Multidrug resistance proteins (MRPs) and implication in drug development

The multidrug resistance protein (MRP)‐related ABCC family (MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8, and MRP9) belongs to the ATP‐binding cassette (ABC) superfamily of transport proteins. They are capable of transporting a structurally diverse array of endo‐ and xenobiotics and their metabolites across cell membranes. These transporters play an important role in the absorption, disposition, and elimination of these compounds in the body. In particular, increased expression of these drug transporters in tumor cells is associated with resistance to a number of important chemotherapeutic agents. This review highlights the biochemical and pharmacological properties of MRP1‐9 and their implications in drug development. A detailed study on the biochemical function and regulation of MRPs is important in drug development, as this may help to avoid drug toxicity, drug resistance, and drug‐drug interactions and to optimize cancer chemotherapy. Drug Dev. Res. 64:1–18, 2005. © 2005 Wiley‐Liss, Inc.     

Optimizing drug delivery systems using systematic "design of experiments." Part II: retrospect and prospects

The first study on application of Design of Experiments (DoE) in optimizing drug formulation appeared in 1967. Since then the number of literature reports on the use of DoE optimization in development of drug delivery technologies has been piling up steadily. Such systematic techniques find their use in every type of conventional dosage form and modern drug delivery system. The drug delivery devices investigated for optimization using response surface methodology include controlled release compressed matrices, microparticulates, macroparticulates, vesicular systems, floating systems, bioadhesive systems, semisolids, transdermals, and inhalations. The optimized processes mainly include extrusion-spheronization, pelletization, microencapsulation, coating, granulation, and tableting. Part I of this article [Crit Rev Ther Drug Carrier Syst 2005; 22(1):27-106] dealt with the salient steps involved in the DoE optimization methodology using diverse experimental designs. Part II deals with various retrospective literature findings as well as the prospective application of such DoE procedures while optimizing varied drug delivery technologies. A vast account of various DoE reports on optimization of diverse drug delivery system and processes along with the critical graphical analysis of various designs, input, and response variables have been presented here in a categorical form. Such an explicit and updated review on drug delivery optimization has not been published anywhere else in the recent past.     

Plasmodium falciparum: Multidrug resistance

Malaria is the most lethal and debilitating disease caused by the protozoan parasite Plasmodium worldwide. The most severe forms of disease and the incidence rates of mortality are associated with P. falciparum infections. With the identification of disease source and symptoms, many chemical entities were developed naturally and synthetically for administration as a potential antimalarial drug. The major classes of approved antimalarial drugs that are governed as first‐line treatment in tropical and subtropical areas include quinolines, naphthoquinones, antifolates, 8‐aminoquinolines, and endoperoxides. However, the efficacy of antimalarial drugs has decreased due to ongoing multidrug resistance problem to current drugs. With increasing resistance to the current antimalarial artemisinin and its combination therapies, malaria prophylaxis has declined gradually. New‐generation antimalarial and novel drug target are required to check the incidence of malaria resistance. This review summarizes the emergence of multidrug resistance to known antimalarial and the development of new antimalarial to resolve drug resistance condition. Few essential proteins are also discussed that can be considered as novel drug target against malaria in future.     

Vesnarinone: a differentiation-inducing anti-cancer drug

Vesnarinone has been shown to be a unique anti-proliferating, differentiation-inducing and apoptosis inducing drug against several human malignancies, including leukemia and several solid tumors. Furthermore, vesnarinone potentiates the effect of conventional cytotoxic chemotherapy or radiation therapy. Combination of differentiation-inducing therapy by vesnarinone with conventional chemotherapy or radiation therapy might be second- or third-line therapy in patients with advanced cancer. Analysis of the molecular mechanisms of the tumor differentiation therapy by vesnarinone might provide selective and targeted molecules for novel tumor dormancy therapy.     

Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy

The nine multidrug resistance proteins (MRPs) represent the major part of the 12 members of the MRP/CFTR subfamily belonging to the 48 human ATP-binding cassette (ABC) transporters. Cloning, functional characterization, and cellular localization of most MRP subfamily members have identified them as ATP-dependent efflux pumps with a broad substrate specificity for the transport of endogenous and xenobiotic anionic substances localized in cellular plasma membranes. Prototypic substrates include glutathione conjugates such as leukotriene C(4) for MRP1, MRP2, and MRP4, bilirubin glucuronosides for MRP2 and MRP3, and cyclic AMP and cyclic GMP for MRP4, MRP5, and MRP8. Reduced glutathione (GSH), present in living cells at millimolar concentrations, modifies the substrate specificities of several MRPs, as exemplified by the cotransport of vincristine with GSH by MRP1, or by the cotransport of GSH with bile acids or of GSH with leukotriene B(4) by MRP4.The role of MRP subfamily members in pathophysiology may be illustrated by the MRP-mediated release of proinflammatory and immunomodulatory mediators such as leukotrienes and prostanoids. Pathophysiological consequences of many genetic variants leading to a lack of functional MRP protein in the plasma membrane are observed in the hereditary MRP2 deficiency associated with conjugated hyperbilirubinemia in Dubin-Johnson syndrome, in pseudoxanthoma elasticum due to mutations in the MRP6 (ABCC6) gene, or in the type of human earwax and osmidrosis determined by single nucleotide polymorphisms in the MRP8 (ABCC8) gene. The hepatobiliary and renal elimination of many drugs and their metabolites is mediated by MRP2 in the hepatocyte canalicular membrane and by MRP4 as well as MRP2 in the luminal membrane of kidney proximal tubules. Therefore, inhibition of these efflux pumps affects pharmacokinetics, unless compensated by other ATP-dependent efflux pumps with overlapping substrate specificities.     

Taurine analogues; a new class of therapeutics: retrospect and prospects

Taurine was discovered more than two hundred years ago from animal sources. It is distributed in both mammals and non-mammals and its content is high in several tissues. For more than a century-and-a-half, taurine was regarded just as an end product of sulfur metabolism. Recently, taurine has been rediscovered and its beneficial effects in processes like epilepsy, hypertension, congestive heart failure and diabetes have been well-documented. It was patented and found some clinical utility, but being an amino acid, therapeutic use confronts limitations like restricted permeability and more. This necessitates the development of pro-drugs (analogues) mainly derivatives of taurine. A large number of taurine derivatives have been reported in the literature with partial to marked activity. Taurine derivatives like taltrimide, acamprosate and tauromustine, are already in the market as anti-convulsant, anti-alcoholic and anti-cancer agents. Many other analogues are effective in experimental models. The in depth analysis of these analogues and their biological actions can provide certain clues for further consideration. In the present review, attempts have been made to provide synopsis, synthesis and symbiosis of chemical and biological actions, which may provide future guidance and facilitate further research in this area. The successful journey of these analogues to clinical utility is a healthy and happy sign and an index of bright future, and we hope that this review will provide enough input to ignite the minds.     

Telomerase as an anti-cancer target: current status and future prospects

As is common with a newly discovered cancer-associated gene/protein, there is a lag between the elucidation of its cellular and molecular biology and appropriate therapeutic intervention. Telomerase represents an interesting and promising anticancer drug target but poses a particular drug discovery challenge. It is unclear at present what is the optimum means of targeting this complex ribonucleoprotein and associated telomeric DNA and binding proteins: various strategies are actively being explored. Some recent data (e.g. 2-5A antisense against telomeric RNA, targeting TRF2, introduction of dominant-negative hTERT into cells) has raised doubts over the previously presumption of a requirement for prolonged enzyme inhibition with gradual telomere erosion, especially in tumour cells with relatively short telomeres. Highly potent and selective in vivo inhibitors are required to validate the target and address these critical issues.     

Multidrug resistance in cancer chemotherapy

Resistance to chemotherapy is the single most important reason for treatment failure in cancer patients. Over the past 15 years, we have gained significant insight into one of the mechanisms responsible for this process: multidrug resistance (MDR). Far from being a phenomenon limited to the laboratory, multidrug resistance has been identified in a wide variety of newly diagnosed and recurrent human tumors. A number of compounds can block p-glycoprotein and overcome MDRin vitro andin vivo. Current strategies to block MDR are discussed in this review. Future research in this area will focus on the identification of more selective and potent MDR reversing agents and the development of entirely new approaches to overcoming multidrug resistance such as monoclonal antibodies, immunotoxins, and gene therapy.     

Multidrug resistance in pediatric oncology

Summary Cancer survival among children and adolescents has improved markedly due to evolution of multimodal treatment that incorporates combination chemotherapy, radiation therapy and/or surgery. However, 20–30% of children with malignancies will succumb to their disease or complications associated with their disease or treatment. A major limiting factor to improvement in survival among these patients is the occurrence of intrinsic and/or acquired resistance to our treatment interventions, chemotherapy and radiotherapy. Among these mechanisms, multidrug resistance, the focus of this review, is a well-documented phenomenon whose biochemistry, pharmacology and molecular biology has been extensively studied. A role for multidrug resistance in chemoresistance and therapeutic failure in childhood malignancies is suggested by the observation of clinical resistance to treatment regimes containing agents that are known substrates of multidrug resistance mechanisms. With the current results from studies in rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, leukemia and retinoblastoma, the role of multidrug resistance is still unclear. Earlier studies attempted to define a role for P-glycoprotein-mediated multidrug resistance; however, a limited number of reports suggest that the multidrug-associated resistance protein may play an active role in neuroblastoma. Further studies will be necessary using standardized and uniform approaches for the analyses of these mechanisms. Clinical trials directed toward reversal of multidrug resistance are premature since the exact role of P-glycoprotein is controversial in pediatric malignancies, the role of other mechanisms of multidrug resistance must be assessed and selective inhibitors of multidrug resistance have yet to be developed. Address for offprints: John F. Kuttesch, Jr., Division of Pediatrics, The University of Texas M.D., Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA     

Multidrug resistance in epilepsy: a pharmacogenomic update

Multidrug resistance is one of the most serious problems in the treatment of epilepsy and is likely to have a complex genetic and environmental basis. Various experimental data support the hypothesis that overexpression of antiepileptic drug transporters may be important. However, key questions concerning their functionality remain unanswered. The first study reporting a positive association – between genetic variation in a putative antiepileptic drug transporter (P-glycoprotein, encoded by ABCB1) and multidrug resistant epilepsy was published in 2003. Since then, several other association genetics studies have sought to confirm this result, but, taken overall, do not support a major role for this polymorphism. Lessons learnt from the ABCB1 studies can help guide future association genetics studies, both for multidrug resistance in epilepsy, and for other epilepsy phenotypes.     

Multidrug resistance in Mycobacterium tuberculosis

All but one of the four major mechanisms of resistance to antimicrobial agents-inactivation of the drug, altered cell wall permeability or drug efflux, drug titration due to target overproduction, and alteration of the target by mutation-appear to be employed by Mycobacterium tuberculosis in its resistance to components of short course chemotherapy regimens. To date no enzymes capable of inactivating any of the frontline drugs have been found. The most common resistance mechanism is alteration of the target leading to inadequate drug binding, or drug activation, as a result of mutations in chromosomal genes. This occurs in the case of the specific antituberculous drugs isoniazid, pyrazinamide and ethionamide as well as in resistance to the broad-spectrum antibiotics, rifampicin, streptomycin and the fluoroquinolones. Overproduction of the drug target also appears to lead to resistance to isoniazid and ethionamide whereas changes in permeability, or the activation of antibiotic-efflux systems, may contribute to the low-level resistance of the tubercle bacillus to streptomycin and fluoroquinolones.     

Multidrug resistance in epilepsy: a pharmacogenomic update

Multidrug resistance is one of the most serious problems in the treatment of epilepsy and is likely to have a complex genetic and environmental basis. Various experimental data support the hypothesis that overexpression of antiepileptic drug transporters may be important. However, key questions concerning their functionality remain unanswered. The first study reporting a positive association--between genetic variation in a putative antiepileptic drug transporter (P-glycoprotein, encoded by ABCB1) and multidrug resistant epilepsy was published in 2003. Since then, several other association genetics studies have sought to confirm this result, but, taken overall, do not support a major role for this polymorphism. Lessons learnt from the ABCB1 studies can help guide future association genetics studies, both for multidrug resistance in epilepsy, and for other epilepsy phenotypes.     

PET in anti-cancer drug development and therapy

Anti-cancer drug development is a major area of research. Monitoring of response to newer anti-cancer drugs has undergone an evolution from structural imaging modalities to targeting functional metabolic activity at cellular level to better define responsive and non-responsive cancerous tissue. This review article highlights the contribution of Positron Emission Tomography (PET) in this field. PET holds a promising role in the future by providing us information pertaining to the drugs effectiveness early in the course of therapy, so that side effects and expenses can be reduced substantially. PET has been used to measure changes in drug induced metabolism, cellular proliferation and tissue perfusion. Also changes induced by immuno-modulating drugs such as apoptosis, telomere activity, growth factor levels and many more can be studied using specific radiolabelled PET tracers whereas conventional imaging modalities which detect changes in tumor size and residual tissue histopathology may not prove useful in such scenario. In future, most PET scanners will be replaced by Hybrid PET-CT scanners, which provide functional and structural information in the same setting. In addition, PET-CT improves characterization of equivocal lesions and decreases interobserver variability. The most important recent patents concerning role of PET in drug development have been presented.     

DNA-intercalating ligands as anti-cancer drugs: prospects for future design

Interest in DNA-intercalating ligands as anti-cancer drugs has developed greatly since the clinical success of doxorubicin. However, despite a great deal of 'rational design' of synthetic DNA-intercalators, only a few such compounds have proved clinically useful. This review briefly surveys the history of DNA-intercalators as clinically-used anti-cancer drugs, summarizes the known structure-experimental activity relationships and modes of action, and concludes that a factor in the slow progress is that much of the work on these compounds has been carried out by chemists, who were generally more interested in ligand/DNA interactions than drug development. Future development of the class rests on a careful consideration of the biochemical reasons behind the common limitations of the present drugs. The most important are: the inherent resistance of non-cycling cells, the rapid development (even by cycling cells) of resistance by the expression of both P-glycoprotein and altered topoisomerase II, limitations on drug distribution to and transport into tumours, low extravascular pH in tumours and the cardiotoxic side-effects of quinonoid chromophores. These considerations provide a set of constraints on physicochemical properties which must be considered in future design. However, within these constraints, there are useful future avenues for the development of DNA-intercalators as anti-cancer drugs. These include: (i) the production of improved topoisomerase inhibitors (by consideration of drug/protein as well as drug/DNA interactions); (ii) the development of reductively-activated chromophores as hypoxia-selective agents; and (iii) the use of DNA-intercalators of known DNA binding orientation as 'carriers' for the delivery of other reactive functionality specifically (sequence-, regio- and site-specifically) to DNA.     

鲍曼不动杆菌抗生素多重耐药性: 耐药机制与感染治疗对策

多重以及泛耐药鲍曼不动杆菌导致的感染流行已成为全球关注的公共卫生问题.大多数细菌耐药基因与表型特征均充分反映在耐药鲍曼不动杆菌.鲍曼不动杆菌的外膜通透屏障与药物主动外排泵的协同作用使其呈现明显的天然多重耐药性,而其染色体可整合获取外源性由转座子/整合子可移动基因元件与多重耐药基因相联系的耐药岛区域或携带含有类似的整合子与多重耐药基因盒的质粒,这些基因结构导致该菌进化形成了对多类化学结构各异的临床常用抗生素的高度获得性耐药性,使其感染治疗的药物选择极其有限.尽管可考虑选用碳青霉烯类、含舒巴坦复合制剂、多黏菌素E或联合使用抗生素等治疗鲍曼不动杆菌感染,严重存在的多重耐药性等要求用药时更密切地观察药物的疗效,并参考药物敏感试验结果调整用药方案.虽然新的抗生素如替加环素等显示一定的体外抗鲍曼不动杆菌活性,但其临床疗效仍待继续研究.采取各种风险管理措施有效控制医院性细菌感染疾病包括合理使用各类抗生素是防止及减少鲍曼不动杆菌感染以及耐药性发生和传播的重要对策.     

Multidrug resistance in cancer: its mechanism and its modulation

One of the major problems related with the curative treatment of cancer patients is resistance against anticancer drugs. This resistance, which may occur from the beginning or is evident only later as an acquired phenomenon, is due to the action of drug transporters. These transmembrane proteins belong to the ATP-binding cassette (ABC) transporters which reduce bioavailability of drugs, but also determine the elimination of xenobiotics into bile, urine and feces. The present review summarizes recent knowledge in this area, highlighting the mechanism of action of these transporters, its clinical significance and its possible modulation. Novel approaches to overcome multidrug resistance include agents which inhibit or circumvent this efflux mechanism. For the latter category developments in nanomedicine may be of consequence. However, in spite of considerable progress in research regarding multidrug resistance, the phase of efficacious clinical use of this knowledge has not been reached yet.