Cellular efflux pump and interaction between cisplatin and paclitaxel in ovarian cancer cells

OBJECTIVE: The aim of this study was to evaluate the combination effect of paclitaxel (PTX) and cisplatin (CDDP) and to determine the mechanisms of interaction between these agents. METHODS AND RESULTS: We used human ovarian adenocarcinoma cell lines, namely a parent cell line (KF), a CDDP-resistant cell line (KFr) and a PTX-resistant cell line (KFTx).The combination effect of PTX and CDDP was synergistic on KF and KFTx and additive on KFr. The incidence of anaphase or telophase, evaluated by immunofluorescence microscopy, decreased with PTX and significantly decreased with PTX and CDDP in KF and KFTx. The concentration of PTX, which was measured by high-performance liquid chromatography, was higher in KF and KFTx cells treated with a combination of PTX and CDDP than those treated with PTX alone. Multidrug resistance gene mRNA appeared in KFTx and its expression decreased after exposure to PTX and CDDP. After exposure to CDDP, the expression of multidrug resistance-associated protein (MRP) and the concentration of glutathione increased in KF, but not in KFr or KFTx. MRP expression slightly increased in KF and KFTx after exposure to PTX. In contrast, its expression decreased in KFr. CONCLUSION: The present study suggests that CDDP enhances PTX accumulation and that the interaction of these agents is synergistic in CDDP-sensitive cells.     

紫杉醇联合卡铂与紫杉醇联合顺铂治疗晚期卵巢癌疗效比较

目的比较紫杉醇+卡铂与紫杉醇+顺铂治疗晚期卵巢癌的疗效和毒性.方法62例初治晚期卵巢癌患者随机分为紫杉醇+卡铂组(A组)30例和紫杉醇+顺铂组(B组)32例,化疗6～8周期后评价临床缓解率和药物毒性.结果A组有效率为73.3%,平均生存时间35个月;B组有效率71.9%,平均生存时间32个月,两组疗效和平均生存时间差异无显著性(P＞0.05).胃肠道反应、肾毒性和肌肉关节疼痛A组较B组轻(P＜0.05).结论紫杉醇+卡铂治疗晚期卵巢癌有效率不低于紫杉醇+顺铂,但毒性反应明显减轻,从临床的实用性和便利性考虑,更容易为临床医师和患者接受,特别适用于老年患者及对顺铂耐受性差的患者.     

In vitro schedule-dependent interaction between paclitaxel and cisplatin in human carcinoma cell lines

 The schedule-dependent interaction of paclitaxel and cisplatin was studied in four human carcinoma cell lines: non-small cell lung cancer, A549; breast cancer, MCF7; ovarian cancer, PA1; and colon cancer, WiDr cells. The cells were exposed simultaneously to the drugs for 24 h and sequentially to paclitaxel first for 24 h followed by cisplatin for 24 h, or vice versa, and then incubated in drug-free medium for 4 and 3 days, respectively. Cell growth inhibition was then determined by the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltetrazolium bromide (MTT) reduction assay. The effects of drug combinations at the IC₈₀ level were analyzed by the isobologram method. On simultaneous exposure to paclitaxel and cisplatin, additive and sub-additive (slight antagonistic) effects were observed in A549, MCF7, and PA1 cells, while sub-additive and protective (antagonistic) effects were observed in WiDr cells. On sequential exposure to paclitaxel first, followed by cisplatin, additive effects were observed in all cell lines. On sequential exposure to cisplatin first, followed by paclitaxel, additive effects were observed in PA1 cells, while additive, sub-additive, and protective effects were observed in A549, MCF7, and WiDr cells. These findings suggest that the interaction of paclitaxel and cisplatin is schedule- and cell line-dependent. The optimal schedule of this combination may be paclitaxel first followed by cisplatin. Received: 15 November 1994/Accepted: 21 June 1995     

Weekly paclitaxel and cisplatin in recurrent ovarian cancer

This study was performed to assess the feasibility of weekly paclitaxel (TXL) and cisplatin (CDDP) in patients with recurrent ovarian cancer. Ten of eleven patients experienced recurrence after more than 6 months after first line CDDP-based chemotherapy. TXL and CDDP were given at initial doses of 60 mg/m2 and 30 mg/m2 on days 1, 8, and 15 in 2 patients and an increase in the respective dose level was planned to 60/35 in 5 patients, 70/35 in 2 patients, and 70/40 in 2 patients. Toxicities were well tolerated. None of the patients suffered from neurotoxicity or myalgia of more than grade 2. Gastrointestinal disorder was recognized as grade 1-2, and grade 3-4 hematological toxicity included leucocytopenia (64%), anemia (36%), and thrombocytopenia (9%). We set the recommended dose of TXL at 70 mg/m2 and that of CDDP at 35 mg/m2, considering toxicity and performed planned schedule. Of eleven patients, nine were assessable by computed tomographic scan. The overall response rate was 67% (CR: 1, PR: 5, NC: 1, PD: 2). One of two patients with standard TXL/CDDP therapy showed PR by switching to a weekly schedule. The median follow-up duration was 490 days and the median response duration was 371 days. From the results presented here, it is suggested that this regimen with increased DI might be quite effective and well tolerated in patients who experience relapse after CDDP-based chemotherapy.     

Cell cycle-dependent antagonistic interactions between paclitaxel and gamma-radiation in combination therapy.

PURPOSE: The promising clinical activity of paclitaxel, a naturally occurring antimicrotubule agent, has promoted considerable interest in combining this drug with radiation therapy, but it remains unclear whether such a combination would increase the therapeutic efficacy. This study is to assess the potential interactions between paclitaxel and gamma-radiation against human tumor cells in vitro. EXPERIMENTAL DESIGN: Paclitaxel and gamma-radiation were administered in three different sequences designated as pre-radiated, co-radiated, and post-radiated to BCap37 (human breast cancer cell line) and KB (human epidermoid carcinoma cell line) cells. The cytotoxic interactions between and mutual influences of these two agents on their antitumor activities were analyzed by a series of assays including cytotoxic, morphological, and biochemical examinations. RESULTS: The combination of paclitaxel and gamma-radiation did not produce a synergistic or additive effect. Instead, the overall in vitro cytotoxicity of these combinations was much lower than that of paclitaxel treatment alone. DNA fragmentation and flow cytometric assays showed that the addition of gamma-radiation interfered with paclitaxel-induced apoptosis. Further analyses indicated that the addition of gamma-radiation resulted in a transient or prolonged cell cycle arrest at G(2) phase, which likely prevented the cytotoxic effects of paclitaxel on both mitotic arrest and apoptosis. In addition, biochemical examinations revealed that gamma-radiation inhibited paclitaxel-induced IkappaBalpha degradation and bcl-2 phosphorylation and increased the protein levels of cyclin B1 and inhibitory phosphorylation of p34(cdc2). CONCLUSIONS: Our results suggest that gamma-radiation might specifically block the cell cycle at G(2) phase, which in turn prevents the cytotoxic effects of paclitaxel on both mitotic arrest and apoptosis. Therefore, it eventually results in a cell cycle-dependent antagonistic effect on the antitumor activity of paclitaxel. This finding may be relevant to the clinical application of combination therapy with paclitaxel and radiation.     

Cell cycle dependent antagonistic interactions between paclitaxel and carboplatin in combination therapy

The combination of carboplatin and paclitaxel is widely used to treat multiple solid tumors including ovarian, lung and breast cancer. Usually these drugs are given simultaneously with little regard to the importance of scheduling to obtain a maximal response. To investigate the importance of sequencing, the human breast Bcap37 and ovarian OV2008 cancer cell lines were exposed to carboplatin and paclitaxel in three different sequences: (1) pretreatment with paclitaxel followed by carboplatin, (2) pretreatment of carboplatin followed by paclitaxel and (3) simultaneous treatment with these two agents. The combination of carboplatin and paclitaxel resulted in antagonistic interactions when tumor cells were exposed to carboplatin prior to paclitaxel or exposed to the two drugs simultaneously, but there was little antagonistic interaction observed when paclitaxel was administered before carboplatin. Biochemical examination revealed that pretreatment or cotreatment of carboplatin inhibited paclitaxel-induced IkappaBalpha degradation and bcl-2 phosphorylation. Further analyses demonstrated that carboplatin could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel was administered before carboplatin. These results indicate that the interaction between paclitaxel and carboplatin is highly schedule dependent. The optimal schedule for this combination is sequential exposure of paclitaxel followed by carboplatin.     

Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial

BackgroundLiposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival.Patients and methodsTwo hundred and thirty-six chemotherapy-naive patients with inoperable non-small-cell lung cancer were randomly allocated to receive either 200 mg/m² of liposomal cisplatin and 135 mg/m² paclitaxel (arm A) or 75 mg/m² cisplatin and 135 mg/m² paclitaxel (arm B), once every 2 weeks on an outpatient basis. Two hundred and twenty-nine patients were assessable for toxicity, response rate and survival. Nine treatment cycles were planned.ResultsArm A patients showed statistically significant lower nephrotoxicity, grade 3 and 4 leucopenia, grade 2 and 3 neuropathy, nausea, vomiting and fatigue. There was no significant difference in median and overall survival and TTP between the two arms; median survival was 9 and 10 months in arms A and B, respectively, and TTP was 6.5 and 6 months in arms A and B, respectively.ConclusionsLiposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel. Nephrotoxicity in particular was negligible after liposomal cisplatin administration. TTP and survival were similar in both treatment arms.     

紫杉醇联合顺铂每周方案与三周方案治疗老年晚期非小细胞肺癌的临床随机对照研究

目的:比较紫杉醇联合顺铂每周方案(TP-QW)和三周方案(TP-Q3W)一线治疗年龄≥70岁老年晚期非小细胞肺癌(NSCLC)患者的疗效和毒副反应.方法:年龄≥70岁初治晚期NSCLC患者(ⅢB和Ⅳ)60例,随机分为TP-QW组30例和TP-Q3W组30例,分别接受TP-QW方案(紫杉醇80 mg/m2,d1,d8;顺铂20 mg/m2,d1,d8,21 d为1个周期)和TP-Q3W方案(紫杉醇135 mg/m2,d1;顺铂18 mg/m2,d1～d4,21 d为1个周期)化疗.结果:TP-QW组:CR 0例,PR 12例,SD 16例,PD 2例,有效率40.0%;TP-Q3W组:CR 0例,PR 10例,SD 17例,PD 3例,有效率33.3%.TP-QW组的有效率略高,差异无统计学意义,P=0.280.TP-QW组中位疾病进展时间4.8个月,TP-Q3W组中位TTP为4.5个月,差异无统计学意义,P=0.709.TP-QW组的中位生存期为14.6个月,1年生存率56.7%;TP-Q3W组的中位生存期为12.7个月,1年生存率46.7%,差异无统计学意义,P=0.208.TP-QW组恶心、呕吐、周围神经毒性和乏力的发生率明显低于TP-Q3W组,差异有统计学意义.结论:TP-QW组的临床疗效与TP-Q3W疗法差异无统计学意义,TP-QW方案的毒副反应较轻,明显低于TP-QW,更适用于年迈体弱的患者和门诊化疗.     

Schedule-dependent interactions between paclitaxel and etoposide in human carcinoma cell lines in vitro

 Clinical studies of paclitaxel in combination with etoposide against solid tumors have been carried out. The combination schedules used in these studies are different. We studied the cytotoxic effects of paclitaxel with etoposide against four human cancer cell lines in vitro to determine the optimal schedule of this combination at the cellular level. Cells were exposed simultaneously to paclitaxel and to etoposide for 24 h or sequentially to one drug for 24 h followed by the other for 24 h, after which they were incubated in drug-free medium for 4 and 3 days, respectively. Cell growth inhibition was determined by an MTT reduction assay. The effects of drug combinations at concentrations producing 80% inhibition (IC₈₀) were analyzed by the isobologram method of Steel and Peckham. The cytotoxic effect of paclitaxel and etoposide was cell line- and schedule-dependent. Simultaneous exposure to paclitaxel and etoposide for 24 h produced additive effects in the lung cancer cell line A549 and ovarian cancer PA1 cells, and antagonistic effects in the breast cancer cell line MCF7 and colon cancer WIDr cells. Sequential exposures to paclitaxel followed by etoposide and vice versa produced additive effects in all four cell lines. These results suggest that maximum cytotoxic effects can be obtained with sequential administration, but not simultaneous administration, of paclitaxel and etoposide. These findings may have important clinical implications for this combination. Received: 11 August 1998 / Accepted: 8 March 1999     

Synergistic interactions between aminoflavone, paclitaxel and camptothecin in human breast cancer cells

Purpose

Aminoflavone is a unique DNA damaging agent currently undergoing phase I evaluation in a prodrug form (AFP464). In anticipation of combination regimens, interactions between aminoflavone and several anticancer drugs were investigated in MCF-7 breast cancer cells to determine whether synergistic cancer cell killing effects were observed.

Methods

Colony formation assays were performed to assess the effect of combining aminoflavone with a variety of anticancer drugs. Changes in initial uptake, retention or efflux of aminoflavone and the second agent were compared to the behavior of drugs alone. Key features required for aminoflavone activity in cell culture models were also explored, focusing on the obligatory induction of CYP1A1/1A2 and binding of reactive aminoflavone metabolites to tumor cell total macromolecules and DNA.

Results

Aminoflavone was synergistic when co-incubated with paclitaxel, camptothecin or SN38. Uptake of neither aminoflavone nor any of the other three compounds was altered in combination incubations. Paclitaxel did not inhibit DNA binding of aminoflavone metabolites, while camptothecin did. Aminoflavone-induced CYP1A1 induction was observed in the presence of camptothecin or paclitaxel.

Conclusions

Aminoflavone is a promising therapeutic agent for breast cancer due to its unique mechanism of action compared to commonly used drugs. Combined treatments utilizing aminoflavone in conjunction with paclitaxel or camptothecin may provide an even greater cytotoxic effect than achieved with aminoflavone alone.     

紫杉醇脂质体与紫杉醇联合顺铂治疗晚期非小细胞肺癌对比研究

目的　探讨紫杉醇脂质体与紫杉醇联合顺铂治疗晚期非小细胞肺癌（ＮＳＣＬＣ）的临床疗效及不良反应。方法　晚期ＮＳＣＬＣ患者７２例,随机分为试验组与对照组,试验组采用紫杉醇脂质体１３５ｍｇ／ｍ^２,对照组采用紫杉醇１３５ｍｇ／ｍ^２化疗,两组均联合顺铂,２１天为１个周期,治疗２个周期后评价疗效。记录近期疗效与治疗期间毒副反应。结果　试验组有效率为４１.７％（１５／３６）,临床受益率为７７.７％（２８／３６）,对照组有效率为３８.９％（１４／３６）,临床受益率为７２.２％（２６／３６）,两组差异均无统计学意义（Ｐ＞０.０５）。白细胞减少和血小板减少的发生率两组差异无统计学意义（Ｐ＞０.０５）,脱发、腹泻、便秘及呼吸困难的发生率两组差异亦无统计学意义（Ｐ＞０.０５）,但试验组恶心、呕吐、皮疹、肌肉痛的发生率明显低于对照组（Ｐ＜０.０５）。结论　紫杉醇脂质体联合顺铂治疗晚期ＮＳＣＬＣ近期疗效确切有效,毒副反应较紫杉醇联合顺铂化疗为轻。     

Schedule-dependent interactions between pemetrexed and cisplatin in human carcinoma cell lines in vitro

The combination of pemetrexed and cisplatin shows good clinical activity against mesothelioma and lung cancer. In order to study the potential cellular basis for this, and provide leads as to how to optimize the combination, we studied the schedule-dependent cytotoxic effects of pemetrexed and cisplatin against four human cancer cell lines in vitro. Tumor cells were incubated with pemetrexed and cisplatin for 24 h at various schedules. The combination effects after 5 days were analyzed by the isobologram method. Both simultaneous exposure to pemetrexed and cisplatin for 24 h and sequential exposure to cisplatin for 24 h followed by pemetrexed for 24 h produced antagonistic effects in human lung cancer A549, breast cancer MCF7, and ovarian cancer PA1 cells and additive effects in colon cancer WiDr cells. Pemetrexed for 24 h followed by cisplatin for 24 h produced synergistic effects in MCF7 cells, additive/synergistic effects in A549 and PA1 cells, and additive effects in WiDr cells. Cell cycle analysis of MCF7 and PA1 cells supported these findings. Our results suggest that the simultaneous clinical administration of pemetrexed and cisplatin may be suboptimal. The optimal schedule of pemetrexed in combination with cisplatin at the cellular level is the sequential administration of pemetrexed followed by cisplatin and this schedule is worthy of clinical investigations.     

Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer.

PURPOSE: To determine the side effects and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer. PATIENTS AND METHODS: Patients were randomly allocated to receive paclitaxel 175 mg/m(2) intravenously as a 3-hour infusion followed by either cisplatin 75 mg/m(2) or carboplatin (area under the plasma concentration-time curve of 5), both on day 1. The schedule was repeated every 3 weeks for at least six cycles. Women allocated to paclitaxel-cisplatin were admitted to the hospital, whereas the carboplatin regimen was administered to outpatients. RESULTS: A total of 208 eligible patients were randomized. Both regimens could be delivered in an optimal dose and without significant delay. Paclitaxel-carboplatin produced significantly less nausea and vomiting (P: <.01) and less peripheral neurotoxicity (P: =.04) but more granulocytopenia and thrombocytopenia (P: <.01). The overall response rate in 132 patients with measurable disease was 64% (84 of 132 patients), and in patients with elevated CA 125 levels at start, it was 74% (132 of 178 patients). With a median follow-up time of 37 months, the median progression-free survival time of all patients was 16 months and the median overall survival time was 31 months. The small number of patients entered onto the study caused wide confidence intervals (CIs) around the hazards ratio for progression-free survival of paclitaxel-carboplatin compared with paclitaxel-cisplatin (hazards ratio, 1.07; 95% CI, 0.78 to 1.48) and did not allow conclusions about efficacy. CONCLUSION: Paclitaxel-carboplatin is a feasible regimen for outpatients with ovarian cancer and has a better toxicity profile than paclitaxel-cisplatin.     

Schedule-dependent interactions between raltitrexed and cisplatin in human carcinoma cell lines in vitro.

Raltitrexed ('Tomudex') is a new anticancer agent which inhibits thymidylate synthase. To provide a rational basis for clinical trial design of the combination of raltitrexed and cisplatin, we studied the cytotoxic effects of this combination using various schedules in vitro and four human colon cancer cell lines, Colo201, Colo320, LoVo, and WiDr. Cell growth inhibition after 5 days was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. The effects of drug combinations at the concentration producing 80% cell growth inhibition (IC(80)) level were analyzed by the isobologram method. Simultaneous exposure to raltitrexed and cisplatin for 24 h, and sequential exposure to raltitrexed followed by cisplatin produced additive effects in the Colo201, Colo320, and LoVo cells, and additive and synergistic effects in WiDr cells. Sequential exposure to cisplatin followed by raltitrexed produced additive effects in the Colo201 cells and antagonistic effects in other three cell lines. Simultaneous and continuous exposure to both agents for 5 days produced additive effects in all four cell lines. These findings suggest that the simultaneous administration of raltitrexed and cisplatin, or the sequential administration of raltitrexed followed by cisplatin, generally produce the expected cytotoxicity at the cellular level and are optimal schedules, while the sequential administration of cisplatin followed by raltitrexed produces antagonistic effects and is inappropriate for this combination. Further in vivo and clinical studies will be necessary to determine the toxicity and antitumor effects of this schedule.     

Biweekly paclitaxel and cisplatin in patients with advanced head and neck carcinoma

Background: Cisplatin is an active drug in head and neck cancer. Paclitaxel seems a promising drug. This article reports a phase II assessment of the combination of the two.Patients and methods: Twenty-three patients were treated with paclitaxel 90 mg/m² over three hours plus cisplatin 60 mg/m² every other week. Sixteen patients had locoregional disease and seven had metastatic disease. None of the patients had previously been treated with chemotherapy. Nine patients had had radiotherapy to the target lesions.Results: One patient was not evaluable for response. Partial responses were observed in 32% of evaluable patients. Toxicity included asthenia (56%), neutropenia, peripheral neuropathy, anemia and vomiting.Conclusions: The overall response rate observed in this study does not seem to justify the use of this chemotherapy regimen in the palliative setting.     

Cytotoxicity of paclitaxel in combination with cisplatin and a new Pt-mercaptopyridine complex

In vitro synergy has been reported for exposure to paclitaxel prior to cis-platin (cis-DDP), whereas the reverse sequence resulted in antagonism. There is no clear evidence for an intracellular origin of the schedule-dependent interaction, but several hypotheses have been proposed, such as effects at the level of DNA crosslinks, or binding to tubulin sites. The purpose of this study was to evaluate the cytotoxicity of these two drugs as single agents, in combination and in sequence, against a human colon adenocarcinoma cell line (LoVo). Moreover, we considered the new Pt-mercaptopyridine complex C/2, was like cis-platin in being able to alter DNA conformation. We have therefore studied the cytotoxic effects after single agent exposure, concomitant exposure (paclitaxel + cis-platin and paclitaxel + C/2) and sequential drugs exposure (paclitaxel-->cis-platin and cis-platin-->paclitaxel or paclitaxel-->C/2 and C/2-->paclitaxel). Our results demonstrate that the most cytotoxic effect is induced by paclitaxel and C/2 exposure both in the case of concomitant cell treatment and sequential exposure paclitaxel-->C/2.     

Sequence-dependent antitumor activity of paclitaxel (taxol) and cisplatin in vivo

The established antitumor efficacy of paclitaxel and cisplatin as single agents and their distinctly different mechanisms of action have prompted laboratory and clinical research into their use in combination. Our in vivo study was performed to investigate the importance of sequence of administration and inter-agent interval. C3Hf/Kam mice bearing OCa-1 tumors received paclitaxel and cisplatin. The antitumor efficacy of the combination, measured as re-growth delay and expressed as the enhancement factor (EF), was determined for inter-agent intervals of I, 9, 24, 48 and 72 hr. Morphometric analysis was used to determine the contribution of induced apoptosis. Our findings showed an additive effect when cisplatin preceded paclitaxel by 1 and 24 hr, producing EF of 1.1 and 1.0, respectively, and a greater than additive effect for 9 and 48 hr, producing EF of 1.3 and 1.8, respectively. This sequence, however, was associated with significant morbidity and mortality. When paclitaxel preceded cisplatin the effect was greater than additive with the EF for I, 9 and 24 hr, being 1.2, 1.5 and 1.5, respectively, and increasing to a maximum of 1.9 at 48 hr. Thus, for this combination, the therapeutic ratio was improved when paclitaxel preceded cisplatin and was greatest when a 48 hr interval was allowed between drugs. We were unable to attribute the efficacy of the drug combination to increased induction of apoptosis and suggest other possible mechanisms. © 1995 Wiley-Liss, Inc.     

Early predictors of peripheral neurotoxicity in cisplatin and paclitaxel combination chemotherapy.

BACKGROUND: We investigated the possible use of clinical signs of chemotherapy-induced peripheral neurotoxicity (CIPN) or of nerve growth factor (NGF) circulating levels to predict the final outcome of CIPN. PATIENTS AND METHODS: Sixty-two women affected by locally advanced squamous cervical carcinoma treated with TP (paclitaxel 175 mg/m2 over a 3 h infusion plus cisplatin 75 mg/m2) or TIP (TP plus ifosphamide 5 mg/m2) were examined and scored according to the Total Neuropathy Score (TNS), before and during chemotherapy. RESULTS: A correlation with the final severity of CIPN was observed with vibration perception and deep tendon reflex evaluation, while pin sensibility, strength, and autonomic symptoms and signs were not informative. A highly significant correlation existed between the decrease in circulating levels of NGF and the severity of CIPN (r = -0.579; P < 0.001; 95% confidence limits -0.702 to -0.423). However, circulating levels of NGF were not effective as predictors of the final neurological outcome of each patient. CONCLUSION: Our study indicates that a precise clinical evaluation of the peripheral nervous system of patients treated with platinum and taxane combination polychemotherapy not only gives reliable information regarding the course of CIPN, but also can be used to predict the final neurological outcome of the treatment.     

DNA-based drug interactions of cisplatin

The interactions of cisplatin with other anti-cancer agents on the DNA level have been studied extensively in pre-clinical experiments. In general, combination of cisplatin with an antimetabolite, taxane, or topoisomerase inhibitor, can result in a modulation of platinum pharmacology on the DNA, for example, enhanced retention of the platinum-DNA adducts. These interactions are mostly sequence and cell type dependent. In cell line models, antimetabolites can enhance the number of platinum-DNA adducts, probably by inhibition of DNA repair pathways. However, in clinical trials, the opposite effect has been observed, with a reduction of these adducts upon combined treatment. For the taxanes it has been shown that they can inhibit the formation of platinum-DNA adducts, whereas topoisomerase I inhibitors increase the number of adducts, resulting in strong synergistic cytotoxicity. For this last interaction a mechanistic model has recently been proposed, in which the topoisomerase I enzyme directly binds to the platinum-DNA adduct. Thereafter, the topoisomerase I inhibitor binds to this complex, which yields large stabilised lesions to the DNA that are probably difficult to repair. Ongoing studies will proceed to elucidate the exact mechanism underlying the interactions between cisplatin and other anti-neoplastic agents on the DNA level. Such increased understanding might help in designing new and more effective treatment regimens for cancer. In this paper, we review the pre-clinical and clinical studies investigating the observed interactions between cisplatin, the antimetabolites, taxanes, and topoisomerase inhibitors on the DNA level.     

奈达铂联合紫杉醇和顺铂联合紫杉醇同步放化疗局部晚期鼻咽癌的临床随机对照实验

目的 通过临床随机对照实验观察奈达铂是否能够替代顺铂与紫杉醇联合同步放化疗局部晚期鼻咽癌,是否能够提高治疗的耐受性.方法 实验组(TN组)30例,采用紫杉醇135 mg/m2ivgtt d1+奈达铂10 mg/m2 ivgttd1诱导化疗,每3周为1个化疗周期,共2个疗程,以后行同样方案同期放化疗,仍然每3周为1个化疗...