铂类抗肿瘤药物的研究近况

自20世纪60年代发现顺铂具有抗肿瘤活性以来,铂类金属抗肿瘤药物的应用和研究得到了迅速的发展。迄今为止,人们大约已合成了数千种铂类化合物,但作为抗肿瘤药物投入临床的仅30种左右,其中20多种因抗肿瘤活性弱或毒性过强而被淘汰。本文拟就目前已进入临床及部分正进行临床试验的铂类抗肿瘤药物的应用及研究情况作一简述。1已上市的铂类抗肿瘤药物1.1顺铂和卡铂1967年,美国学者发现顺铂具有抗肿瘤活性,1969年即被应用于临床,是首个上市的铂类抗肿瘤药物。在美国和加拿大,顺铂被推荐为治疗食道癌、非小细胞肺癌等18种肿瘤的首选药物,此外,还在…     

抗体偶联药物研究进展

靶向治疗已成为肿瘤治疗新趋势。抗肿瘤靶向药物与传统的细胞毒性化疗药物相比具有特异性高、选择性强和非细胞毒性等优点,抗体偶联药物（ ADC）属于抗肿瘤靶向药物,由抗体、“弹头”药物（细胞毒性药物）通过链分子连接而成。 ADC 将抗体的靶向性与细胞毒性药物的抗肿瘤作用相结合,可以降低细胞毒性抗肿瘤药物的不良反应,提高肿瘤治疗的选择性,还能更好地应对靶向单抗的耐药性问题。     

铂类抗肿瘤药物的研究进展

目的综述铂类抗肿瘤药物的作用机制及新型铂类抗肿瘤药物的设计策略。方法查阅国内外近10年相关文献,对其进行归纳、总结,从铂类抗肿瘤药物的研究概况、作用机制及新型药物的设计策略几方面进行了介绍。结果铂类药物在抗肿瘤领域发挥着重要作用,为解决现有药物存在的耐药性、组织毒性等缺点,靶向给药、Pt(Ⅳ)模式前药、单功能团铂类抗肿瘤药物等更先进的设计策略越来越受到重视。结论铂类药物及新型铂类药物仍是抗肿瘤药物的研究热点,值得进一步研究开发。     

铂类抗肿瘤药物的发展历程及临床评价

近年来,铂类抗肿瘤药物的临床研究进展迅速,其抗肿瘤谱广,抗肿瘤活性增强,不良反应降低,已成为目前有关抗肿瘤药物研发的重要领域。新的铂类抗肿瘤药物将从那些在临床研究中显示出低毒性、抗肿瘤谱广、与现有药物无交叉耐药性的化合物中产生。该文对铂类抗肿瘤药物的抗肿瘤机理、研究进展和未来研究趋势进行了综述;     

化学合成类靶向抗肿瘤药物的研究进展

非细胞毒性靶向抗肿瘤药物的应用使肿瘤患者的生存质量显著提高,甚至长期带瘤生存也成为可能.随着肿瘤发生机制的逐步揭示,细胞与分子靶向治疗在肿瘤治疗中的作用越来越受到重视,这为肿瘤治疗开辟了新的途径.在这些靶向抗肿瘤药物中,化学合成类药物占多数.对化学合成类靶向抗肿瘤药物的研究进展进行综述.     

铂类抗肿瘤药物的研究现状

自从顺铂作为第一代抗肿瘤药物被开发利用以来，人们一直在寻找广谱、高活性、低毒性和无交叉耐药性的铂类抗肿瘤药物，合成和筛选出各种铂络合物。分别介绍根据不同设计思路合成的四价铂络合物、具有活性配体的铂络合物、生物载体为配体的靶向铂络合物、反式铂络合物和具有立体位阻效应的铂络合物及其抗肿瘤活性，综述当前铂类抗肿瘤药物的研究现状。     

钙镁合剂联合肉桂防治奥沙利铂神经毒性的疗效观察

奥沙利铂(oxaliplatin,L-OHP)属第三代铂类金属抗肿瘤药物,其联合化疗方案已广泛应用于胃肠道肿瘤。L-OHP有很好的耐受性,肾、胃肠道和血液的毒性很低,其剂量限制性毒性为神经毒性,而且发生率很高。L-OHP神经毒性可分     

铂类抗肿瘤药物的研发进展及市场情况

近年来,铂类抗肿瘤药物的临床研究进展较快,其抗肿瘤谱广,抗肿瘤活性增强,不良反应降低,已成为目前有关抗肿瘤药物研发的重要领域。新的铂类抗肿瘤药物将从那些在临床研究中显示出低毒性、抗肿瘤谱广、与现有药物无交叉耐药性的化合物中产生。本文就其作用机制、国内外上市开发现状、国内外销售情况及国内研究开发进展等进行综述。     

肺癌靶向治疗药物进展

近年来分子靶向治疗是抗肿瘤研究的热点,本文就酪氨酸激酶抑制剂吉非替尼(gefifinib)、小分子TKI化合物tarceva、单克隆抗体西妥昔(cetuximab)、抗肺癌血管生成靶向药物内皮抑素(endostatin)、整合素拮抗剂西仑吉肽(cilengitide)、金属蛋白酶抑制剂(TIMP)等靶向治疗药物做一综述。     

常见抗肿瘤药物化疗累积剂量毒性管理的研究进展

抗肿瘤药物已广泛用于肿瘤的治疗,其累积剂量毒性通常会被临床忽视,如铂类抗肿瘤药物的周围神经毒性及肾毒性,长春花生物碱类抗肿瘤药物的神经毒性,以及蒽环类药物的心脏毒性等。该综述通过对抗肿瘤药物累积剂量毒性相关管理情况进行总结,以了解抗肿瘤药物累积剂量毒性特点、防治措施以及相关临床研究证据,为临床决策提供参考依据。     

Ruthenium complexes as anticancer agents

Cancer is one of the major cases of death in the world. Current treatment of cancer is limited to surgery, radiotherapy, and the use of cytotoxic agents, despite their well known side effects and problems associated with the development of resistance. For most forms of disseminated cancer, however, no curative therapy is available, and the discovery and development of novel active chemotherapeutic agents is largely needed. Since the development of cisplatin, an inorganic platinum complex, numerous platinum and non-platinum metal complexes were synthesized and tested for anticancer activity. Very few match the clinical efficacy of cisplatin. Ruthenium complexes were prepared to ameliorate cisplatin activity, particularly on resistant tumours, or to reduce host toxicity at active doses. Since many years a lot of scientific groups have actively worked in the field of inorganic antitumor drugs and have developed a number of Ru(II) and Ru(III) complexes, which were shown to possess good antitumor and, above all, antimetastatic properties against animal models. Ruthenium complexes are presently an object of great attention in the field of medicinal chemistry, as antitumor agents with selective antimetastatic properties and low systemic toxicity. Ruthenium compounds appear to penetrate reasonably well the tumor cells and bind effectively to DNA. In this review, the achievements in the field of medicinal chemistry, DNA binding modes, and the development status of Ru(II) and Ru(III) complexes as anticancer agents are discussed. The aim of this review is therefore that of critically examining the past and the actual work on ruthenium compounds with emphasis on their proposed role in cancer therapy.     

Complexes of metals other than platinum as antitumour agents

The earliest reports on the therapeutic use of metals or metal-containing compounds in cancer and leukemia date from the sixteenth and nineteenth centuries. They were forgotten until the 1960s, when the antitumour activity of the inorganic complex cis-diammine-dichloroplatinum(II) (cisplatin) was discovered. This led to the development of other types of non-organic cytostatic drugs.Cisplatin has developed into one of the most frequently used and most effective cytostatic drugs for the treatment of solid carcinomas. Numerous other metal compounds containing platinum, other platinum metals, and even non-platinum metals were then shown to be effective against tumours in man and experimental tumours in animals. These compounds comprise main-group metallic compounds of gallium, germanium, tin, and bismuth, early-transition metal complexes of titanium, vanadium, niobium, molybdenum, and rhenium, and late-transition metal complexes of ruthenium, rhodium, iridium, platinum, copper, and gold.Several platinum complexes and four non-platinum-metal antitumour agents have so far entered early clinical trials. Gallium trinitrate and spirogermanium have already passed phase II clinical studies and have shown limited cytostatic activity against certain human carcinomas and lymphomas. The two early-transition metal complexes budotitane and titanocene dichloride have just reached the end of phase I clinical trials and have been found to have an unusual pattern of organ toxicity in man. Titanocene dichloride will soon enter phase II clinical studies.     

Innovative treatments for

Lung cancer remains the most frequent and most lethal cancer worldwide. Non-small cell lung cancer (NSCLC) comprises the vast majority of the histological types. Surgery remains the standard therapy for early stage disease but for advanced stage disease, modern treatment is unsatisfactory. However, during the past ten years, improvements in response and survival have been seen with the use of newer chemotherapy regimens. Early studies of neo-adjuvant (pre-operative) chemotherapy for resectable stage III patients have shown promising results. For patients with non-resectable NSCLC platinum-based doublets are now established as first-line treatment, either alone or in combination with radiotherapy. Innovative non-platinum based combinations are actively being evaluated. The most promising non-platinum agents at this time include gemcitabine, paclitaxel, docetaxel, irinotecan and vinorelbine. These agents appear to be effective as single agents and in combinations and also have improved toxicity profiles. Several other systemic approaches are under active evaluation; the most promising areas include anti-angiogenesis agents, immunotoxins, interleukins, vaccines and molecular therapy.     

Multifunctional ligands in medicinal inorganic chemistry--current trends and future directions

This review will highlight recent advances in ligand design for innovative applications in medicinal inorganic chemistry. Ligands that effectively bind metal ions and also include specific features to enhance targeting, reporting, and overall efficacy are driving innovation in areas of disease diagnosis and therapy. Increasing the potency of therapeutic compounds, while limiting side-effects, is a common goal in medicinal chemistry. In an effort to achieve this goal, compounds are being developed that either target a disease site, or are activated by a disease specific biological process. Metal complexes containing targeting functions and/or bioactive ligands, as well as agents that are activated by specific enzymes, or changes in pH and pO2, provide new avenues for drug development. Radiodiagnostic compounds, magnetic resonance imaging agents, and optical probes containing transition metals offer versatility unavailable to organic imaging agents. In certain cases, dual modality agents have been developed, and will be highlighted. Finally, we will discuss targeted metal binding compounds for treatment of metal overload disorders, and the recent application to neurodegenerative disease.     

Recent developments in the field of tumor-inhibiting metal complexes

25 years after the first approval of cisplatin in the clinic against a number of cancer diseases, cisplatin and related compounds continue to be among the most efficient anticancer drugs used so far. Efforts are focused to develop novel platinum- and non-platinum-based antitumor drugs to improve clinical effectiveness, to reduce general toxicity and to broaden the spectrum of activity. In the field of non-platinum compounds exhibiting anticancer properties, ruthenium complexes are very promising, showing activity on tumors which developed resistance to cisplatin or in which cisplatin is inactive. Furthermore, general toxicity was found to be very low. The first ruthenium compound NAMI-A entered phase I clinical trials in 1999 as an antimetastatic drug, whereas the ruthenium complex KP1019 will enter phase I clinical trials in 2003 as an anticancer drug which is among others very active against colon carcinomas and their metastases. Remarkable progress is also seen in developing tumor inhibiting gallium compounds. One of them, KP46, will also enter phase I clinical trials in 2003. This article reviews briefly the achievements in the field of anticancer metal complexes focusing the discussion onto the impact of the group of Bioinorganic Chemistry at the Department of Inorganic Chemistry at the University of Vienna. The development of pH sensitive platinum prodrugs, platinum-based drug targeting strategies with low-molecular-weight carriers, kinetically inert platinum(IV) complexes, as well as tumor inhibiting non-platinum anticancer drugs based on ruthenium and gallium is covered in the following sections.     

Prevention of HIV-1 infection by platinum triazines

To identify and explore the activity of compounds which may act as anti-HIV virucidal agents, we have investigated platinum compounds, especially those containing N-donor aromatic ligands. After screening over 70 related agents, including N-donor aromatic ligands and metal precursors, we have identified a novel class of platinum(II) complexes with 2-pyridyl-1,2,4-triazine derivatives and Pt(II) formulations with these derivatives (ptt compounds) as having the highest anti-HIV activity. The maximum activity was observed when the agents were added immediately post-infection. The ptt agents did not block cell fusion activity of HIV-1 Env proteins in cells bearing CD4X4 or CD4R5 receptors, indicating a lack of interaction with the Env protein. The ptt compounds exhibit low toxicity for human epithelial cells, and are thus promising candidates for use as microbicides or antiviral agents against HIV.     

Metal complexes with aromatic N-containing ligands as potential agents in cancer treatment

Cisplatin (cis-Diamminedichloroplatinum(II)) is now clinically used as one of the most effective anticancer drugs in the treatment of a variety of human solid tumors, such as genitourinary. Unfortunately, its usefulness is limited due to development of resistance in tumor cells and its significant side effects. Thus, a continuing effort is being made to develop analogs to overcome the above shortcomings. However, direct structural analogs of cisplatin have not shown greatly improved clinical efficacy in comparison with the parent drug. The explanation for this finding is that all cis-[PtX(2)(amine)(2)] compounds have shown similar DNA-binding modes, thereby resulting in similar biological consequences. One approach is to look beyond structure-activity on the basis of cisplatin analogs antitumor agents, by identifying novel materials that can be utilized as building blocks. These may have DNA binding modes quite different from that of cisplatin. The introduction of such aromatic N-containing ligands as pyridine, imidazole and 1,10-phenanthroline, and their derivatives (whose donor properties are somewhat similar to the purine and pyrimidine bases) to antitumor agents is drawing attention. Many platinum and non-platinum metal complexes such as palladium, ruthenium, rhodium, copper, and lanthanum, with these aromatic N-containing ligands, have shown very promising antitumor properties in vitro and in vivo in cisplatin-resistant model systems or against cisplatin-insensitive cell lines. For example, one Ru(III) compound, [ImH][trans-Cl(4)(Me(2)SO)(Im)Ru(III)] (Im = imidazole, NAMI-A) successfully entered phase I clinical trials. In this review, medicinal chemistry, DNA binding modes, and the development status of these metal complexes are discussed.     

Effective control of blood glucose status and toxicity in streptozotocin-induced diabetic rats by orally administration of vanadate in an herbal decoction.

Vanadium compounds have been well recognized for hypoglycemic effects, but questions remain on gastrointestinal disturbance and possible tissue vanadium accumulation thus slowing the acceptance of vanadium compounds as diabetic therapeutic agents. Our intestinal permeability and toxicity studies of vanadium compounds have suggested that the co-administration of vanadate with Salvia miltiorrhiza Bunge decoction could benefit the therapeutic use of hypoglycemic vanadium compounds. In the present paper, we tested the hypoglycemic effects of vanadate ingested in an aqueous extract of S. Bunge using a streptozocin (STZ)-induced diabetic rat model. Oral administration of vanadate in S. Bunge herbal decoction produced a stable (free of hypoglycemic shock) and long-lasting ( approximately 70day) control of blood glucose status. Effective protection of animal organs from hyperglycemic damage was also observed. As expected, the herbal extract significantly alleviated vanadium toxicity, i.e. GI stress and metal accumulation. In addition, the result suggesting that vanadium-induced amelioration of the diabetic state appears to be secondary to the preservation of a functional portion of the pancreatic beta-cells which initially survived STZ-toxicity. These studies provide new insight into the therapeutic treatment of diabetics with vanadium compounds.     

Purine and pyrimidine pathways as targets in Plasmodium falciparum

Malaria is a leading cause of morbidity and mortality in the tropics. Chemotherapeutic and vector control strategies have been applied for more than a century but have not been efficient in disease eradication. Increased resistance of malaria parasites to drug treatment and of mosquito vectors to insecticides requires the development of novel chemotherapeutic agents. Malaria parasites exhibit rapid nucleic acid synthesis during their intraerythrocytic growth phase. Plasmodium purine and pyrimidine metabolic pathways are distinct from those of their human hosts. Thus, targeting purine and pyrimidine metabolic pathways provides a promising route for novel drug development. Recent developments in enzymatic transition state analysis have provided an improved route to inhibitor design targeted to specific enzymes, including those of purine and pyrimidine metabolism. Modern transition state analogue drug discovery has resulted in transition state analogues capable of binding to target enzymes with unprecedented affinity and specificity. These agents can provide specific blocks in essential pathways. The combination of tight binding with the high specificity of these logically designed inhibitors, results in low toxicity and minor side effects. These features reduce two of the major problems with the current antimalarials. Transition state analogue design is being applied to generate new lead compounds to treat malaria by targeting purine and pyrimidine pathways.