培美曲塞联合奈达铂有效治疗腹膜间皮瘤1 例

培美曲塞(pemetrexed disodium for injection,PEM)是一种含有核心为吡咯嘧啶基团的抗叶酸制剂,通过破坏细胞内叶酸依赖性的正常代谢过程,抑制细胞复制,从而抑制肿瘤的生长.主要用于治疗无法手术的恶性胸膜间皮瘤.临床前研究显示培美曲塞体外可抑制间皮瘤细胞系(MSTO-211H和NCI-H2052)的生长.间皮瘤细胞系MSTO-211H的研究显示出培美曲塞与顺铂联合有协同作用.奈达铂(nedaplatin,NDP),广谱抗癌药,是一种疗效好、不良反应少的新一代铂类抗癌药.它与肿瘤细胞的DNA碱基结合,阻碍DNA复制,而发挥其抗肿瘤效果.培美曲塞和奈达铂作为二线抗肿瘤药物,多用于一线药物治疗无效的肿瘤患者.本文报道1例晚期腹膜间皮瘤顺铂治疗失败后应用培美曲塞+奈达铂治疗有效的病例.     

培美曲塞——多靶点抗癌新药

培美曲塞是礼来公司研制成功的新一代抗代谢类抗癌新药,于2004年2月被美国食品药品监督管理局(FDA)批准用于治疗恶性胸膜间皮瘤,随后又被批准用于晚期非小细胞肺癌的二线治疗,英文商品名为Alimta?,中文商品名为力比泰。培美曲塞是一种多靶点的抗癌药物,它发挥作用的靶点均为叶酸代谢途径中的几个关键酶,而该途径能够显著影响癌细胞的DNA合成和癌症的生长。因此理论上,培美曲塞对癌症的抑制作用应该十分显著,并且对多种癌症可能均有治疗效果。事实上也正是如此。培美曲塞被最早批准用于治疗晚期胸膜间皮瘤,该肿瘤的恶性程度高、进展迅速、对放化疗等多种治疗手段均疗效不佳,而培美曲塞在该肿     

培美曲塞及其在消化道肿瘤中应用研究进展

培美曲塞(pemetrexed)是一类新型的抗代谢类抗肿瘤药物,它作用于叶酸依赖性代谢途径中的多个酶,为多靶点抗叶酸药物,具有较好的临床应用前景。除FDA批准的适应症恶性胸膜间皮瘤(MPM)和非小细胞肺癌(NSCLC)外,培美曲塞单药或联合化疗对多种消化道肿瘤有明显的治疗作用,尤其对常规方案治疗失败后的患者,培美曲塞给他们带来了新的希望。1药物基础1·1化学结构培美曲塞是一个全合成的抗叶酸代谢药物,其化学名为N-[4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯[2,3-d]嘧啶-5-y1)乙基]苯甲酰]-L-谷氨酸二钠,分子式为C20H19N5Na2O6·7H2O,分子量59…     

培美曲塞的实验和临床研究进展

培美曲塞是一种多靶点的抗代谢类药物.目前培美曲塞已被批准用于恶性胸膜间皮瘤的一线治疗和非小细胞肺癌的二线治疗,且已在多种肿瘤中开展了多项有关培美曲塞的研究.本文综述其实验研究及临床研究进展.     

培美曲塞治疗非小细胞肺癌

培美曲塞是一种多靶点的新型叶酸代谢拮抗剂,它通过抑制胸苷酸合成酶、二氢叶酸还原酶和甘氨酰胺核苷酸甲酰转移酶破坏细胞内叶酸依赖性代谢过程干扰细胞复制,从而抑制肿瘤生长。目前有关培美曲塞治疗包括恶性胸膜间皮细胞瘤、非小细胞肺癌、乳腺癌、胰腺癌、胃肠道肿瘤、头颈部肿瘤等多种恶性肿瘤的临床研究均有报道,本文综述培美曲塞单药或多药联合治疗在非小细胞肺癌的临床研究。     

胃癌中胸苷酸合成酶与培美曲塞／雷替曲塞敏感性的初步研究

目的 探讨胃癌组织中胸苷酸合成酶（TS）mRNA表达与培美曲塞或雷替曲塞药物敏感性之间的关系。方法 收集50例经病理确诊的新鲜人胃癌标本,采用三维微组织块培养法（HDRA）进行两种药物的体外敏感试验;实时荧光定量PCR检测对应胃癌石蜡组织中TS mRNA水平。结果 新鲜胃癌组织对培美曲塞或雷替曲塞的敏感性以及胃癌石蜡组织中TS mRNA水平均与临床病理特征无明显相关性。培美曲塞敏感组与耐药组的TS mRNA相对表达量分别为6.72 ±1.34和15.39 ± 2.43（P=0.002）;雷替曲塞敏感组与耐药组的TS mRNA相对表达量分别为7.96 ± 1.70和14.14 ± 2.37（P=0.028）。结论 胃癌石蜡组织TS mRNA水平与新鲜胃癌组织对培美曲塞或雷替曲塞的敏感性呈负相关,TS在胃癌应用新型抗叶酸代谢类药物个体化治疗中具有潜在的指导价值。     

培美曲塞在非小细胞肺癌治疗中的研究进展

培美曲塞（Pemetrexed，Alimta^R）是一种新型的多靶点抗叶酸药物．作为局部晚期或转移性非小细胞肺癌的二线治疗药物，目前已经有多个临床研究表明．培美曲塞单药或与其它药物联合在非小细胞肺癌的治疗中均获得显著疗效。该文对此作一回顾。     

培美曲塞治疗晚期复治非小细胞肺癌临床观察

目的 评价培美曲塞治疗晚期复治非小细胞肺癌(NSCLC)的疗效和毒副反应.方法 30例经病理学确诊既往化疗失败的晚期NSCLC,给予培美曲塞500 mg/m2静脉滴注,第1天,21 d为1个周期,并口服地塞米松、叶酸和肌肉注射维生素B12以减轻毒副反应.治疗后评价疗效和毒副反应.结果 30例NSCLC中,总有效率为20.0%,疾病控制率为83.3%.毒副反应主要为骨髓抑制.结论 培美曲塞治疗晚期复治NSCLC疗效肯定,毒副反应轻.     

培美曲塞二钠联合顺铂治疗中晚期非小细胞肺癌36例疗效分析

非小细胞肺癌由于起病隐匿，多数就诊时已属中晚期，目前尚无有效的治疗方法。培美曲塞二钠是一种多靶点抗叶酸制剂，由于其耐受性较好，近年来用于非小细胞肺癌的治疗，并取得较好疗效。2007年6月至2009年12月，     

2006年培美曲塞研究新进展

培美曲塞是一种多靶点的抗代谢类药物,目前已经在70余个国家批准上市,用于治疗恶性胸膜间皮瘤和非小细胞肺癌。在过去的两年间,在多种肿瘤中开展了多项有关培美曲塞的临床研究,部分研究结果在今年的ASCO年会上报道,我们对这些资料进行了汇总。     

New analogues of methotrexate]

New antifolate antimetabolites are currently developed and three analogues of methotrexate (MTX) (Trimetrexate, Edatrexate, TNP-351) are undergoing clinical trials in Japan. Trimetrexate characteristically enters cells primarily by passive transport, which is different from the mechanism of MTX. The increased therapeutic efficacy of Edatrexate is expected, because of the higher concentration of polyglutamates than MTX in tumor cells. TNP-351 is a novel antifolate, which has a different chemical structure from other antifolates. The current state of clinical trials of three antifolates and the indications for chemotherapy of lung cancer are reviewed.     

A novel folate transport activity in human mesothelioma cell lines with high affinity and specificity for the new-generation antifolate,pemetrexed

Pemetrexed is a novel antifolate effective in the treatment of mesothelioma. Studies were undertaken to characterize the transport of this antifolate in this tumor. We report the presence of a novel, concentrative high-affinity transport activity in three human mesothelioma cell lines, characterized in detail in the NCI-H28 line, with a pemetrexed influx K(t) of 30 nM and V(max) of 10 nmol/g protein/min. This route is highly specific for pemetrexed, with a substrate specificity pattern quite different from that of the reduced folate carrier and folate receptors. In particular, there is an apparent relatively low affinity for other antifolate inhibitors of dihydrofolate-reductase (MTX, aminopterin, PT523) and thymidylate synthase (ZD1694, ZD9331). Besides its impact on the transport of pemetrexed, this high-affinity route may represent another pathway by which physiological folates are transported into human cells.     

Resistance to antifolates

The antifolates were the first class of antimetabolites to enter the clinics more than 50 years ago. Over the following decades, a full understanding of their mechanisms of action and chemotherapeutic potential evolved along with the mechanisms by which cells develop resistance to these drugs. These principals served as a basis for the subsequent exploration and understanding of the mechanisms of resistance to a variety of diverse antineoplastics with different cellular targets. This section describes the bases for intrinsic and acquired antifolate resistance within the context of the current understanding of the mechanisms of actions and cytotoxic determinants of these agents. This encompasses impaired drug transport into cells, augmented drug export, impaired activation of antifolates through polyglutamylation, augmented hydrolysis of antifolate polyglutamates, increased expression and mutation of target enzymes, and the augmentation of cellular tetrahydrofolate-cofactor pools in cells. This chapter also describes how these insights are being utilized to develop gene therapy approaches to protect normal bone marrow progenitor cells as a strategy to improve the efficacy of bone marrow transplantation. Finally, clinical studies are reviewed that correlate the cellular pharmacology of methotrexate with the clinical outcome in children with neoplastic diseases treated with this antifolate.     

Molecular basis of antifolate resistance

Folates play a key role in one-carbon metabolism essential for the biosynthesis of purines, thymidylate and hence DNA replication. The antifolate methotrexate has been rationally-designed nearly 60 years ago to potently block the folate-dependent enzyme dihydrofolate reductase (DHFR) thereby achieving temporary remissions in childhood acute leukemia. Recently, the novel antifolates raltitrexed and pemetrexed that target thymidylate synthase (TS) and glycineamide ribonucleotide transformylase (GARTF) were introduced for the treatment of colorectal cancer and malignant pleural mesothelioma. (Anti)folates are divalent anions which predominantly use the reduced folate carrier (RFC) for their cellular uptake. (Anti)folates are retained intracellularly via polyglutamylation catalyzed by folylpoly-γ-glutamate synthetase (FPGS). As the intracellular concentration of antifolates is critical for their pharmacologic activity, polyglutamylation is a key determinant of antifolate cytotoxicity. However, anticancer drug resistance phenomena pose major obstacles towards curative cancer chemotherapy. Pre-clinical and clinical studies have identified a plethora of mechanisms of antifolate-resistance; these are frequently associated with qualitative and/or quantitative alterations in influx and/or efflux transporters of (anti)folates as well as in folate-dependent enzymes. These include inactivating mutations and/or down-regulation of the RFC and various alterations in the target enzymes DHFR, TS and FPGS. Furthermore, it has been recently shown that members of the ATP-binding cassette (ABC) superfamily including multidrug resistance proteins (MRP/ABCC) and breast cancer resistance protein (BCRP/ABCG2) are low affinity, high capacity ATP-driven (anti)folate efflux transporters. This transport activity is in addition to their established facility to extrude multiple cytotoxic agents. Hence, by actively extruding antifolates, overexpressed MRPs and/or BCRP confer antifolate resistance. Moreover, down-regulation of MRPs and/or BCRP results in decreased folate efflux thereby leading to expansion of the intracellular folate pool and antifolate resistance. This chapter reviews and discusses the panoply of molecular modalities of antifolate-resistance in pre-clinical tumor cell systems in vitro and in vivo as well as in cancer patients. Currently emerging novel strategies for the overcoming of antifolate-resistance are presented. Finally, experimental evidence is provided that the identification and characterization of the molecular mechanisms of antifolate-resistance may prove instrumental in the future development of rationally-based novel antifolates and strategies that could conceivably overcome drug-resistance phenomena.     

Folylpolyglutamyl synthetase gene transfer and glioma antifolate sensitivity in culture and in vivo.

BACKGROUND: Although antifolates are popular agents for use in chemotherapy, they display minimal toxicity against slow-growing tumors and are toxic to actively replicating cells in normal tissues. These drugs are converted intracellularly into polyglutamate derivatives by the enzyme folylpolyglutamyl synthetase (FPGS). Because tumors with high expression of FPGS often respond to nontoxic antifolate doses, we investigated whether augmenting tumoral FPGS activity by gene delivery would enhance tumoral antifolate sensitivity. METHODS: 9L rat gliosarcoma cells were stably transfected with a human FPGS complementary DNA (cDNA), producing 9L/FPGS cells. The sensitivity of these cells to the antifolates methotrexate and edatrexate was measured in culture and in subcutaneous tumors, as was their ability to increase the chemosensitivity of nearby nontransfected cells, i.e., a bystander effect. The antifolate sensitivity of nonselected cells transduced with a hybrid amplicon vector that expressed FPGS was also ascertained. RESULTS: In comparison with 9L cells, 9L/FPGS cells displayed enhanced sensitivity to 4-hour pulses of antifolate. Subcutaneous 9L/FPGS tumors responded as well to methotrexate given every third day as 9L tumors did to daily treatment. A modest bystander effect was observed with edatrexate treatment in culture and in vivo. The observed bystander effect appeared to result from the release of antifolates by transfected cells after the removal of extracellular drug. In culture, enhanced antifolate sensitivity was also seen in other stably transfected rodent and human glioma cell lines, including one with high pre-existing FPGS activity, and in canine and human glioblastoma cell lines transduced with a vector bearing FPGS cDNA. CONCLUSIONS: FPGS gene delivery enhances the antifolate sensitivity of several glioma cell lines and merits further evaluation as a therapeutic strategy.     

Novel therapeutic developments other than EGFR and VEGF inhibition in colorectal cancer

Developments that may improve existing cytotoxic therapy for colorectal cancer (CRC) include alternatives to 5-fluorouracil (5-FU) such as the liposomal Thymidylate Synthase inhibitor OSI-7904L and the multitargeted antifolate pemetrexed. Studies have explored means of reformulating irinotecan, modulating its pharmacokinetics, and enhancing its activity by maximizing DNA damage through poly(ADP-ribose) polymerase inhibition. Cell cycle inhibitors may offer an alternative to combination with 5-FU. However, as standard regimens become more complex, so do the clinical trials needed to develop new agents, and the path to registration becomes ever more tortuous. It is therefore likely that several drugs with promise in CRC will not be developed for this indication.     

Mechanisms of natural resistance to antifolates in human soft tissue sarcomas.

Efforts to use fresh human sarcoma cells for evaluating antifolate resistance with an in situ thymidylate synthesis assay using 5-[3H] deoxyuridine were unsuccessful because of low thymidylate synthesis activity in enzymatically disaggregated tumors. By incubating tumor cell suspensions in supplemented RPMI-1640 medium with 10% fetal bovine serum for 3 days, activity of the in situ thymidylate synthesis assay markedly increased (1.42 versus 0.03 pmol/h/10(7) cells), thus allowing 75% of samples to be evaluated for antifolate sensitivity. By criteria developed with a methotrexate-resistant and -sensitive cell line, this assay indicated that most sarcomas are naturally resistant to methotrexate (12 of 15). Natural resistance to 10-ethyl-10-deazaaminopterin and trimetrexate was also observed in 60% of the samples (nine of 15, respectively). The results from the 3-day in situ assay were confirmed by specific tests for resistance mechanisms in most sarcoma samples. The resistance mechanisms detected were impaired polyglutamylation, an increased level of dihydrofolate reductase, and amplification of this gene. These results encourage further exploration of this assay to predict response to antifolates in individual patients and to evaluate efficacy of new antifolates as candidates for clinical trial.     

Chemotherapy for Malignant Pleural Mesothelioma

All MPM patients with a good performance status should be considered for enrollment on clinical trials. With that said, the standard frontline therapy for fit MPM patients remains an antifolate/platinum doublet, based on large, well powered randomized clinical trials that showed not only a survival benefit for antifolate/platinum regimens but also improvements in quality of life and/or symptoms. For less fit patients, single agents can be used as frontline therapy. In the second line setting, there is benefit from retreatment with single agent pemetrexed after prior exposure to that agent, as well as after exposure to other chemotherapeutic agents. Other single chemotherapy agents and combinations are viable options for fit patients who have had relatively long time to progression after their frontline therapy. Additionally, several prognostic scales designed for MPM (CALGB and EORTC) provide additional means to better select patients for frontline and second line chemotherapy.     

Antimetabolites in the management of non-small cell lung cancer

Opinion statement Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. Although chemotherapy has been shown to increase survival for patients with advanced-stage disease, survival benefits have been modest and come at the cost of significant toxicity. Treatment options in the second-line setting have been limited. Pemetrexed, a multitargeted antifolate, has activity as a single agent and as part of combination chemotherapy against NSCLC. As reported in a recent phase III clinical trial, survival outcomes in the second-line setting for patients treated with pemetrexed or docetaxel are similar. More importantly, major toxicity with the use of pemetrexed with vitamin B₁₂ and folate supplementation is far less than with docetaxel. Based on its single agent activity, ease of administration, and favorable toxicity profile, pemetrexed has the potential to be incorporated in various settings against NSCLC, including metastatic disease, as adjuvant therapy, and for locally advanced disease.     

Design and rationale for novel antifolates

The goals of new antifolate development are: 1) improved selectivity, 2) improved penetration into pharmacologic sanctuaries, and 3) effectiveness vs. tumors either with intrinsic or acquired resistance to methotrexate (MTX). The major target for antifolate development has been dihydrofolate reductase (DHFR), but other critical folate-dependent enzymes, i.e., thymidylate synthase, methionine synthetase, and folylpolyglutamate synthetase are also important targets for new antifolate development. The possibility that DHFR from tumor tissue differs significantly from normal tissue DHFR now seems improbable, and the ideas of the late Bill Baker to design specific inhibitors of the tumor enzyme vs. the normal tissue DHFR are unlikely to succeed. However, the experience with triazinate (Baker's antifol; TZT) indicates that transport of antifols could be exploited to provide selective toxicity, as well as to provide agents effective vs. MTX-resistant cells. This work led to a second generation of "nonclassical" folate antagonists, of which trimetrexate (JB-11; TMQ) is now in clinical trial. Uptake of TMQ is via an MTX-independent membrane system, and extremely high intracellular levels of this drug are achieved in human leukemia cells.