Schedule-dependent inhibition of T-cell lymphoma cells by cotreatment with the mTOR inhibitor everolimus and anticancer drugs

Objective Everolimus (RAD001) is a novel mammalian target of rapamycin (mTOR) inhibitor, and anti-proliferative activity in various malignancies has been reported. This study evaluated the anti-tumor effects and schedule-dependent synergism of everolimus in combination with other chemotherapeutic agents in T-cell lymphoma cell lines. Materials and methods Human T-cell lymphoma cell lines Hut-78 and Jurkat were treated with increasing doses of everolimus, alone or in combination with doxorubicin, etoposide, vincristine, or bortezomib, using different dosing schedules. Anti-tumor effects were measured by assays for cell proliferation, apoptosis, and cell cycle distribution. Drug interactions were determined by median effect analysis. Results Exposure to everolimus alone induced G1 phase cell cycle arrest without significant apoptosis. With certain dosing schedules, everolimus showed synergism with doxorubicin, etoposide, and bortezomib, but antagonism with vincristine. Cytotoxic synergism was observed following cotreatment with doxorubicin and everolimus, bortezomib and everolimus, doxorubicin followed by everolimus, and bortezomib followed by everolimus. By contrast, cell exposure to everolimus followed by doxorubicin or followed by bortezomib resulted in antagonistic effects. Sequential exposure to doxorubicin or bortezomib followed by everolimus effectively prevented potential negative interactions, and resulted in drug synergism. Drug combination synergisms or antagonisms were associated with variable effects on the cell cycle distribution. Conclusions Everolimus effectively inhibited the growth of T-cell lymphoma cells in vitro. Specific schedule-dependent combinations of everolimus with other anti-tumor agents which avoid potential drug antagonism and produce effective synergism may lead to clinically effective treatments for T-cell lymphoma.     

Everolimus: targeted therapy on the horizon for the treatment of breast cancer

The mammalian target of rapamycin (mTOR) is a signaling kinase of the phosphatidylinositol 3-kinase/protein kinase B (also known as Akt) signaling pathway that mediates cell growth and metabolism. Dysregulation of the mTOR pathway creates a favorable environment for the development and progression of many cancers, including breast cancer, and is associated with the development of resistance to endocrine therapy and to the anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody trastuzumab. Therefore, the addition of mTOR inhibitors to conventional breast cancer therapy has the potential to enhance therapeutic efficacy and/or overcome innate or acquired resistance. Everolimus, an mTOR inhibitor with demonstrated preclinical activity against breast cancer cell lines, has been shown to reverse Akt-induced resistance to hormonal therapy and trastuzumab. Phase I-II clinical trials have demonstrated that everolimus has promising clinical activity in women with HER2-positive, HER2-negative, and estrogen receptor-positive breast cancer when combined with HER2-targeted therapy, cytotoxic chemotherapy, and hormonal therapy, respectively. Everolimus is generally well tolerated; hematologic abnormalities and stomatitis are most common adverse events when this drug is combined with cytotoxic chemotherapy. Based on these promising results, everolimus is currently under evaluation in a series of phase III Breast Cancer Trials of Oral Everolimus (BOLERO) trials of women with HER2-positive and estrogen receptor-positive breast cancer. Results of these trials will help to establish the role of everolimus in the treatment of clinically important breast cancer subtypes.     

Combination antitumor effects of micelle-loaded anticancer drugs in a CT-26 murine colorectal carcinoma model

Experiments were designed to evaluate the in vitro cytotoxic interactions of anticancer drugs in combination, evaluate synergistic activity in vivo and utilize micelle-forming polymeric drugs as drug carriers in a murine cancer model. Antitumor effects of 5-fluorouracil, cisplatin, CPT-11, oxaliplatin, etoposide, mitomycin-C, doxorubicin and paclitaxel were evaluated by determination of in vitro cytotoxicity to CT-26 colorectal tumor cells or in vivo following a subcutaneous transplant in BALB/c mice. Single agent and combination in vivo studies were also performed using drug-loaded polymeric micelles composed of poly(γ-benzyl l-glutamate) and poly(ethylene oxide) (GEG) or poly(l-lactide)/poly(ethylene glycol) (LE) diblock copolymer. After 3 days exposure, the mean IC₅₀ (μg/mL) for 5-fluorouracil, cisplatin, CPT-11, oxaliplatin, etoposide, mitomycin-C, doxorubicin and paclitaxel were 0.95, 2.01, 4.47, 3.34, 3.5, 1.96, 1.8 and 2.1, respectively. When tumor cells were exposed to doxorubicin concurrently with etoposide or paclitaxel, evidence of synergy was observed in CT-26 cells in vitro. Doxorubicin and paclitaxel loaded into GEG or LE copolymers at a high concentration (19.5 and 16.7 wt%, respectively) were almost completely released (83.2% and 93.7%, respectively) by day 3. When tumor-bearing mice were treated in combination with doxorubicin–paclitaxel or doxorubicin–etoposide, substantial antitumor activity was evident compared with single therapy. These data suggest that in vitro cytotoxicity of anticancer drugs is related to in vivo results, and chemotherapy using micelle-loaded anticancer drugs represents a promising potential as a carrier system in modulating drug delivery.     

Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models

Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar levels of EGFR expression, the antitumor activity of erlotinib is robust both as monotherapy and in combination with chemotherapies.     

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.     

mTOR 抑制剂依维莫司在肿瘤治疗中的临床应用

依维莫司（everolimus）是雷帕霉素的40—O—2-（羟乙基）衍生物,为哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂。除了免疫抑制作用外,它能持续抑制mTOR靶点,达到抑制肿瘤生长与增殖、抑制肿瘤营养代谢和抑制肿瘤新生血管形成等三重抗肿瘤作用。在国外已被批准用于治疗晚期肾癌、乳腺癌、不能外科切除的进展性或转移性胰腺神经内分泌瘤以及伴有结节性硬化症（TSC）的室管膜下巨细胞星形细胞瘤（SEGA）;在我国也已被批准用于晚期肾癌。依维莫司对其他的肿瘤的疗效及安全性也正在进行临床试验。本文简要介绍依维莫司的作用机制以及在肿瘤治疗中的临床应用。     

Everolimus enhances gemcitabine-induced cytotoxicity in bladder-cancer cell lines

The purpose of this study was to determine whether everolimus, a rapamycin derivative, might significantly enhance the cytotoxicity of gemcitabine, an antitumor drug, in two human bladder-cancer cell lines. Human bladder-cancer T24 and 5637 cells were incubated with gemcitabine and everolimus in a range of concentrations either alone or in combination for 72 h. Flow cytometry, comet assay, MTT method and optical microscopy were used to assess cell proliferation, cell cycle, DNA damage, and morphological alterations. Gemcitabine exerted an inhibitory effect on T24 and 5637 cell proliferation, in a concentration-dependent manner. Everolimus significantly reduced proliferation of 5637 bladder cancer cells (IC??) at 1 μM), whereas T24 demonstrated marked resistance to everolimus treatment. A significant antiproliferative effect was obtained combining gemcitabine (100 nM) with everolimus (0.05-2 μM) with an arrest of cell cycle at S phase. Furthermore, an increase in frequency of DNA damage, apoptotic bodies, and apoptotic cells was observed when T24 and 5637 cancer cells were treated simultaneously with both drugs. Data show that in vitro combination produced a more potent antiproliferative effect when compared with single drugs.     

Heterogeneity of chemosensitivity of metastatic cutaneous melanoma.

Advanced melanoma has a poor prognosis and chemotherapy provides little benefit for most patients. This may be related to heterogeneity of chemosensitivity as well as frequent constitutive resistance to individual cytotoxic drugs. We have therefore examined the heterogeneity of chemosensitivity in metastatic cutaneous melanoma specimens using an ex vivo ATP-based chemosensitivity assay (ATP-TCA). Melanoma deposits (n=55) in skin or lymph node were tested using the ATP-TCA, performed in three separate laboratories. Analysis of the data collected (based on an arbitrary sensitivity index < 300) shows considerable heterogeneity of chemosensitivity. The most active single cytotoxic agents in the assay were identified as cisplatin, treosulfan, paclitaxel, vinblastine, gemcitabine and mitoxantrone. There was also a limited direct inhibition of melanoma cell growth by interferon-alpha2b, although this agent is known to have a number of indirect biological antitumor effects. Exposure of tumor cells to combinations of drugs at the concentrations tested as single agents showed the most active combinations to be treosulfan+gemcitabine, cisplatin+paclitaxel and vinblastine+paclitaxel. There was considerable heterogeneity of chemosensitivity: some tumors responded well to one agent or combination, while others showed no response to this and instead responded to one of the alternatives tested. Occasional highly resistant tumors showed no response to any of the single agents or combinations tested. The degree of heterogeneity observed suggests that the ATP-TCA could be used to select patients who might benefit from specific chemotherapeutic agents alone or in combination. This provides the rationale for future randomized controlled trials of ATP-TCA-directed chemotherapy versus physician's choice to determine whether assay-directed chemotherapy can improve patient response and survival.     

Effects of mTOR and calcineurin inhibitors combined therapy in Epstein–Barr virus positive and negative Burkitt lymphoma cells

Post-transplant lymphoproliferative disorder is a severe complication in solid organ transplant recipients, which is highly associated with Epstein–Barr virus infection in pediatric patients and occasionally presents as Burkitt- or Burkitt-like lymphoma. The mammalian target of rapamycin (mTOR) pathway has been described as a possible antitumor target whose inhibition may influence lymphoma development and proliferation after pediatric transplantation. We treated Epstein–Barr virus positive (Raji and Daudi) and negative (Ramos) human Burkitt lymphoma derived cells with mTOR inhibitor everolimus alone and in combination with clinically relevant immunosuppressive calcineurin inhibitors (tacrolimus or cyclosporin A). Cell proliferation, toxicity, and mitochondrial metabolic activity were analyzed. The effect on mTOR Complex 1 downstream targets p70 S6 kinase, eukaryotic initiation factor 4G, and S6 ribosomal protein activation was also investigated. We observed that treatment with everolimus alone significantly decreased Burkitt lymphoma cell proliferation and mitochondrial metabolic activity. Everolimus in combination with cyclosporin A had a stronger suppressive effect in Epstein–Barr virus negative but not in Epstein–Barr virus positive cells. In contrast, tacrolimus completely abolished the everolimus-mediated suppressive effects. Moreover, we showed a significant decrease in activation of mTOR Complex 1 downstream targets after treatment with everolimus that was attenuated when combined with tacrolimus, but not with cyclosporin A. For the first time we showed the competitive effect between everolimus and tacrolimus when used as combination therapy on Burkitt lymphoma derived cells. Thus, according to our in vitro data, the combination of calcineurin inhibitor cyclosporin A with everolimus is preferred to the combination of tacrolimus and everolimus.     

Preparation and in vivo evaluation of liposomal everolimus for lung carcinoma and thyroid carcinoma

Everolimus has demonstrated antitumor efficacy for various cancers as a result of its inhibition of the mammalian target of rapamycin (mTOR) signaling cascade, which activates cell growth and cell proliferation. However, the low water solubility and low bioavailability of everolimus have prevented its clinical development as an anticancer drug. Therefore, to address the unsuitable characteristic of everolimus, we attempted to prepare liposomal everolimus as a viable drug delivery system, and then evaluated the anticancer efficacy of this system against a medullary thyroid carcinoma cell line (TT cells), a breast cancer cell line (MCF-7 cells) and a small lung carcinoma cell line (NCI-H446 cells). The particle size and entrapment efficacy of liposomal everolimus was ca. 80 nm and more than 90%, respectively. Liposomal everolimus showed higher cytotoxicity against NCI-H446 cells compared with TT cells. Against NCI-H446 tumors, significant suppression of the tumor volume was observed in liposomal everolimus-treated mice by intravenous injection, compared with free everolimus-treated mice by intraperitoneal injection, at a dose of 5 mg/kg without body weight loss. This study showed that liposomal everolimus could be a powerful formulation with anticancer efficacy for some cancers.     

Screening of anticancer drugs for chemoembolization of hepatocellular carcinoma

The aim of this study was to select the best candidate drug for transarterial chemoembolization by in-vitro cytotoxic evaluations of 11 anticancer drugs on three human hepatocellular carcinoma (HCC) cell lines. The SNU-398, HepG2, and SNU-449 human HCC cell lines were exposed for 30 min to 11 concentrations of doxorubicin, epirubicin, idarubicin, mitoxantrone, carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, gemcitabine, mitomycin C, or paclitaxel. Cytotoxicity was measured using a quantitative colorimetric assay. For each drug and cell line, we calculated the drug concentration that caused 90% cell death (IC90). To enable comparisons of drugs with different concentration ranges, we computed the cytotoxic index (CyI) as the ratio of maximal drug concentration of more than IC90. Parameters were estimated using nonlinear regression models. Idarubicin was the most active drug on all three cell lines. With SNU-398 cells, the idarubicin CyI was 2.4-fold, 2.5-fold, 57-fold, 148-fold, and more than 58 748-fold higher than the CyIs of mitoxantrone, epirubicin, doxorubicin, gemcitabine, and other drugs, respectively. With HepG2 cells, the idarubicin CyI was 27-fold, 28-fold, 51-fold, and more than 1343-fold higher than the CyIs of doxorubicin, epirubicin, mitoxantrone, and other drugs, respectively. On the resistant SNU-449 cell line, the idarubicin CyI was 2.9-fold and 14-fold higher than the CyIs of paclitaxel and gemcitabine, respectively, the only other drugs effective on this cell line. Among 11 chemotherapeutic agents including doxorubicin, cisplatin, and epirubicin, the most effective on three HCC cell lines was idarubicin. Further clinical investigations are needed to evaluate the safety and efficacy of idarubicin for transarterial chemoembolization in HCC.     

Everolimus: a review of its use in renal and cardiac transplantation

Everolimus (Certican) is an orally administered mammalian target of rapamycin inhibitor (proliferation signal inhibitor) derived from sirolimus (rapamycin), which is used as part of immunosuppressant therapy in kidney and heart transplantation. When evaluated as part of triple therapy with ciclosporin and corticosteroids, everolimus showed equivalent efficacy to mycophenolate mofetil after renal transplantation, and superiority to azathioprine in cardiac transplant recipients, in terms of reducing efficacy failure after transplantation. Everolimus potentiates ciclosporin-associated nephrotoxicity, and it is recommended that concentration-controlled everolimus is used with reduced-dosage ciclosporin in order to limit renal toxicity while retaining immunosuppressive efficacy. Ongoing trials with everolimus, such as the evaluation of ciclosporin-withdrawal strategies, should help clarify its optimal usage. The use of everolimus may be associated with reduced rates of cytomegalovirus (CMV) infection and of cardiac allograft vasculopathy. Available data suggest that everolimus may be cost-neutral for healthcare providers.     

Clinical pharmacology confounders in older adults

The activity of chemotherapy as salvage therapy for recurrent bladder cancer has been well defined, although the optimum therapy combination is less clear. Since the early nineties several cisplatin based regimens have been compared but no one regimen has reported a superior benefit. Currently, regimens such as methotrexate, vinblastine, doxorubicin and cisplatin and gemcitabine-cisplatin should be considered two equal alternatives in patients eligible for cisplatin, but the differing toxicity profiles should be evaluated in the choice of treatment. The use of a triple combination with paclitaxel, gemcitabine and cisplatin should be avoided in clinical practice, although its use may be carefully considered in patients needing a rapid downsizing of disease and with primary bladder tumor. Despite this evidence, several questions remain, and there is a need for answers in the future.     

Antiangiogenic and antitumor effects of a protein kinase C beta inhibitor in human hepatocellular and gastric cancer xenografts

Hepatocellular carcinoma and gastric cancer are the most prevalent tumors worldwide. Hep3B hepatocellular carcinoma and HS746T gastric cancer were used as models for these diseases in culture and in vivo. The PKC beta inhibitor 317615.2HCl was not very cytotoxic toward HS746T or Hep3B cells in culture and was, in the main, additive in cytotoxicity with cisplatin, 5-fluorouracil and gemcitabine when cell in monolayer were exposed to these agents in combination with 317615.2HCl. Treatment of nude mice bearing HS746T or Hep3B xenografts with 317615.2HCl orally twice daily resulted in a small decreased in CD31-stainable intratumoral vessels in the HS746T tumors and 60% decrease in CD31-stainable vessels in the Hep3B tumors. Somewhat larger decreases were observed in the vessel stained with CD105. As a single agent 317615.2HCl produced tumor growth delays between 6.5 and 15 days in the HS746T xenograft and between 5 and 25 days in the Hep3B xenograft over the dosage range (3 to 30 mg/kg). Sequential and simultaneous combinations with 317615.2HCl and 5-fluorouracil and gemcitabine resulted in increases in tumor growth delay on both schedules. Gemcitabine produced a 15-day tumor growth delay of the HS746T gastric carcinoma that was increased to 40 days when combined simultaneously with 317615.2HCl and to 30 days with the sequential treatment regimen. 5-Fluorouracil produced a 9-day tumor growth delay of the Hep3B hepatocellular carcinoma that increased to 31 days by simultaneous treatment with 317615.2HCl and to 43 days with the sequential treatment regimen. Treatment with the protein kinase C beta inhibitor 317615.2HCl decreased HS746T and Hep3B angiogenesis and improved treatment outcome with 5-fluorouracil and gemcitabine.     

TM208与5-氟尿嘧啶联合应用对小鼠肝癌H22移植瘤的抗肿瘤作用及其机制研究（英文）

4-甲基哌嗪-1-二硫代甲酸-（3-氰基-3,3-二苯基）丙酯盐酸盐（TM208）是一种新合成的氨基二硫代甲酸酯类化合物,具有良好的体内抗肿瘤作用,且毒性较低。探讨TM208与临床已知抗癌药联用能否提高疗效并降低毒性,可为TM208的临床试验提供依据。本实验通过小鼠肝癌H₂₂移植瘤模型考察了TM208与顺铂（DDP）、环磷酰胺（CTX）、5-氟尿嘧啶（5-Fu）分别联合用药的体内抗肿瘤作用及毒性。体内实验结果证实,5-Fu（5 mg/kg/2d）与TM208（100 mg/kg/d）联用后可显著增强对H₂₂肿瘤的抑制作用（P<0.01）,且几乎不增加毒性;而DDP和CTX则不能。进一步研究表明,TM208与5-Fu联用可通过下调cyclin B1,cdc2,cdk7和上调p21,p53的表达引起H₂₂实体瘤细胞发生G₂/M周期阻滞。同时此联合用药方案也可下调cyclin D1,cyclin E的表达,对cdk4,cdk2的表达则没有影响。Cdc2 mRNA的表达与其蛋白表达趋势一致,而cyclin B1mRNA表达在各组间没有差异。总之,TM208与5-Fu联用可提高抗肿瘤疗效,毒性不变,其抗肿瘤作用与细胞周期阻滞及其相关蛋白的表达变化有关。     

mTOR as a target of everolimus in refractory/relapsed Hodgkin lymphoma

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.     

Effects of 13-hydroxy SM5887 in combination with other anticancer agents on human tumor cell lines

Summary A new anthracycline derivative, SM5887, in combination with commonly used anticancer agents was evaluated against T-cell leukemia MOLT-3 and human osteosarcoma MG-63 cell lines in culture. MOLT-3 and MG-63 cells were incubated with various concentrations of 13-hydroxy SM5887 (SM5887-OH, the active metabolite of SM5887) and other drugs for 3 and 4 days, respectively. Cell growth inhibition was determined by MTT assay. The antitumor effects of the drug combinations at 80% inhibitory concentration (IC₈₀) were analyzed by the isobologram of Steel and Peckham. In MOLT-3 cells, SM5887-OH had additive effects with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, 4-hydroperoxy ifosfamide, 5-fluorouracil, cytarabine, and vincristine, whereas it had mainly protective (marked antagonistic) effects with methotrexate. In MG-63 cells, SM5887-OH had additive effects with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, 4-hydroperoxy ifosfamide; mainly subadditive (mild antagonistic) effects with 5-fluorouracil and cytarabine; and mainly protective (marked antagonistic) effects with vincristine and methotrexate. These findings suggest that SM5887 is suitable for simultaneous administration with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, or ifosfamide and not suitable for simultaneous administration with methotrexate. The effects of SM5887 in combination with 5-fluorouracil, cytarabine or vincristine may be variable, depending on cell lines. To find optimal combinations, further in vitro and in vivo studies of antitumor activity and toxicity appear to be warranted.     

Antitumor effect and enhancement of cytotoxic drug activity by cetuximab in nasopharyngeal carcinoma cells

BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common head and neck cancer in southern China and South East Asia. Epidermal growth factor receptor (EGFR) has been proposed as a new target for anticancer therapy. EGFR was over-expressed in 85% of NPC tissues and was associated with poor prognosis. MATERIALS AND METHODS: EGFR protein expression in four NPC cell lines, CNE-2, HONE-1, HK1 and C666-1, was examined by Western immunoblotting. The antitumor effect of cetuximab was studied in the cell lines, either alone or in combination with cisplatin or paclitaxel. RESULTS: EGFR protein expression was highest in the HK1 cell line, moderate in CNE-2 and HONE-1, and lowest in C666-1. Single agent cetuximab demonstrated significant antitumor effect in the HK1 and HONE-1 cell lines, but minimal activity in CNE-2 and C666-1 cells. When cetuximab was combined with cisplatin or paclitaxel in the HK1 and HONE-1 cell lines, an additive enhancement of cytotoxic drug activity was demonstrated. CONCLUSION: Cetuximab demonstrated single agent activity selectively in NPC cell lines with moderate to high EGFR protein expression. Cetuximab could also additively enhance the antitumor effects of cisplatin or paclitaxel in these NPC cell lines. These results support the rationale of combining cetuximab with current standard chemotherapy to further improve the therapeutic ratio in the treatment of NPC. Future studies should aim at defining the predictive markers for response to cetuximab in order to select the responsive tumor for the correctly targeted agents.     

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

The epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib resistance and able to maintain S6K phosphorylation after gefitinib treatment.Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.     

Everolimus: in patients with subependymal giant cell astrocytoma associated with tuberous sclerosis complex

Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR). Everolimus (starting dosage 3.0?mg/m(2)) was associated with a significant reduction in the volume of the largest subependymal giant cell astrocytoma (SEGA) in 28 patients aged ≥3 years with tuberous sclerosis complex (TSC) in a phase II trial (C2485). At 6 months, 32% of patients treated with everolimus had a ≥50% reduction in the volume of their largest SEGA lesion (assessed via an independent central radiology review); 75% had a ≥30% reduction. No patients developed new lesions. During the extension phase of this trial (median duration 34 months), the reduction in SEGA volume was maintained, with no everolimus recipient requiring surgery or other therapy for SEGA or hydrocephalus. In a phase III trial (EXIST-1) in 117 patients with SEGA associated with TSC, 35% of everolimus recipients (starting dosage 4.5?mg/m(2)) versus none of the placebo recipients (p?相似文献