Cryptophycin 52 and cryptophycin 55 in sequential and simultaneous combination treatment regimens in human tumor xenografts

The antitumor activity of cryptophycin 52 (C52) and cryptophycin 55 (C55) in sequential and simultaneous combination treatment regimens in human tumor xenografts models was explored. The antitumor activity of C52 and C55 was compared alone and in sequential combination with gemcitabine or paclitaxel in four lung cancer models, H460 and Calu-6 NSCLC and SW2 and H82 small cell lung carcinoma. The combination of C52 followed by gemcitabine was additive in three tumors and greater-than-additive in the fourth. The combination of C55 followed by gemcitabine was additive in three tumors and less-than-additive in the fourth. The combination of C52 followed by paclitaxel was greater-than-additive in one tumor, additive in one tumor and less-than-additive in two tumors. The combination of C55 followed by paclitaxel was greater-than-additive in two tumors and less-than-additive in two tumors. The simultaneous combination of C52 or C55 with fractionated radiation therapy was assessed in the H460 NSCLC tumor. Both cryptophycins produced a tumor response that was additive along with radiation therapy. The HCT116 colon carcinoma was used to compare the antitumor activity of simultaneous or sequential combination of 5-fluorouracil or irinotecan with C52. C52 produced greater-than-additive tumor response when administered either simultaneously with or sequentially with 5-fluorouracil or iriniotecan. Finally, when administered to animals bearing intraperitoneal OVCAR-3 ovarian carcinoma, C52, docetaxel and paclitaxel resulted in mean survival times of 123, 80 and 85 days compared with 72 days in the untreated controls. In combination with carboplatin, C52, docetaxel and paclitaxel resulted in mean survival times of 140, 105 and 135 days. Cryptophycins have the potential to be useful chemotherapeutic agents in a wide variety of clinical combinations regimens.     

Preclinical anti-tumor activity of XR5944 in combination with carboplatin or doxorubicin in non-small-cell lung carcinoma

XR5944 (MLN944) is a novel bis-phenazine currently in phase I clinical trials that has demonstrated potent cytotoxic activity against a variety of tumor models. The combinations of XR5944 with carboplatin or doxorubicin were investigated in COR-L23/P human non-small-cell lung carcinoma (NSCLC) cells in vitro and the corresponding xenografts in vivo. In vitro cytotoxicity was evaluated by the sulforhodamine B assay and the drug interactions following simultaneous or sequential exposure were determined using median-effect analysis to calculate combination indices (CIs). XR5944 demonstrated potent cytotoxicity compared to either carboplatin or doxorubicin in COR-L23/P cells. Simultaneous or sequential exposure of XR5944 followed by carboplatin led to a synergistic response (CI<1), whereas the reverse order of addition showed an additive or antagonistic response (CI< or =1). Sequential administration of doxorubicin followed by XR5944 demonstrated marginally improved cytotoxicity (CI=1.31-0.77) than other schedules (CI=1.50-1.22) relative to individual drugs. Anti-tumor activity against COR-L23/P xenografts in nude mice was enhanced by administration of XR5944 (2 or 5 mg/kg) immediately before carboplatin (50 mg/kg) compared to single-agent treatment at the same doses. Improved efficacy was also observed by sequential administration of 7 mg/kg doxorubicin 48 h before 2.5 or 5 mg/kg XR5944. No additional toxicity was observed with combinations compared to single-agent treatment alone as determined by body weights. These data suggest that combinations of XR5944 with carboplatin or doxorubicin are of significant interest for clinical use, and that the schedule of administration may be important for achieving clinical efficacy over single-agent therapy.     

Paclitaxel for non-small cell lung cancer

Paclitaxel, a tubulin-binding agent, is widely used for the treatment of non-small cell lung cancer (NSCLC). The combination of paclitaxel and a platinum compound is an approved regimen for the treatment of advanced NSCLC. The dose-limiting toxicity of paclitaxel is myelosuppression when administered on a prolonged infusion schedule, whereas neuropathy is more common with short infusions. Although the 3-weekly schedule of paclitaxel is the commonly utilised regimen for the treatment of advanced NSCLC, the weekly regimens appear to be associated with lesser myelosuppression and neuropathy. A randomised clinical trial is currently underway to compare the efficacy of the weekly versus 3-weekly regimen of paclitaxel, in combination with carboplatin for the treatment of advanced NSCLC. The radiosensitising effect of paclitaxel has led to its incorporation into multi-modality treatment of NSCLC patients in combination with thoracic radiation. Paclitaxel has also demonstrated synergistic interaction with several molecularly-targeted agents and is at present being evaluated in the neoadjuvant and adjuvant treatment settings for early stage NSCLC.     

Docetaxel in ovarian cancer

Docetaxel, a semisynthetic taxane, is a potent inhibitor of cell replication and, similar to paclitaxel, promotes in vitro assembly of stable microtubules and, therefore, prevents the depolymerisation process. Docetaxel has a higher affinity for the tubulin subunit and is associated with a 100-fold greater phosphorylation of BCL-2 inducing apoptosis. Docetaxel in combination with carboplatin demonstrates similar activity to paclitaxel/carboplatin in the upfront management of advanced ovarian cancer with less neurological, but greater haematological toxicity. This article reviews the rationale and indications for the use of docetaxel in ovarian cancer.     

Paclitaxel for non-small cell lung cancer

Paclitaxel, a tubulin-binding agent, is widely used for the treatment of non-small cell lung cancer (NSCLC). The combination of paclitaxel and a platinum compound is an approved regimen for the treatment of advanced NSCLC. The dose-limiting toxicity of paclitaxel is myelosuppression when administered on a prolonged infusion schedule, whereas neuropathy is more common with short infusions. Although the 3-weekly schedule of paclitaxel is the commonly utilised regimen for the treatment of advanced NSCLC, the weekly regimens appear to be associated with lesser myelosuppression and neuropathy. A randomised clinical trial is currently underway to compare the efficacy of the weekly versus 3-weekly regimen of paclitaxel, in combination with carboplatin for the treatment of advanced NSCLC. The radiosensitising effect of paclitaxel has led to its incorporation into multi-modality treatment of NSCLC patients in combination with thoracic radiation. Paclitaxel has also demonstrated synergistic interaction with several molecularly-targeted agents and is at present being evaluated in the neoadjuvant and adjuvant treatment settings for early stage NSCLC.     

Taxanes for advanced non-small cell lung cancer

The emergence of novel chemotherapeutic agents with promising anticancer activity in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded role for chemotherapy in the management of this disease. The taxanes (paclitaxel and docetaxel) are novel microtubule stabilising agents, and have become an integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes inhibit the growth of lung cancer cell lines, exhibit synergistic interaction with other chemotherapy agents and enhance the efficacy of radiation in vitro. When used in low doses (metronomic dosing), they have important antiangiogenic properties. Several Phase II and III clinical trials have established the efficacy of the taxanes, as single agents and when used in combination with a platinum compound, in the treatment of advanced NSCLC. The use of a taxane in combination with a platinum compound has become an acceptable standard for patients with advanced or metastatic NSCLC. In addition to its efficacy in the first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing the efficacy of combining molecularly targeted agents with taxane-based regimens for the treatment of advanced NSCLC.     

Taxanes for advanced non-small cell lung cancer

The emergence of novel chemotherapeutic agents with promising anticancer activity in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded role for chemotherapy in the management of this disease. The taxanes (paclitaxel and docetaxel) are novel microtubule stabilising agents, and have become an integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes inhibit the growth of lung cancer cell lines, exhibit synergistic interaction with other chemotherapy agents and enhance the efficacy of radiation in vitro. When used in low doses (metronomic dosing), they have important antiangiogenic properties. Several Phase II and III clinical trials have established the efficacy of the taxanes, as single agents and when used in combination with a platinum compound, in the treatment of advanced NSCLC. The use of a taxane in combination with a platinum compound has become an acceptable standard for patients with advanced or metastatic NSCLC. In addition to its efficacy in the first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing the efficacy of combining molecularly targeted agents with taxane-based regimens for the treatment of advanced NSCLC.     

Docetaxel in ovarian cancer

Docetaxel, a semisynthetic taxane, is a potent inhibitor of cell replication and, similar to paclitaxel, promotes in vitro assembly of stable microtubules and, therefore, prevents the depolymerisation process. Docetaxel has a higher affinity for the tubulin subunit and is associated with a 100-fold greater phosphorylation of BCL-2 inducing apoptosis. Docetaxel in combination with carboplatin demonstrates similar activity to paclitaxel/carboplatin in the upfront management of advanced ovarian cancer with less neurological, but greater haematological toxicity. This article reviews the rationale and indications for the use of docetaxel in ovarian cancer.     

CT-2103: emerging utility and therapy for solid tumours

CT-2103 (XYOTAX, Cell Therapeutics, Inc.) is a conjugate of paclitaxel to a polyglutamate polymer. Its macromolecular nature exploits enhanced permeability and retention in tumour tissues. This compound is stable and inactive in aqueous solution and undergoes predominantly intracellular metabolism at the site where active paclitaxel is released. Because it does not require a Cremophor EL vehicle, it can be administered by short infusion into peripheral veins. In preclinical models, compared with the same dose of unconjugated paclitaxel in Cremophor EL-ethanol, CT-2103 yields >or= 12-fold increase in area under the curve in both plasma and tumour tissue. This alteration in drug pharmacokinetics and biodistribution is attributable to the ability of macromolecules to concentrate in areas of vascular leakiness, such as tumour tissue. CT-2103 is taken up by both tumour cells and normal phagocytic cells and is transported to lysosomes, where it is released by specific proteases through enzymatic action. In syngeneic and xenogeneic tumour models, at the maximally tolerated dose, CT-2103 appears to be more active than the standard doses of paclitaxel. It has also demonstrated activity in paclitaxel-resistant tumour models. Its potential enhancement of efficacy and decrease in drug-related toxicities make this agent an attractive option for therapeutic investigation. In Phase I trials it has been relatively well-tolerated, with acceptable toxicity at doses 相似文献   

CT-2103: emerging utility and therapy for solid tumours

CT-2103 (XYOTAX?, Cell Therapeutics, Inc.) is a conjugate of paclitaxel to a polyglutamate polymer. Its macromolecular nature exploits enhanced permeability and retention in tumour tissues. This compound is stable and inactive in aqueous solution and undergoes predominantly intracellular metabolism at the site where active paclitaxel is released. Because it does not require a Cremophor^® EL vehicle, it can be administered by short infusion into peripheral veins. In preclinical models, compared with the same dose of unconjugated paclitaxel in Cremophor EL-ethanol, CT-2103 yields ≥ 12-fold increase in area under the curve in both plasma and tumour tissue. This alteration in drug pharmacokinetics and biodistribution is attributable to the ability of macromolecules to concentrate in areas of vascular leakiness, such as tumour tissue. CT-2103 is taken up by both tumour cells and normal phagocytic cells and is transported to lysosomes, where it is released by specific proteases through enzymatic action. In syngeneic and xenogeneic tumour models, at the maximally tolerated dose, CT-2103 appears to be more active than the standard doses of paclitaxel. It has also demonstrated activity in paclitaxel-resistant tumour models. Its potential enhancement of efficacy and decrease in drug-related toxicities make this agent an attractive option for therapeutic investigation. In Phase I trials it has been relatively well-tolerated, with acceptable toxicity at doses ≤ 225 mg/m² every 3 weeks. In combination with carboplatin the maximum tolerated dose is 235 mg/m² and the recommended Phase II dose 210 mg/m². Activity has been demonstrated in both non-small cell lung carcinoma (NSCLC) and in ovarian cancer, Phase III studies are currently testing this agent versus standard paclitaxel as maintenance therapy for first-line treatment-naive ovarian cancer. In addition, CT-2103 at a dose of 210 mg/m² (performance status [PS] 0 – 1) or 175 mg/m² (PS 2) is being compared with docetaxel (75 mg/m²) for the second-line treatment of NSCLC. In front-line PS 2 NSCLC patients, this agent in combination with carboplatin is undergoing comparison with paclitaxel/carboplatin; in a separate effort, single-agent CT-2103 is being compared with either gemcitabine or vinorelbine. These studies will determine whether the preclinical and early clinical promise of this agent can be realised in the clinical treatment of solid tumours.     

紫杉醇联合卡铂治疗非小细胞肺癌的临床观察

目的观察紫杉醇联合卡铂治疗晚期非小细胞肺癌的临床疗效及不良反应。方法将114例非小细胞肺癌患者随机分为两组,治疗组57例采用紫杉醇联合卡铂治疗,对照组57例采用传统化疗药物顺铂治疗,进行疗效比较观察,所有患者完成4个周期用药。结果治疗组总有效率（CR＋PR）为91.23%,对照组总有效率（CR＋PR）为70.18%。治疗组明显优于对照组,经统计学处理,差异有统计学意义（P〈0.05）。结论紫杉醇和卡铂联合治疗非小细胞癌有显著效果,副反应发生较轻,治疗非小细胞肺癌效果显著,是一种安全、有效、值得临床推广应用的化疗方案。     

Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer

This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m² followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m², which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m² as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted.     

The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines

Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Using median effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5′DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation.     

Role of gemcitabine in the treatment of advanced non-small cell lung cancer: review of the main phase II and phase III trials

Marked advances in the treatment of non-small cell lung cancer (NSCLC) have been made thanks to new agents. Among these agents, gemcitabine appears to be a major compound in advanced stage NSCLC chemotherapy. To start with, several phase III trials (conducted in Europe and in the USA) studied the gemcitabine/cisplatin combination (GC): US study protocois compared GC to cisplatin alone, to the standard treatment (etoposide/cisplatin) or to platinum/taxane doublets; in these studies, as a result of treatment with GC, a higher survival rate was observed. A study conducted in Italy, which is undergoing analysis, observes GC versus paclitaxel/carboplatin versus cisplatin/vinorelbine. In addition, in newer clinical protocols, it was observed that gemcitabine combined with taxanes or with vinorelbine demonstrated efficacy at least equal to that of combinations with platinum analogs. Newer agents acting on epithelial growth factor are also undergoing evaluation.     

Antineoplastic agents in the management of ovarian cancer: current status and emerging therapeutic strategies

The intent of this review is to critically examine the status of the current chemotherapeutic management of ovarian cancer and possible future directions. Standard systemic chemotherapy includes a platinum agent (cisplatin or carboplatin) and a taxane (paclitaxel or docetaxel), a strategy that has not changed in more than a decade. Phase-III-trial data have revealed the superior efficacy of intraperitoneal cisplatin, compared with systemic platinum delivery, in small-volume residual advanced ovarian cancer, but in general this approach is associated with greater toxicity. Several regimens have been shown to be active in recurrent and platinum-resistant ovarian cancer, but an optimal management strategy has not been defined. Although 'targeted therapeutic approaches' are currently being explored in this disease, with the important exception of anti-angiogeneic agents, to date, limited biological and clinical activity have been demonstrated.     

Selective cell kill of the combination of gemcitabine and cisplatin in multilayered postconfluent tumor cell cultures.

Both gemcitabine (2',2'-difluorodeoxycytidine, dFdC) and cisplatin (cis-diammine-dichloroplatinum) have significant anticancer activity against ovarian, head and neck, and non-small cell lung cancer (NSCLC). dFdC can be incorporated into DNA and RNA, and inhibit DNA repair, while cisplatin can form Pt-DNA adducts. We previously observed schedule-dependent synergism of the combination of dFdC and cisplatin in monolayer cell cultures. We now evaluated whether the combination would also enable selective cell kill in multilayered postconfluent cell cultures, since each compound showed variable activity in multilayered cells. The combination was tested in multilayered cultures from cell lines with a different histological origin: the human head and neck squamous cell carcinoma cell line UMSCC-22B (22B), the human NSCLC cell line H322, and ADDP, a cisplatin-resistant variant of the human ovarian cancer cell line A2780. Sensitivity of the multilayered cells was dependent on exposure duration and sequence of the drug combinations, which were added in a constant molar ratio (dFdC:cisplatin 1:100), with a total exposure time of 96 h. The type of interaction was related to the degree of resistance of the cell lines to either dFdC or cisplatin. Thus, the very sensitive 22B cells only showed an additive effect when cells were preincubated for 24 h with dFdC prior to exposure to the combination. In contrast, in the resistant ADDP and H322 cells, synergism was the most common profile (three out of four schedules tested). This is of special relevance when we take into account that these drugs only show cytostatic effects when administered alone, whereas the combination produced cytotoxic cell killing. In conclusion, combining dFdC with cisplatin can be at least additive, but synergistic in multilayered postconfluent cells resistant to dFdC and cisplatin.     

Differential impact of Raf-1 kinase activity on tumor cell resistance to paclitaxel and docetaxel

Docetaxel (Taxotere) is becoming increasingly important in the treatment of many tumor sites and is unusually active in tumors that are resistant to the structurally similar taxane, paclitaxel. These data suggest that the processes that confer cellular paclitaxel resistance may have a substantially lower impact upon the cytotoxicity induced by docetaxel. We have recently reported that there is a marked Raf-1 kinase dependency of paclitaxel resistance in human cervical and ovarian tumor cell lines. We therefore characterized the impact that inherent and genetically induced variations in Raf-1 kinase activity have on the docetaxel cytotoxicity in human ovarian and cervical cancer cell lines. Our data suggest that docetaxel cytotoxicity is independent of Raf-1 kinase activity in the cell lines studied and that the lack of cross-resistance between these two taxane compounds may be due to the differential impact that Raf-1 kinase activity has on their cytotoxicity. Should these relationships pertain to the clinical situation, these findings could form the basis for a molecular-based triage of patients to receive docetaxel when response to paclitaxel may be unlikely due to high Raf-1 kinase activity.     

Paclitaxel: a hope for advanced non-small cell lung cancer?

Recent studies have shown that paclitaxel (Taxol); Bristol-Myers Squibb Co., Princeton, NJ) is an active agent in the treatment of advanced non-small cell lung cancer (NSCLC). Early trials in patients with advanced NSCLC utilised a 24 h infusion schedule and reported objective tumour responses in 21 - 24% of patients. Shorter infusion schedules have equivalent efficacy, and combined results from 14 separate trials of single agent paclitaxel in advanced NSCLC show an overall tumour response rate of 26%. Alternative schedules of paclitaxel from the traditional regimen every three weeks are under active investigation, but it is premature to assess whether these will yield improved efficacy for patients with advanced NSCLC. A single multicentre randomised trial of paclitaxel versus best supportive care in advanced NSCLC showed a significant survival advantage for the chemotherapy arm. Two large randomised Phase III trials have shown that paclitaxel and cisplatin is modestly more effective than cisplatin and podophyllotoxin combinations. The addition of cisplatin or carboplatin to paclitaxel results in higher response rates than for each of the drugs as single agents, but it is unclear whether the combinations yield superior survival or quality of life compared to single agent paclitaxel, or to other paclitaxel-containing regimens.     

紫杉醇联合卡铂化疗治疗卵巢癌的临床观察

目的观察紫杉醇联合卡铂化疗方案治疗卵巢癌的疗效和毒副反应。方法40例卵巢癌患者用“紫杉醇＋卡铂”全身化疗或“紫杉醇＋卡铂”腹腔化疗,观察其疗效及不良反应。结果40例中,CR12例,PR18例,SD6例,PD4例,总有效率75％,主要不良反应为骨髓抑制、脱发、恶心、呕吐,但均可耐受。结论紫杉醇联合卡铂化疗方案治疗卵巢癌有较好疗效,不良反应可耐受。     

Role of farletuzumab in epithelial ovarian carcinoma

Epithelial ovarian cancer (EOC) is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Standard treatment for EOC is surgical debulking followed by platinum-based chemotherapy. While the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately relapse. The major focus of current clinical trials for treatment of recurrent ovarian cancer is the use of targeted biologic agents. Folate receptor alpha (FRα) is upregulated in majority of EOC and correlated with tumor stage and grade. It is hypothesized that the presence of overexpressed FRα correlates with the propagation rate of the tumors. FRα is largely absent from normal tissue, making it an attractive therapeutic target. Farletuzumab (MORAb-003), a humanized monoclonal antibody against FRα, has shown antitumor activity in preclinical xenograft models. A Phase 1 dose escalation study did not demonstrate dose-limiting toxicities, or severe adverse effects. A phase 2 efficacy and safety study of farletuzumab with carboplatin and taxane in patients with platinum-sensitive EOC in first relapse, have shown an improved response rate and time to progression compared with historical controls. Recently, preliminary safety data from a phase 1 trial reported that the combination of farletuzumab, carboplatin and PLD has an acceptable safety profile in patients with platinum- sensitive EOC following first or second relapse. Two randomized, double-blind, placebo-controlled Phase 3 studies with farletuzumab plus chemotherapy have been done. A trial of: farletuzumab with weekly paclitaxel in platinum-resistant EOC closed in December 2011 with full report pending. A second trial of farletuzumab with carboplatin and taxane in platinum-sensitive EOC in first relapse is slated to complete accrual in early 2012. Results from these trials will help define the role of farletuzumab in EOC.