海洋化合物Kahalalide F.doc

PharmaMars Kahalalide F, Phase II Trials for the Treatment of Severe PsoriasisMADRID, October 28 /PRNewswire/ - PharmaMar today announced that Kahalalide F (KF), its marine-origin compound, has entered into Phase II trials for the treatment of patients with severe psoriasis.KF is currently undergoing Phase II clinical trials in various tumours: melanoma, non-small lung cancer and hepatocarcinoma.During the Phase I clinical trials on oncological patients treated with KF, it was found that the compound had clinical potential to treat severe psoriasis. These signs of activity, together with the products excellent safety profile, led to the initiation of the clinical development of KF for psoriasis, thereby widening the range of therapeutic applications for this compound beyond the field of oncology.Regulatory authorities have approved the commencement of Phase II studies on patients with psoriasis, which will be undertaken in hospitals in both Spain and France.This is not the first compound with anti-proliferative activity to show both anti-tumoural and anti-psoriatic activity: methotrexate is a clear example of such dual usage.Approximately 100 million people worldwide suffer from psoriasis, a chronic, non-contagious inflammation of the skin, characterised by reddish plaques and patches with scales. It affects all ages, but it is most prominent among adults (it is equally common among men and women). The disease is difficult to treat and impairs patients quality of life.Commenting on the announcement, Isabel Lozano, CEO of PharmaMar, said: PharmaMar continues to focus on advancing cancer care, however where it makes sense to widen the range of therapeutic applications for our compounds, we will explore the opportunity.Notes to editorsKahalalide FKahalalide F is one of a family of novel peptides isolated from the Hawaiian mollusk, Elysia rufescens. It is currently in Phase II trials for hepatocarcinoma.PharmaMarPharmaMar is a biopharmaceutical company, advancing cancer care through the discovery and development of innovative marine-derived medicines. PharmaMars clinical portfolio currently includes Yondelis (TM) in phase II clinical trials (co-developed with Johnson & Johnson Pharmaceutical Research & Development), designated Orphan Drug for STS by the EMEA in 2001 and Orphan Drug for ovarian cancer in 2003; Aplidin(R), in phase II, designated Orphan Drug for acute lymphoblastic leukaemia in 2003; Kahalalide F in phase II and ES-285 in phase I clinical trials.PharmaMar, based in Madrid, Spain, is a subsidiary of the Zeltia Group (Spanish stock exchange: ZEL.MC; Bloomberg: ZEL SM; Reuters: ZEL.MC). PharmaMar can be found on the Web atDistributed by PR Newswire on behalf of Zeltia Group简介Title:Kahalalide FCAS Registry Number:149204-42-2Manufacturers Codes:PM-92102Molecular Formula:C75H124N14O16Molecular Weight:1477.87Percent Composition:C 60.95%, H 8.46%, N 13.27%, O 17.32%Literature References:One of a family of cyclic depsipeptides isolated from the Hawaiian marine mollusk,Elysia rufescens. First reported diet-derived chemical defense peptide; production of which depends on consumption of the green alga,Bryopsissp. Isoln: P. J. Schaueret al.,EP610078(1994 to Pharma Mar); M. T. Hamann, P. J. Scheuer,J. Am. Chem. Soc.115, 5825 (1993); of the family: M. T. Hamannet al.,J. Org. Chem.61, 6594 (1996). Synthesis: A. Lpez-Maciet al.,J. Am. Chem. Soc.123, 11398 (2001). Stereochemistry: G. Goetzet al.,Tetrahedron55, 7739 (1999). Updated stereochemistry: I. Bonnardet al.,J. Nat. Prod.66, 1466 (2003). Identification as defensive peptide: M. A. Becerroet al.,J. Chem. Ecol.27, 2287 (2001). LC/MS/MS determ in plasma: E. Stokviset al.,J. Mass Spectrom.37, 992 (2002). Toxicology: A. P. Brownet al.,Cancer Chemother. Pharmacol.50, 333 (2002).In vitrocytotoxic activity: Y. Surezet al.,Mol. Cancer Ther.2, 863 (2003). Mechanism of cytotoxicity: J. M. Sewellet al.,Eur. J. Cancer41, 1637 (2005). Clinical pharmacology in prostate cancer: J. M. Rademaker-Lakhaiet al.,Clin. Cancer Res.11, 1854 (2005). Review of development and therapeutic potential: M. T. Hamann,Curr. Opin. Mol. Ther.6, 657-665 (2004).Properties:White amorphous powder. aD-8 (c = 4.32 in CH3OH). LD50in male, female rats (mg/kg): 375, 600 i.v. (Brown).Optical Rotation:aD-8 (c = 4.32 in CH3OH)Toxicity data:LD50in male, female rats (mg/kg): 375, 600 i.v. (Brown)Therap-Cat:Antineoplastic.Keywords:Antineoplastic; Alkaloids/Natural Products.The antitumoral compound Kahalalide 作用机理The primary mechanism of action of KF has not been identified yet, although multiple targets have been found and each is a membrane-associated event that may be related to the hydrophobic nature of the compound. COMPARE analysis was negative(9)suggesting that KF has a novel mechanism of action. A cell cycle block in G0-G1has been determined in a variety of tumor cell lines that include prostate (DU145), cervical (HeLa), colon (HT29), and head and neck (HN30). Earlierin vitrostudies identified some mechanisms of action. Cells exposed to biologically relevant concentrations of KF detach from their substrate and become markedly swollen associated with the formation of large intracellular vacuoles(10). The earliest studies have identified lysosomes as the most likely intracellular target based upon the evidence that KF disrupts the integrity of lysosomal membranes(10, 11). If the mechanism of action is at the lysosomal level, then those tumor cells containing a higher proportion of lysosomes would be more suitably treated with KF. This is a feature of prostate cells in which lysosomes are actively secreting proteins, acid, and alkaline phosphatases and contain high concentrations on zinc(1215). It has been recently published that tumor cells with higher HER-2/neuand/or HER3 expression are particularly sensitive to KF, which induces a form of cell death that is independent of caspase, cathepsin B, or cathepsin D activity, and correlates with down-regulation of Akt signaling(16).KF的主要作用机理目前尚未确定，但已经有一些与细胞膜相关的发现，可能与该化合物的疏水性有关。比较分析呈阴性表明KF具有独特的作用机理。在多种癌细胞株中已检测到细胞在分裂G0-G1 期被阻断 ，包括前列腺（DU145），子宫颈（HaLa），直肠 （HT29），以及头部和颈部（HN30）。早起体外实验也证实了一些作用机理。 暴露在高浓度KF下的细胞从基质中脱落并明显溶胀，这与细胞内液泡的生成有关。早期研究发现，KF破坏溶酶体膜的完整性，所以溶酶体最可能是其细胞内的攻击目标。如果作用机制是在溶酶体水平上的，那么含有更多溶酶体的细胞更适合用KF治疗。前列腺细胞的特点之一便是分泌大量的蛋白质，酸，碱性磷酸酶，并含有高浓度的锌。最近公开的一项发现表明更多地表达HER-2/NEUAND/HER3的癌细胞对KF尤其敏感，这里细胞死亡与半胱天冬酶，组织蛋白酶B，组织蛋白酶D无关，而与Akt信号的向下调节有关。Kahalalide F Enters Phase II Trials in Lung Cancer and MelanomaMADRID, Spain, July 19 /PRNewswire/ - PharmaMar announces today that Kahalalide F has begun Phase II trials in non-small cell lung cancer (NSCLC) and in melanoma. These trials are based on the strength of Phase I results when this compound showed a very favourable safety profile and clinical benefit in NSCL and melanoma as well as in a broad spectrum of tumour types.Phase II trial in NSCLThe NSCLC trial is a multicentre open label study of Kahalalide F (KF) in patients who have relapsed or progressed after first line chemotherapy. KF will be administered weekly at a dose of 0.65mg/m2 in a one-hour infusion. 25 patients will be included in the first instance with the potential to increase this to 34 patients. 12 European hospitals will participate in this clinical trial. The primary end point is response rate. Secondary objectives are the evaluation of the pharmacokinetics and further investigation of the safety profile of the product.According to the World Health Organization, every year there are more than 1.2 million new cases worldwide of lung and bronchial cancer and approximately 1.1 million deaths. In the US, lung cancer accounts for about 13% of all new cancer cases diagnosed and 28% of all cancer deaths, one of the highest death rates of any cancer among both men and women. To put these numbers in perspective, more people die of lung cancer than of colon, breast, and prostate cancers combined. More than 173,000 people will be diagnosed with lung cancer in the US in 2004 and approximately 200,000 in the EU. Despite the availability of several treatment regimens, more than 160,000 patients will die of this disease in the US in 2004.Phase II trial in MelanomaThe melanoma trial is an open label study of KF as a one-hour weekly infusion in patients with advanced malignant melanoma. KF will be administered at a dose of 0.65mg/m2. 18 patients will be included in the first stage of the trial, potentially increasing to 32 patients. The trial will be conducted in 12 European centres. The primary end point is response rate. Secondary end points will evaluate the pharmacokinetics and safety profile of the product.There is no standard treatment for patients with metastatic melanoma. Treatment options include the surgical resection of isolated metastases, therapy with dacarbazine, combination chemotherapy and immunotherapy. However, response rates associated with these measures range between 15% and 20%, hence the urgent need for the development of new therapies.Melanoma is the deadliest form of skin cancer. Approximately 132,000 people are diagnosed with melanoma worldwide every year (WHO, 2000 data). In the US, the American Cancer Society estimates that approximately 55,100 new melanomas will be diagnosed in 2004 and about 7,900 people will die of the disease. In the EU, approximately 35,000 people were diagnosed with melanoma in 2000 and 9,000 people died of the disease.Dr Miguel Angel Izquierdo, Director of Clinical Development at PharmaMar, said:The clinical benefit seen in the Phase I trials both in melanoma and NSCL justify the beginning of these new Phase II trials. In addition, we are encouraged by the exceptional safety profile of Kahalalide F which has allowed the continuous administration of the drug for up to 20 months in patients showing clinical benefit.EU info: Globocan 2000; US info: ACS 2004About Kahalalide FKahalalide F is a new marine compound derived from the sea slug Elysia rufescens.It alters the function of the lysosomal membrane, a mechanism that distinguishes it from all other known anti-tumour agents. Studies demonstrate that it induces cell necrosis in vivo (oncosis) and shows selectivity for tumour compared with normal cells in vitro. The cytotoxic activity of Kahalalide F is mediated by neither mRNA and protein synthesis de novo nor caspase activation.Phase I clinical studies with Kahalalide F showed that the dose limiting toxicities were acute, reversible and asymptomatic grade 3-4 increases in liver transaminases. In these studies, Kahalalide F has shown a very favourable safety profile, with no grade 3-4 myelotoxicity reported to date. In addition, emesis, alopecia, mucositis and