² (CAP), followed by six courses of combination chemotherapy consisting of etoposide, 80mg/m² days 1 through 5 and cisplatin, 70 mg/m² on day 5 every 4 weeks. After five courses of EP, the lymph node metastases had virtually disappeared. The patient is now disease-free 21 months after the initial surgery. These findings suggest that EP may be useful in treating OCCA.     

中剂量阿糖胞苷联合米托蒽醌及依托泊甙巩固治疗对难治复发性AML患儿的疗效及安全性

【摘要】目的 探讨中剂量阿糖胞苷联合米托蒽醌及依托泊甙巩固治疗对难治复发性急性髓系白血病（AML）患儿的疗效及安全性。方法 选取2008年12月～2012年12月我院收治的行阿糖胞苷联合米托蒽醌、依托泊甙巩固治疗的难治复发性AML患儿96例作为研究对象,采用回顾性分析法分析所有患儿的临床及随访资料,根据阿糖胞苷使用剂量的不同将其分为低剂量组、中剂量组和高剂量组3组,每组各32例,治疗结束后分析并比较3组患儿近期和远期临床疗效,并记录3组患儿治疗过程中不良反应的发生情况。结果 近期临床总有效率3组相比较差异均无统计学意义（P＞0.05）,且所有部分缓解的患儿中8例患儿进行骨髓移植治疗后治愈,余42例继续采用药物进行治疗;3组患儿5年总生存率（OS）比较差异有统计学意义（P＞0.05）,中剂量组和高剂量组患儿5年OS均高于低剂量组（P＞0.05）,但中剂量和高剂量组5年OS比较差异无统计学意义（P＞0.05）,3组患儿其5年无事件生存年率（EFS）比较差异均无统计学意义（P＞0.05）;3组患儿在骨髓抑制和心脏毒性的不良反应方面比较差异无统计学意义（P＞0.05）,但中剂量组和高剂量组患儿其感染、胃肠道反应以及肝肾功能损伤的不良反应发生率均显著高于低剂量组,且高剂量组患儿胃肠道和肝肾功能损伤的不良反应发生率均高于中剂量组患儿,组间比较差异均有统计学意（P＞0.05）。结论 中剂量阿糖胞苷联合米托蒽醌及依托泊甙巩固治疗对难治复发性AML患儿具有较好的临床疗效和较低的毒副反应,存在一定的安全性,可作为临床上治疗AML患儿的首选治疗方案。     

足叶乙苷为基础的方案在中国复发性肾母细胞瘤极高危组患儿中的应用经验及文献复习

目的观察足叶乙苷为基础的方案治疗复发性肾母细胞瘤极高危组患儿的疗效及不良反应。方法回顾分析3例治疗案例并结合相关文献进行讨论。结果 3例患儿均不同程度从中获益,且未经历Ⅲ/Ⅳ级不良反应。结论应用足叶乙苷为基础的化疗方案治疗复发性肾母细胞瘤极高危组患儿的疗效值得进一步研究及探讨。