Combination chemotherapy with paclitaxel and intraperitoneal cisplatin for ovarian cancer with disseminated lesions in the peritoneum and the diaphragm

Background: In ovarian cancer, the management of micrometastases disseminated in the peritoneal cavity is extremely important. We performed intravenous paclitaxel (PAC) infusion combined with cisplatin (CDDP) intraperitoneal infusion for progressive ovarian cancer. Methods: Twelve patients with progressive epithelial ovarian cancer (FIGO IIIc), which was resected using an optimal method at primary surgery, except for disseminated lesions in the peritoneum and the diaphragm, were studied. At primary surgery, a reservoir was placed in the peritoneal cavity. If metastases were identified in the diaphragm, then another reservoir was also placed in the subdiaphragm (double reservoirs). The basic regimen was set at 175 mg/m² with divided doses of PAC and 75 mg/m² CDDP by intraperitoneal injection. When a double reservoir was used, 30 mg/m² of subdiaphragmatic CDDP and 45 mg/m² of intraperitoneal CDDP were administered. The patients received five courses of this regimen. The response to the therapy was evaluated with tumor markers, and by using cytodiagnoses on the peritoneal washing fluid collected from the reservoirs. Results: After five courses of the chemotherapy, the tumor marker levels and cytodiagnoses of all patients became negative. With reference to adverse effects, grade 3–4 neutropenia was detected in 2 patients (16.6%), peripheral neuropathy was detected in 4 patients (33.3%), and alopecia was detected in 11 patients (91.6%). The median follow-up period was 29.2 months and median progression-free survival was 25.6 months. Conclusion: The combination chemotherapy with intravenous PAC and intraperitoneal CDDP was effective on ovarian cancer with disseminated lesions in the peritoneum and the diaphragm, having only mild adverse effects. Received: February 20, 2002 / Accepted: October 9, 2002 Correspondence to:F. Terauchi     

Synergistic Enhancement of Cisplatin Cytotoxicity by SN-38, an Active Metabolite of CPT-11, for Cisplatin-resistant HeLa Cells

A cisplatin ( cis -diamininedichloroplatinuin(II); CDDP)-resistant HeLa cell line (HeLa/CDDP cells), which showed more than 8-fold resistance to CDDF compared to the parent cells, was newly established for this study. HeLa/CDDP cells accumulated 50% less platinum than the parent cells. There was no difference in intracellular glutathione (GSH) content between the parent and HeLa/ CDDP cells. The dose modification factor by DL-buthionine-S, R-sulfoximine (BSO) pretreatment was similar in both cell lines. HeLa/CDDP cells had cross-resistance to diammine (l, l-cyclobutanedicarboxylato)platinum(II) (CBDCA), ( cis -diammine (glycolato)platinum (254-S), but not to (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)platinum(II) (DWA2114R), adriamycin, or VP-16. HeLa/CDDP cells showed a collateral sensitivity to 7-ethyl-10-hydroxycampto-thecin (SN-38), an active metabolite of 7-ethyl-10-[4-(l-piperidino)-l-piperidino]carbonyloxycamptothecin (CPT-11). Furthermore, isobologram analysis indicated synergistic interaction of CDDP and SN-38 only for HeLa/CDDP cells. The present study suggests that combination therapy with CDDP and CPT-11 may he potentially useful in the treatment of some patients with CDDP-resistant cancer.     

Feasibility of concurrent cisplatin use during primary and adjuvant chemoradiation therapy: a phase I study in Japanese patients with cancer of the uterine cervix

Background Although the prognostic advantages of concurrent cisplatin (CDDP) chemoradiation therapy (CCRT), for uterine cervical cancer (UCC) has been demonstrated, the feasibility of concurrent CDDP administration has not yet been evaluated. We determined the optimal CDDP dose for both weekly and monthly schedules during primary and adjuvant CCRT in patients with UCC. Methods The study was conducted as a phase I, dose-escalation trial. Concurrent CDDP was started at the dose of 30 mg/m² for the weekly schedule and at 50 mg/m² for the monthly schedule, and the doses were steadily escalated to the maximum tolerated dose (MTD). Results A total of 45 patients with UCC (25 receiving primary CCRT and 20 receiving adjuvant CCRT) were entered in the study. In both the primary and adjuvant CCRT patients, the MTD was observed to be 40 mg/m² for the weekly schedule and 80 mg/m² for the monthly schedule. Dose-limiting toxicity was observed in 10 patients (granulocytopenia in 9 patients and diarrhea in 1 patient). Disease recurrence was confirmed in 6 patients in the primary CCRT group during a mean follow-up period of 22.4 ± 13.2 months, and in patients 3 in the adjuvant CCRT group during a mean follow-up period of 17.7 ± 6.8 months. Conclusion For Japanese patients with UCC receiving primary or adjuvant CCRT therapy, the recommended CDDP dose was determined to be 30 mg/m² for the weekly schedule and 75 mg/m² for the monthly schedule.     

复方丹参滴丸治疗冠心病心绞痛182例临床对照研究

目的：探讨复方丹参滴丸治疗冠心病心绞痛的临床疗效,为临床完善治疗方案提供依据。方法：采用方便抽样方法抽取364例冠心病心绞痛患者,采用随机数字表法将患者随机分为观察组和对照组,各182例。对照组采用常规治疗,观察组在常规治疗的基础上加用复方丹参滴丸治疗,比较两组治疗效果。结果：观察组有效率明显高于对照组,组间比较差异具有统计学意义（χ2=8.759,P〈0.01）。观察组不良反应发生率明显低于对照组,组间比较差异具有统计学意义（χ2=16.497,P〈0.01）。结论：在常规治疗的基础上联合应用复方丹参滴丸治疗冠心病心绞痛可有效提高治疗效果,降低心绞痛发病频率,值得临床推广。     

Arterial infusion therapy with low-dose cisplatin and continuous 5-fluorouracil for isolated hepatic recurrence of gastric carcinoma

Patients with metachronous liver metastasis after curative resection of gastric carcinoma generally have a poor prognosis, even when recurrence is confined to the liver. We report a patient in whom hepatic arterial infusion therapy with bolus low-dose cisplatin (CDDP) and continuous 5-fluorouracil (5-FU) was effective against large metastases confined to the liver. An 83-year-old man was admitted with huge liver metastases from gastric carcinoma. Intra-arterial bolus injection of low-dose CDDP (5 mg) and continuous intra-arterial infusion of 5-FU (250 mg/day for 7 days) was started. After four courses of this arterial infusion therapy, computed tomography scans revealed shrinkage of the liver metastases. He was followed-up as an outpatient and continued to receive the arterial infusion therapy once every 4 weeks. Throughout the course of the chemotherapy, a partial response of the liver metastases was maintained. The patient had an improved quality of life after starting the chemotherapy, and he survived for 16 months from the commencement of the therapy. Arterial infusion therapy with bolus low-dose CDDP and continuous 5-FU may be recommended for patients with isolated hepatic recurrence of gastric carcinoma. Received: September 6, 1999 / Accepted: January 31, 2000     

Identification and functional analysis of genes which confer resistance to cisplatin in tumor cells

The efficacy of cisplatin during cancer chemotherapy is often impaired by the emergence of cancer cells which become resistant to chemotherapeutic agents. While various mechanisms have been proposed to explain resistance to cisplatin, the genes involved in this process still remain unclear. By using DNA microarrays, we performed a genome-wide analysis of cisplatin-resistant HeLa cells in order to identify genes involved in resistance. We identified nine genes (NAPA, CITED2, CABIN1, ADM, HIST1H1A, EHD1, MARK2, PTPN21, and MVD), which were consistently upregulated in two cisplatin-resistant HeLa cell lines. The upregulated genes, here referred to as cisplatin resistance genes (CPR), were further analyzed for their ability to modify the response of HEK293 cells to cisplatin. Short-hairpin RNA (shRNA) knockdown of CPR genes, individually or in combination, was shown to sensitize HEK293 cells to cisplatin, but not to vincristine or taxol, suggesting that CPR genes may be involved specifically in cisplatin resistance. Among the treatments performed, shRNA knockdown of NAPA was the most efficient treatment able to sensitize cells to cisplatin. Furthermore, shRNA knockdown of a single CPR gene was sufficient to partially reverse acquired cisplatin resistance in HeLa cells. Sensitization to cisplatin following knockdown of CPR genes was also observed in the tumorigenic cell lines Sk-ov-3, H1155, and CG-1. Based on these results, we propose that the CPR genes identified here may represent potential candidates for novel target therapies aimed at preventing resistance to cisplatin during chemotherapy.     

Salvage thoracic surgery in patients with primary lung cancer

Background

Patients with advanced non-small cell lung cancer (NSCLC) continue to have a poor prognosis. The majority of patients are not indicated for surgery for a radical cure, and systemic chemotherapy is the mainstay of treatment. However, long-term survival is rare due to the resistance to therapy. On the other hand, surgery is performed only under certain conditions for colon cancer and esophageal cancer. Few reports are available about salvage thoracic surgery in patients with primary lung cancer. The purpose of this study was to show the outcomes of salvage surgery for lung cancer, and we discuss possible future treatment strategies based on our findings.

Methods

Three hundred and fifty-two patients with primary lung cancer underwent surgical resection, and we evaluated those who underwent salvage operations. We also examined the relationships between the performance of a salvage operation and the clinicopathological characteristics of the patients. The clinical outcomes of salvage surgery for lung cancer were assessed.

Results

Salvage thoracic operations were performed in eight (2.3%) of the 352 patients. The surgical procedures were lobectomy in four patients, segmentectomy in two, and pneumonectomy and wedge resection were each performed in one patient. There was no postoperative mortality. All patients were alive at the time of the analysis. The mean follow-up period for the salvage operation cases was 14.0 months. No significant correlation was identified between the incidence of salvage surgery and the age, gender, histology, postoperative stay or hospital stay. The incidence of advanced stage disease was higher in the salvage cases than in the overall cases.

Conclusions

Salvage thoracic surgery was possible, and moderately improved the prognosis, without prolongation of the postoperative stay or hospital stay. A salvage operation might be considered a reasonable and proper treatment for carefully selected patients.     

顺铂联合米托蒽醌调节脑胶质瘤U87细胞Sonic Hedgehog信号通路的研究

目的：观察米托蒽醌（Mitoxantrone,MXT）联合顺铂（Cisplatin,CDDP）对脑胶质瘤U87细胞杀伤活性及对Sonic Hedgehog信号通路的影响。方法：应用MTT法检测不同浓度米托蒽醌、顺铂以及两药物联合对U87细胞成活率的影响。显微镜观察细胞的形态变化DiOC6荧光染料对细胞线粒体染色检测其膜电位变化来反映细胞凋亡。RT-PCR法检测顺铂、米托蒽醌及两药联合对U87细胞Gli1和Ptch基因表达的影响。结果：MTT结果显示顺铂、米托蒽醌均可以有效抑制U87细胞的增殖,当米托蒽醌和顺铂浓度≤0.625μg/ml时,两药联合对U87细胞增殖具有协同抑制作用;细胞形态变化及线粒体膜电位结果显示,单药处理可促进U87细胞凋亡,而联合用药可以协同促进U87细胞的凋亡;RT-PCR法检测显示顺铂对Gli1基因的表达有上调作用,而米托蒽醌、米托蒽醌联合顺铂能下调Ptch和Gli1基因的表达。结论：胶质瘤U87细胞在化疗药物米托蒽醌以及两药物联合作用下可影响Sonic Hedgehog信号通路,协同发挥其促凋亡作用,进而增强肿瘤细胞对化疗药物的敏感性。     

以hTERT基因反义核酸抑制端粒酶活性增加白血病细胞对CDDP诱导凋亡的敏感性(英文)

目的以 hTERT 反义核酸抑制白血病细胞(HL-60和 K562)端粒酶活性,研究 CDDP 诱导凋亡敏感性的变化。方法全硫代反义核酸由上海生物化学研究所合成和纯化;端粒酶活性用试剂合测定(宝灵曼公司产品);用形态学方法和流式细胞仪检测细胞调亡。结果实验结果显示,hTERT 全硫代反义核酸,通过下调 hTERT 基因表达,显著地抑制端粒酶活性;端粒酶活性下降以后,白血病细胞对 CDDP 诱导调亡的敏感性显著升高。结论以 hTERT 基因反义核酸抑制端粒酶活性增加白血病细胞对 CDDP 诱导凋亡的敏感性。     

Tca8113细胞系耐药性的实验研究

目的：建立耐顺铂（CDDP）人舌鳞状细胞癌细胞系Tca8113/CDDP,对其耐药特性进行研究,方法：应用间歇性加药,逐步递增剂量,体外连续透导培养方法,获得Tca8113耐药细胞,采用MTT法,琼脂糖凝胶电泳和免疫组化法对细胞增增时间、裸鼠成瘤性、化疗药敏感性,P-gp和GST－π蛋白表达进行研究。结果：初步建成耐CCDP的人舌鳞癌细胞系（Tca8113／CDDP）,其耐CDDP浓度为10μmol/L。该细胞同时对卫猛（Vm-26)、博来霉素（BLM）、长春地辛、（VDS）、表阿霉素（E－ADM）、泰素（Taxol)等化疗药物产生交叉耐药。连续传代1月后,倍增时间从29．9h降至16．7h,具有裸鼠成瘤性,瘤体倍增加速。CDDP作用Tca8113细胞后,电泳显示有凋亡细胞特有的“梯状”条带,耐药细胞Tca8113／CDDP则无。P－gp（P－糖蛋白）及GST－π表达量升高,表明MDR－1mRNA表达水平增高,结论：CDDP能致Tca8113细胞耐药性。Tca8113／CDDP细胞系具有多药耐药特性,GSH／GST解毒系统可能与Tca8113／CDDP耐药性的产生。