培美与白血病英文.doc

1: Drugs. 2007;67(15):2153-71.Related Articles, LinksTreatment of acute lymphoblastic leukaemia : a new era.Apostolidou E, Swords R, Alvarado Y, Giles FJ.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.Acute lymphocytic leukaemia (ALL) is a heterogeneous group of disorders that result from the clonal proliferation and expansion of malignant lymphoid cells in the bone marrow, blood and other organs. Distinct clinicopathological ALL entities have been identified, resulting in the adoption of risk-oriented treatment approaches. Advances in ALL therapy have led to long-term survival rates of 80% in children. However, only approximate, equals30-40% of adults achieve long-term disease-free survival. Contemporary ALL treatment programmes include induction, intensified consolidation, maintenance phases and CNS prophylaxis. The optimal treatment of Philadelphia chromosome-positive patients requires the addition of BCR-ABL tyrosine kinase inhibitors, such as imatinib, whereas allogeneic stem-cell transplantation remains the preferred approach for high-risk patients in first remission. Since only approximate, equals38% of adult ALL patients are free of disease 5 years after diagnosis and the outcome of salvage chemotherapy is very poor (complete remission rates of 20-30%, median survival of 3-6 months), novel agents are desperately required. Of those currently in clinical studies, the outlook for sphingosomal vincristine, pegylated asparaginase (pegaspargase), liposomal annamycin, ABT-751, pemetrexed, talotrexin, nelarabine and the novel BCR-ABL kinase inhibitors is discussed.PMID: 17927282 PubMed - in process2: Anticancer Res. 2007 Mar-Apr;27(2):769-73.Related Articles, LinksAntifolate pseudo-resistance due to elevated levels of thymidine and hypoxanthine in a commercial serum preparation.Simon M, Blatter J, Granzow C.Department Molekulare Toxikologie (G120), Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany.BACKGROUND: Batch variability of sera used for cell culture is of considerable experimental concern. A novel fetal calf serum product, FCS Gold, was claimed to be the first defined fetal calf serum free of batch variation. MATERIALS AND METHODS: The efficacy of methotrexate (MTX) and LY231514 (multitargeted antifolate, MTA) in CCRF-CEM cells and KB cells was compared using media supplemented with FCS Gold or conventional fetal bovine serum. RESULTS: IC50 values from tests using conventional serum corresponded to published data. FCS Gold fully protected the cells from antifolate drug cytotoxicity. Dialysis of FCS Gold restored responsiveness to antifolate drugs. Elevated levels of hypoxanthine and thymidine were present in FCS Gold. They were approximately 10-fold greater than the concentrations required to overcome growth arrest mediated by 2 microM MTX. CONCLUSION: FCS Gold or identical products, e.g. FBS Gold, should not be used in studies on antifolate drug action.PMID: 17465201 PubMed - indexed for MEDLINE3: Expert Opin Emerg Drugs. 2007 Mar;12(1):165-79.Related Articles, LinksEmerging therapeutic options for Philadelphia-positive acute lymphocytic leukemia.Alvarado Y, Apostolidou E, Swords R, Giles FJ.Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.Acute lymphocytic leukemia (ALL) is a heterogeneous group of disorders that are associated with a cure rate of 80% in children. The prognosis in adults is considerably inferior, with age, disease bulk, leukemia karyotype and immune phenotype being prognostically relevant. Adult ALL treatment programs include induction, intensified consolidation and maintenance phases with CNS prophylaxis. The addition of imatinib in patients with BCR-ABL-positive ALL has improved the prognosis of this subgroup, but their survival is still poor. Initial data on the second-generation BCR-ABL inhibitors, dasatinib and nilotinib, indicate a potentially greater efficacy than imatinib, but the improvement is likely to be modest. The overall efforts in terms of developmental therapeutics in ALL are very modest and not in keeping with the urgent need for improvement. Most agents being investigated have mechanisms of action similar to those of existing agents for ALL therapy and thus represent modest opportunities to improve results. Of such agents, data on BCR-ABL inhibitors, sphingosomal vincristine, pemetrexed, talotrexin, annamycin and ABT-751 are reviewed.Publication Types: ReviewPMID: 17355221 PubMed - indexed for MEDLINE4: Cancer Metastasis Rev. 2007 Mar;26(1):111-28.Related Articles, LinksHuman reduced folate carrier: translation of basic biology to cancer etiology and therapy.Matherly LH, Hou Z, Deng Y.Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, The Cancer Biology Graduate Program, Detroit, MI 48201, USA. This review attempts to provide a comprehensive overview of the biology of the physiologically and pharmacologically important transport system termed the reduced folate carrier (RFC). The ubiquitously expressed RFC has unequivocally established itself as the major transport system in mammalian cells and tissues for a group of compounds including folate cofactors and classical antifolate therapeutics. Loss of RFC expression or function may have potentially profound pathophysiologic consequences including cancer. For chemotherapeutic antifolates used for cancer such as methotrexate or pemetrexed, synthesis of mutant RFCs or loss of RFC transcripts and proteins results in antifolate resistance due to incomplete inhibition of cellular enzyme targets and insufficient substrate for polyglutamate synthesis. Since RFC was first cloned in 1994, tremendous advances have been made in understanding the complex transcriptional and posttranscriptional regulation of RFC, in identifying structurally and functionally important domains and amino acids in the RFC molecule as a prelude to establishing the mechanism of transport, and in characterizing the molecular defects in RFC associated with loss of transport in antifolate resistant cell line models. Many of the insights gained from laboratory models of RFC portend opportunities for modulating carrier expression in drug resistant tumors, and for designing a new generation of agents with improved transport by RFC or substantially enhanced transport by other folate transporters over RFC. Many of the advances in the basic biology of RFC in cell line models are now being directly applied to human cancers in the clinical setting, most notably pediatric acute lymphoblastic leukemia and osteogenic sarcoma.Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Govt ReviewPMID: 17334909 PubMed - indexed for MEDLINE5: Cancer Metastasis Rev. 2007 Mar;26(1):153-81.Related Articles, LinksMolecular basis of antifolate resistance.Assaraf YG.The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 32000, Israel. assaraftx.technion.ac.ilFolates 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-gamma-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.Publication Types: ReviewPMID: 17333344 PubMed - indexed for MEDLINE7: Cancer Chemother Pharmacol. 2006 Jul;58(1):1-12. Epub 2005 Dec 15.Related Articles, LinksMultidrug resistance proteins and folate supplementation: therapeutic implications for antifolates and other classes of drugs in cancer treatment.Hooijberg JH, de Vries NA, Kaspers GJ, Pieters R, Jansen G, Peters GJ.Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands.Over the past decades, numerous reports have covered the crucial role of multidrug resistance (MDR) transporters in the efficacy of various chemotherapeutic drugs. Specific cell membrane-associated transporters mediate drug resistance by effluxing a wide spectrum of toxic agents. Although several excellent reviews have addressed general aspects of drug resistance, this current review aims to highlight implications for the efficacy of folate-based and other types of chemotherapeutic drugs. Folates are vitamins that are daily required for many biosynthetic processes. Folate supplementation in our diet may convey protective effects against several diseases, including cancers, but folate supplementation also makes up an essential part of several current cancer chemotherapeutic regimens. Traditionally, the folate leucovorin, for instance, is used to reduce antifolate toxicity in leukemia or to enhance the effect of the fluoropyrimidine 5-fluorouracil in some solid tumors. More recently, it has also been noted that folic acid has the ability to increase antitumor activity of several structurally unrelated regimens, such as alimta/pemetrexed and cisplatin. Moreover, studies from our laboratory demonstrated that folates could modulate the expression and activity of at least two members of the MDR transporters: MRP1/ABCC1, and the breast cancer resistance protein BCRP/ABCG2. Thus, folate supplementation may have differential effects on chemotherapy: (1) reduction of toxicity, (2) increase of antitumor activity, and (3) induction of MRP1 and BCRP associated cellular drug resistance. In this review the role of MDR proteins is discussed in further detail for each of these three items from the perspective to optimally exploit folate supplementation for enhanced chemotherapeutic efficacy of both antifolate-based chemotherapy and other classes of chemotherapeutic drugs.Publication Types: Research Support, Non-U.S. Govt ReviewPMID: 16362298 PubMed - indexed for MEDLINE8: Semin Oncol. 2005 Apr;32(2 Suppl 3):S114-8.Related Articles, LinksCombined modality trials in unresectable stage III non-small cell lung cancer: the Cancer and Leukemia Group B experience.Socinski MA.Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of South Carolina, 101 Manning Drive, Chapel Hill, NC 27599, USA. Lung cancer remains the leading cause of cancer-related mortality in the United States and 30% to 40% of newly diagnosed patients with non-small cell lung cancer present with regionally advanced and unresectable stage III disease. Combined-modality therapy is the current standard of care in patients with good performance status at the time of diagnosis and recent trials have suggested a survival advantage for the concurrent use of chemotherapy and thoracic radiation therapy at the risk of increased toxicity (mainly esophagitis and myelosuppression). The Cancer and Leukemia Group B has been instrumental in shaping the standard of care in the combined-modality approach to unresectable stage III non-small cell lung cancer. Currently, Cancer and Leukemia Group B is conducting trials evaluating novel thoracic radiation therapy strategies as well as the incorporation of molecularly targeted agents, yielding encouraging preliminary data. In addition, a change in the therapeutic platform is planned that explores a full-dose systemic approach with the antifolate pemetrexed that possesses radiosensitizing properties.Publication Types: ReviewPMID: 16015547 PubMed - indexed for MEDLINE9: Biochem Pharmacol. 2003 Apr 1;65(7):1163-70.Related Articles, LinksDecreased expression of the reduced folate carrier and folypolyglutamate synthetase is the basis for acquired resistance to the pemetrexed antifolate (LY231514) in an L1210 murine leukemia cell line.Wang Y, Zhao R, Goldman ID.Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine Cancer Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA.Pemetrexed (LY231514) is a new-generation antifolate that, in its polyglutamyl forms, is a potent inhibitor of thymidylate synthase and glycinamide ribonucleotide formyltransferase (GAR transformylase). This study explored the mechanisms of resistance to pemetrexed in L1210 murine leukemia cells using chemical mutagenesis with 5-formyltetrahydrofolate (5-formylTHF) as the growth substrate. A cell line, MTA-13, was identified that was 8.5-fold resistant to pemetrexed with comparable cross-resistance to ZD1694 (Tomudex) and lesser cross-resistance (5-fold) to ZD9331 (2S)-2-(O-fluoro-p-N-(2,7-dimethyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-N-(prop-2-ynyl)aminobenzamido)-4-(tetrazol-5-yl)-butyric acid, DDATHF (dideazatetrahydrofolate) (3.5-fold), and methotrexate (MTX) (2.7-fold) but comparable sensitivity to trimetrexate. Influx of pemetrexed, MTX, and 5-formylTHF into MTA-13 cells was decreased by 56, 47, and 38% compared to wild-type cells. Folate receptor expression was negligible in both cell lines. Net drug uptake declined within 15min to a slower, constant rate over the next 45min, reflecting the rate of accumulation of pemetrexed polyglutamate derivatives. This rate in the MTA-13 line was half that of the wild-type cells. Accumulation of 50nM 3Hpemetrexed, 25nM 3H5-formylTHF, or 50nM 3HDDATHF after 3 days was decreased to 35, 46, and 56% the level of L1210 cells. The reduced folate carrier (RFC) message and protein were decreased by 50%, and folypolyglutamate synthetase (FPGS) message was decreased by 65% in MTA-13 cells. No mutations were detected in either protein by DNA sequence analysis. There was a slight decrease (approximately 25%) in thymidylate synthase mRNA, without mutations in the protein, and there was no change in GAR transformylase message. The data indicate that resistance to pemetrexed in the MTA-13 cell line was due to changes in both RFC and FPGS expression, two proteins that act in tandem to regulate polyglutamation of folates and antifolates in cells, resulting in cellular depletion of these active pemetrexed congeners.Publication Types: Research Support, U.S. Govt, P.H.S. PMID: 12663051 PubMed - indexed for MEDLINE10: Semin Oncol. 2002 Dec;29(6 Suppl 18):35-42.Related Articles, LinksEmerging insights into the biology and therapy of malignant mesothelioma.Vogelzang NJ.University of Chicago Cancer Research Center, Chicago, IL 60637, USA.Malignant mesothelioma is an aggressive malignancy that may be caused by environmental carcinogens (asbestos and erionite), viruses (SV40), and genetic predisposition. Pleural malignant mesotheliomas are far more common than the peritoneal variants. Diagnosis relies on radiographic studies as well as histology and molecular biologic analyses. The prognostic scoring systems of the Cancer and Leukemia Group B and the European Organization for Research and Treatment of Cancer are the most useful of those currently available. These systems rate performance status, age, histology, and hematologic parameters as the best prognostic factors for mesothelioma. Most patients with mesothelioma are not candidates for surgical or radiotherapy treatment, and cytotoxic agents are the only options. Historically, no classes or combinations of agents consistently yielded response rates over 20%. Recently, pemetrexed has been evaluated in phase I, II, and III clinical trials with promis