Antimitotic Prodrugs Advantages And Disadvantages

Antimitotic Prodrugs Advantages And Disadvantages Abstract The intricate prodrug therapy has made possible the synthesis and identification of novel drug discovery that have significant structural modifications or intermediate derivatives which may facilitated and enhanced therapeutic parameter during in vitro and in vivo studies. Along with improved target delivery of prodrugs provides the capability to not only overcome certain limitation of antimitotic drugs, but to increases the chances to undergo clinical phase trial studies to get in to action. Development of these new prodrugs as improved alternatives gone through from significant challenges; nevertheless these potential therapies also use to analysed and give suggestion about their further development by clinical studies. Introduction Cancer is diseases in which the bodys cells become abnormal and split without control. Cancer cells may show aggression nearby tissues. They may spread through the bloodstream and lymphatic system to other parts of the body. [1, 2, 3]. Now the days there are mainly three types of treatments are in use surgery, radiation and chemotherapy. Among these, surgery and radiotherapy are to be employed for specific treating are and chemotherapy employed during the systemic treatment of metastases in local as well as regional cancer cells. Chemotherapeutic drugs can be divided in to alkylating agents, antimetabolites plant alkaloids (antimitotics), topoisomerase inhibitors, and other antitumor agents. All of these drugs affect the cell division or DNA synthesis and translation, and function in other ways. The proliferation rate is the play the key role in for the effects of these drugs thus; they are not much selective of tumours. Chemotherapy is treatment with drugs that kill cancer cells and make them less active. It is the treatment of disease by chemicals, especially by killing micro-organisms or cancerous cells. In popular usage, it refers to antineoplastic drugs used to treat cancer or the combination of these drugs into cytotoxic standardized treatment regimen. In its non-oncological use, the term may also refer to antibiotics, long time use of chemotherapy consequences natural cell deaths in the treatments of tumour [4]. Sometime these agents produce remission and re-growth which result in proliferation of cancer cells along with resistance of drugs. Although, intense researches have been conducted in the field of cancer, there are some pioneering ideas need to come in this field to decrease toxicities, physicochemical properties and therapeutic index [5]. The use of prodrug is generally established as a strategy to improve the physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically potent agents, and thereby increase the develop ability and usefulness of a potential drug [6,7]. The aim of the prodrug establishment is to improve (i) physicochemical properties like solubility, chemical stability, taste and odour etc. (ii) selectivity; (iii) pharmacokinetic and pharmacodynamic problems and (iv) therapeutic index. Thus; by these improvements, we can overcome the formulations challenges of the drugs [8, 9]. The most of the antimitotic prodrugs developed with conjugating prodrug molecules to low to high molecular weight molecules like sugars, enzymes, vitamins, antibodies, polymers and nanoparticals. These are the carriers which transport prodrug in to tumour and drug release with conjugating the drug to the carrier through a spacer that include particular point which make the specific targeting of the drug. These carriers are very complicated in the structure and demand very hard work to make carries linked prodrugs. Hetrogenecity, biodistribution, expression of multidrug resistance, interstitial pressure and amount of the drug reaching to the target site, are the problems which make the task more difficult. Along with that targeting properties will preserved or not with structural changes are major problems in the formulation of carrier liked prodrug molecules. Here I provide an overview of recent developments in targeted antimitotic prodrug and conjugate design. These are examples which, illustrating the salient features of different targeting strategies. I have focused on prodrug and conjugate examples in priclinical trials or advanced preclinical studies with advantages and disadvantages associated to each strategy are also discussed. Antimitotics In the process of mitosis eukaryotic cell isolate the chromosome in its cell nucleus into two the same sets which are divided in two nuclei. In cancer the single cell start converts from normal cell to cancerous cells by the process of mitosis. The mitosis inhibitors contain certain different cancer drugs. They are different in mechanism of action from the other classes of cancer drugs [12]. They mainly interfere with cell proliferation of cell rather than alter DNA structure and function. Mitosis includes DNA replication which divides the cells in to two new cells. Spindle fibers separate newly replicates chromosomes and convert them in to two forming cells. The fibres which are produce microtubules which fix with the replicated chromosomes. Now chromosomes pull one of this copy to each side of the cell which includes spindle fibers, without that cell cannot divide. Antimitotics inhibit this earlier uncertain spindle function during cell cycle. Spindle fibers form of long chains of smaller subunit of tubuline protein. In the process of polymerisation tubuline subunits can add to microtubule. Some types of antimitotics stop the process of forming of tubuline monomers which inhibits the microtubule. In this process they arrest movement of chromosomes as well as spindle tubule [13]. Examples of mitotic inhibitors include Taxanes, paclitaxel (Taxol) and docetaxel (Taxotere), Epothilones like ixabepilone (Ixempra), and Vinca alkaloids: vinblastine (Velban), vincristine (Oncovin), and vinorelbine (Navelbine), estramustine (Emcyt) and Colchicines. Vinca alkaloids and colchicines are those who have more over same mechanism of action. Vinblastine inhibiting the formation spindle fibers which are responsible for position of chromosome and the separation of the chromosomes during anaphase. It also inhibits the formation of microtubules which are responsible for the formation of cell division. Vinca alkaloids have many side effects like others [14]. Vincristine also binds to the tubuline monomers and arrests the formation of spindle microtubules. As result of this, it blocks the movements of chromosome during cell division. Speficity is the major problem with vincristine because it also affects the healthy cells with cancer cells during cell division. Vindesine is another Vinca alkaloid who binds to the microtubules. It has target specificity problem which makes them less potent [15]. Texel is natural antimitotic drug and different in mechanism of action from Vinca alkaloids. Paclitaxal and docetaxel are the two important analogues . Paclitaxel inhibits microtubuline assembly rather than monomers. It binds to microtubules and prevent this breakdown because these two processes, polymerisation and breakdown, both are requiring for movement of replicated chromosomes. The prevention of chromosomes breakdown inhibits them to move to opposite direction of dividing cells. Reduction in bone marrow function which may result in anaemia, blood in stools or black stools, fast or irregular heart beat, are common side effects associated with paclitaxel [16]. Docetaxel has same mechanism of action as paclitaxel but if the drug is give with combination it will cause major side effects than paclitaxel [17]. Epothilones is microtubule function inhibitor. It binds to beta-tubuline subunit on microtubules and preventing polymerization during cell division and eventually causes cell death. Mainly peripheral neuropathy, mylosuppersion with white blood cells and hypersensitivity reactions are the side effects which cause by Epothilo nes [18]. Colchicines are antimitotics which have same mechanism of action as Vinca alkaloids. It also binds to tubuline and inhibits polymerization of microtubules. Tubuline availability is necessary for mitosis process and colchicines are inhibiting these tubules as spindle poison. Cancer cell have nature to proliferate most and this make them more susceptible to Colchicines drugs [19]. These are natural anitimitotics and their analogues. Their mechanism of action is mainly on tubuline and sometime called antitubuline agents. But they have their own challenges like insolubility, bioavability, pharmacokinetic and pharmacodynemics, and toxicities problems. Tubuline plays a key role in their effects to bind mitosis but to overcome these challenges, proteins which are involve in the mitosis, are founded. They are presently under process to develop the capacity of clinical efficacy that those drugs have established [20]. Present scenario in antimitotics drug development (Specific druggable protein targets) The targeted proteins with specific function of new generation of anti mitotics are identified with molecularly targeted drug discovery. These new agents play important role in the unique way to provide the significant effects, which take beyond the certain limitations of drugs as well as extend the scope of their clinical efficacy of current antitubuline drugs. Although, they are facing some considerable challenges, but molecular mechanism of action of mitotic-checkpoint plays important role in mitosis [21]. Antitubuline drugs have complex chemical structure and are complicated to isolate and synthesised from their natural sources. Neurotoxicity and insolubities are the major problems with Vinca alkaloids and Taxanes. They also interfere in function of microtubules in axons, which provoke the neuronal vesicle motility. The non-structural components of mitosis as potential drug targets are one of the solution for therapy. They have unique effects in morphological stages during the mi tosis which is bring mitotic Kinesins, Aurora kinases and polo-like kinases (PLKs), as druggable protein target classes [22]. Targeting these proteins is well known as mitotics kinesin, kinesin spindle protein (KSP) are requires for the proliferation from prophase to prometaphase and Centromeric protein E (CENPE) is required during prometaphase to metaphase and also have effects in mitotic checkpoint [23, 24]. These protein targets are only finds in dividing cells so non-dividing cells are not effected. This showed that, this kind of target inhibition have potential and improved therapeutic index compare to tubuline target anti mitotic drugs. Although, proteins inhibitors might not enough effects on both the mitotic spindle and cytoskeleton but they have some significant role out side the mitosis. Moreover, to support these new agents, the role played by them in the mitosis, cause target inhibition to be connected with tumour growth inhibition. By the using pharmacodynemic marker, significant effective dose during drug development founded. These doses were affected instead of maximally tolerated dose, might also caused improved therapeutics index. The mechanism of action of these agents by which they inhibits tumour cells undergo cell death was not properly defined but they have many positive effects on these proteins. Activation of caspace 3 (significant effectors) has been identified in studies of protein target drugs, along with that mitotic catastrophe has also been founded [25, 26, 27]. Actually, catastrophe is cell death occurs from metaphase of mitosis against the drugs that produce DNA damage because of in this stage the caspace 2 is involved rather than caspase 3 which produces many morphological and therapeutic aspects of cell death. On the other hand, mitotic check point as effectors of cell death against protein inhibitors was contentious. It was suggested that KSP inhibitors needed mitotic checkpoint. In contrast to that, role of checkpoint studies involved that; this signalling might cause cell death with mitotic damage [28, 29, 30]. This mechanism might supported by Aurora B inhibitors [31]. Eventually, the mechanism of action of these new protein inhibitors became more understandable that, they are more involved in killing cell by unique mechanism but also, different genetic alterations, which may produce during cancer, play the important role during inhibition by these agents. Although, this studies is unfinished so its hard to get these new agent in action because they needed further more researches. KSP Inhibitors: Ispinesib was first KSP inhibitor and studied in clinic to check the therapeutic effects. Small molecules of KSP ATPase were targeting by this drug but it was not involved in effecting ATP and ADP. In terms of specificity, it was 40,000 times more selective as compare to other kinesins. Firstly it was studied intravenously and results founded that during different number of days, the cumulative dose delivery was same and dose limiting toxicity on both occasion was neutropenia as well as haematopoietic lineages, along with that nausea, vomiting and diarrhoea also observed. Raise in the dose also increases the amounts of phosphor-histones-H3 in tumour which involved inhibition of proliferation of tumour cells with dose. As consequence, the pharmacodynamic activities also increased. In earlier, the renal cell, hepatocellular and colorectal cancers are not responding to anti tubuline agents, but this KSP inhibitor extend the time duration of stability for more than 6 months. This agent a lso needed following treatments of natural anti tubuline agents [32]. The next KSP ATPase inhibitor is same to Ispinesib, and during clinical evaluation it came from the chemical synthesis [33]. It has more efficacious than first one. During the studies it is connected with dose limiting toxicities that is neutropenia and hyperbilirubinaemia [34, 35]. For cholangiocarcinoma, it gives some positive effect and two more cancers extend as stable diseases for more than six months. Third potent KSP inhibitor is MK-0731. It is more selective about more than 20,000 fold and associated with increased activity of hepatic transaminases and neutropenia [36]. Finally, clinical experience of KSP inhibitors showed that these agents associated with common dose limiting toxicities like neutropenia, increased activity of hepatic transaminases which are also observed with tubulin inhibitors. Although, some of toxicities like alopecia, mucositis and neuropathy, are not often seen. Nausea and vomiting have seen uncommonly with these protein targeting inhibitors. AURORA and PLK inhibitors One of the potent drug called as VX-680 also know as MK0457 as ATP competitive inhibits Aurora A, B and C to inhibit the cell differentiation in cell culture [37]. Its mechanism of action is to inhibit the FMS-related tyrosine kinase 3 and imatinib-resistant mutants forms of Abelson tyrosine (ABL) kinase. Imatinib and dasatinib are the resistant to those agents. During the studies, cancer cell from different patients, were tested against intravenous infusions. As results, neutropenia was mostly observed dose limiting toxicity and when the dose increased the some pharmacodynemic effects in skin was also observed. To evaluate that, phospho-histone-H3, Ki67 (antigen) and cycline B1 expressions are being checked before and after these studies. In the skin biopsies, there was no strong evidence observed, which showed the mitotic arrest or decrease in cell proliferation in the skin, during clinical studies. There was strong proof about the effects on cell proliferation which are haematopoi etic, but it was not case with skin biopsies. Mitotic inhibition, aneuploidy, was expected from the pan-Aurora but only delay in the mitotic progression observed during studies. Moreover, these agents inhibit the Aurora B and decrease the PHH3 levels when other anti-mitotic agent increases this biomarker. To overcome this limitation, the assays procedures developed which are capable to find out the decrease in the level of PHH3. Skin was not responding to these drugs. Extended stable disease for more than 6 months observed [21]. Another ATP-competitive Aurora B inhibitor is AZD1152 with significant IC50 cellular proliferation. This inhibitor evaluated in two schedules. In the both schedules, neutropenia observed as dose limiting toxicity for intravenous infusion. Moreover, next assessments reached in phase I and II studies for cancer like leukaemia [38]. BI 2536 is first ATP-competitive inhibitor of PLK1. There were three different partitions to evaluate this small molecule inhibitor. Every partition was evaluated by intravenous infusion and as result of that, same toxicity and dose delivery were obtained. Thrombocytopenia and neitropaenia were major dose limiting toxicities in every partition [39]. The second ATP non-competitive inhibitor of PLK1 is ON 01910. It may support PLK, to bind the substrates. It is currently under trail for two different doses because it has low potency to FLT1 and platelet derived growth factor receptor (PDGFR). Increased activity of hepatic enzymes, anaemia, leucopoenia and gastrointestinal symptoms, are the adverse effects with this inhibitor [40]. All over, neutropaenia without significant neuropathy was major dose limiting toxicity with these inhibitors. Challenges and Developments in New Antimtotic Drugs Although, these novel antimitotic drugs have very significant role in inhibition of mitosis, they are facing many problems during their developments. Their appropriate ways, potential to reduce toxicities, activities, safety profile, and efficacy are some promising questions are yet to be solved. These agents have reduced risk of neurotoxicity, which is proved in clinic, but they also have dose limiting toxicities like neutropenia with relative sparing of the other haematopoietic lineages. So it will be difficult to tell yet that they have potential [41]. Another challenge was that, there was no clear perceptive between inhibition of respective mitotic target and cell death. Because they have mechanism of action is to arrest mitosis but whether this mitosis arrest initiate by activating by mitotic checkpoint or it is followed by mitotic slippage for further cell death. To identify the patients who are best responding to these agents is also a challenge in developments in theses agents. In addition to that, during clinical development, it is difficult to develop surrogate tissue to check the pharmacodynemic responses of these drugs because targets of these agent, was absent in most of them [42]. Along with pharmacodynemic effects, duration of such effect both is also crucial determinants for apoptosis. Therapeutic window can be calculated by evaluation of tumour markers at maximum tolerated dose (MTD) or below the MTD if possible but this might be achieved by incorporation of serial tumour biopsies was uniquely challenging. In addition to, which schedules would be sufficiently discover pharmacodynemic and pharmacokinetic data was difficult [43]. Considerable steps have already come in to view, to overcome these limitations and evade toxic side effects, produced by these agents. Such steps make two different types of practices; they are prodrugs and drug targeting methods. During these practices both methods led to increase some of biochemical properties along with pharmacokinetic and pharmacodynemic effects. Prodrug Prodrugs are chemically modified versions of pharmacologically active agents that must undergo transformation in vivo to release the active drug. The prodrug is administered in an inactive or significantly less active form. The use of prodrugs is generally established as a strategy to improve the physicochemical, biopharma-ceutical or pharmacokinetic properties of pharmacologically potent agents, and thereby increase the develop ability and usefulness of a potential drug [6]. Antimitotic Prodrugs which are in Use or Developing The following are the antimitotic prodrugs which try to develop to overcome these limitation associated with specific antimitotic drugs like Vinca alkaloids, Texans, Cochicines and phodopyllotoxins. A) Hydrolytically Activated Paclitaxel Prodrug Paclitaxel is well using in diseases like ovarian cancer, breast cancer and lung cancer but it has limitation like low water solubility, less effective, drug resistance and some effects. At high dose it produces hypersensitive reactions, hematologic toxicity, and neurotoxicity. It also limited by granulocyte colony-stimulating factors dependent neutropenia. It has dose dependent neurotoxicity expressed by loss of sensation [44]. Adapt from [44] By masking position7 hydroxyl group of paclitaxel with hydrophilic side chain (*) and resulted 7-(2, 3-dihydroxypropyl carbonoxy) paclitaxel is biologically inert and is activated at low pH conditions by hydrolytic cleavage of the carbamate linkage, obtaining active paclitaxel, dihydroxy propanol, and CO2 [44]. Following are the results obtained by analysing paclitaxel prodrug. Figure, (A) Figure, (B) Table 1, Figure A and Figure B, Adapt from [44]. Table 1 is hydrolytic activation of paclitaxel prodrug in vivo, indicating decrease in prodrug and increase in active drug. Figure (A), for conversion to active paclitaxel in vivo, indicating peak plasma concentrations were observed at 3 hours for paclitaxel prodrug (P1) and at 6 hours for active paclitaxel (P2), for 1 patient. Figure (B), for activation of paclitaxel in vivo, demonstrates the slow-release mechanism in vivo, for 5 pateints [44]. B) First enzymatically activated Taxotere Prodrugs Designed for ADEPT (Antibody Directed Enzyme Prodrug Therapy) and PMT (Prodrug Mono Therapy) Paclitaxel and its semi synthetic analogue docetaxel is essential drugs in the treatment of cancer as antimitotic drugs. There is slight difference between them is substitution at 3- nitrogen on the side chain and the 10-posititon of the taxoid core. They have high potency to solid tumour but they have number of undesirable side effects and poorer water solubility and also with detergent they initiate hypersensitivity reaction on body. These drugs delivery have evaluated on enzymatic hydrolysis in ADEPT (Antibody Directed Enzyme Prodrug Therapy) and PMT (Prodrug Mono Therapy).The two docetaxel prodrugs in figure A have synthesised with glucuronic moiety is linked to a double spacer. Para hydroxyl bezyle alcohol connected to diamer tether through a carbamate linkage in this spacer. This complex was shown to be more potent and labrets drugs in the presence of ÃŽÂ ²-Dglucuronidase enzyme in ADPET and PMT therapy [45]. Figure A, structure of scheme 2 and scheme 3 (Prodrug 4), scheme 2 and scheme 4 (Prodrug 5) and Prodrug 3 Adapt from [45] Following are the results by the comparison of these two drugs. Both of prodrugs have 24 hr-run of stability and there was no release from the prodrug during this time. Table 1 showed that these two prodrugs have compatible IC 50 values for the ADEPT and PMT strategy. Figure A and figure B showed that, during HPLC detection, prodrug level decreased until finished and spacer and parent drug, docetaxel, reached at area of stability [45]. Table 1, measured for L1210 cell lines were (HPLC): Prodrug, Scheme 2 and scheme 3 : 4.86 uM Docetaxel : 14. 4 uM Spacer: 75.3uM Prodrug, Scheme 2 and scheme 4: 2.69 uM Spacer:45.8uM Figure A, Comparison of the disappearance of the three prodrugs. Figure B, Enzymatic cleavage of prodrug 5 Figure 2, Scheme 2 and Scheme 4. Table 1, Figure A and Figure B adapt from [45]. C) Zyn-Linked colchicines: Controlled-release lipophilic prodrugs With enhanced antitumor efficacy Zyn-linked drug have rapid binding property to cell membrane. These Zyn-linkers prolong their binding and preservation in tissues, make sense to produce Zyn-linkers conjugates those who have better local delivery of therapeutics. Colchicine has chosen for these studies because this drug and its analogues are still under examination. Five Zyn linked colchicine analogues with either cleavable hydrazone or imine bonds, have synthesised and evaluated their stability ,cytotoxicity and antitumour activity [46]. Fig.1. Structures of colchicine and modifications to form the analogues for Zyn-Linking are shown. Fig. 2.Structures of the Zyn-Linkers modified for attachment of the colchicine analogues. Fig.3. Structures of Zyn-Linker conjugates are shown with the bonds subject to hydrolysis indicated by an arrow: (a) hydrazones conjugates linked at the B-ring of the colchincine moiety, (b) imine conjugate, and (c) hydrazones conjugate linked at the A ring of the colchicine moiety. Figure 1, 2 and 3, adapt from [46] Following are the results for their relationship among different properties. Table 1 Table2 Table3 Table 1, 2 and 3, adapt from [46] Table 1 showed that, ZYN 162 and PKH 158 at pH 7.2, are two potential products and out of them one is expected and one is unidentified products. Table 2 showed that, 80% to less than 1%, was range of therapeutic and unhydrolysed conjugated, was inactive. Zyn-linkers had no antimitotic activity; on the other hand, drug or Zyn-linked drugs were active. Table 3 showed that, with 4-formayl group thiocolchicine have reduced their toxicities and enhanced therapeutic activity [46]. D) Preparation, characterization, cytotoxicity and pharmacokinetics Of liposome containing water-soluble prodrugs of paclitaxel Paclitaxel have antimitotic effect against the various cancers like breast cancer, ovarian cancer, head and neck cancers. Due to its aqueous insolubility, it was dissolving in the mixture of 50 % Ethanol and 50 % Cremopher EL (caster oil). Neurotoxicity and hypersensitivity are side effects of this Cremopher. So to reduce this side effect and to enhance the drug entrapment in liposome with better aqueous solubility, three prodrugs and prodrugs liposome formulations have synthesised and evaluated their pharmacokinetic parameter, stability and antitumor activity with parent drug [47]. Following are the results obtained during comparison in stability, cytitoxicity and pharmacokinetic property of drug, prodrugs and their prodrug liposome. 1) Stability Table1 Table 2 Figure 1, 2 and 3, Table 1 and 2, adapt from [47] Figure 2 and 3 showed that, by the changing the property like diameter, membrane fluidity and charge, liposome containing 2-mPEG-paclitaxel composed of PC-PG-CHOL 9:1:5 showed better stability more than 2 months and good entrapment ability. Table 1 and 2 showed that, in vitro cytotoxic effects of liposome containing compound 3 and 4 on two cell line, HT-29 and MeWo, maintained, but rapidly hydrolysed and giving free parent drugs, while liposome loaded paclitaxel-2succinyl had more resistance to hydrolysed. 2-PEG-paclitaxel also had ability to make difference in pharmacokinetic parameters as compare to free drug [47]. D) Synthesis and evaluation of water-soluble docetaxel prodrugs- Docetaxel esters of malic acid. Paclitaxel and docetaxel are semi synthetic analogues widely used for various cancers. But water solubility is major limitation for these drug and to come over from this limitation, at C20, C7 -or/and C10 position several research group introduced solubilising moieties [48]. Figure A Figure A, table 1 and table 2, adapt from [48] Figure A, table 1 and table 2 showed that, 20-DLmalyl docetaxel sodium salt 3a come out with excellent water solubility, more active than docetaxel in vitro and antitumor activity in vivo [48]. E) Synthesis of Water Soluble Prodrugs of the Cytotoxic Agent Combertastatin A4 Combertastatin A4 has structure similar to colchicine. It is an inhibitor of tubulin polymerisation to stop proliferation of cells. Although, this drug has potential for antimitotic activity, it is soluble in the few pharmaceutically accepted solvents. Synthesis of water soluble glycosides of combertastatin A4, have conducted by make modification by hydroxyl function. To increase the yield, they have reversed the components of the Witting reaction [49]. Adapt from [49] The ammonium salt have prepared and converted into potassium salt to make crystal form. This ammonium salt was more stable in buffer solution and degraded slowly in plasma at 37 C when incubated with acid phosphates and alkaline phosphatise [49]. F) Prodrugs of 40-Demethyl-4-deoxypodophyllotoxin: Synthesis and Evaluation of the Antitumor Activity 4-Deoxypodophyllotoxin (DPT) and 4-demethyl-4-deoxypodophyllotoxin (DDPT) have comparable in vitro potency against different cell lines but free hydroxyl group at 4 position in structure of DDPT loss its in vivo antitumor activity against BDF1/3LL model. Replacing this free group by bioreversible functionality might improve in vivo activity. For that series of prodrugs have synthesised and evaluated their cytotoxic and antitumor activities [50]. Following are the results obtained during studies. Adapt from [50]. Table showed that 10 and 11 derivatives were properly transferred in to parent drug 2 but weak in vivo activity and 6 derivative showed IR of 95% of antitumor activity. The carbamates and carbonates of two compounds, 6 and 9, showed potent antitumor activity, might be by intermolecular cyclic rearrangements of hydroxyl side chain. Moreover, amino acid prodrugs, 12 to 17, demonstrated better water solubility and potent antitumor activity [50]. Discussion Presently the antimitotics prodrugs are novel compounds and hold many promises and may have abilities to improve the drawbacks of anti tubuline or specific protein inhibitors, which are regulating the cell cycle, demonstrated by clinical data. With observations to clinical activity, it is too premature to tell for most of the agents in development. There are number of prodrugs have been developing and some have evaluated in laboratory. Antimitotic prodrugs may improve limitations of these drugs during in vitro and in vivo studies but there are still need more information about clinical phase trails by using number of patients, to these prodrugs. In particular, hydrolytically activated paclitaxel prodrug has decreases toxicity in vivo and produced better responses in patients with end stage in cancer. Serum half- life also dramatically increased with maximum plasma concentration, in vivo, but more studies require about responses in phase III trails, as it was evaluated in 10 patients. Moreover, information needed about, high concentration expose to tumour tissue for critical time, as significant G2M phase arrest is primary mechanism of action. First prodrugs of docetaxel have synthesised for the ADPET (Antibody Directed Enzyme Prodrug Therapy) and PMT (Prodrug Mono Therapy) strategies. Spacer have nitro group on the aromatic ring. In the hydrogenesis step it could be preserved which is not seen in the previous paclitaxel prodrugs. This nitro and amino groups containing prodrugs have expressed good kinetics and enzymatic hydrolysis in particular cell line, but more information needed about self immolative spacer for its effects on the paclitaxel on various cell lines. This issue need more clarification prior to clinical trails in malignancy models. Four conjugates of Zyn-linked colchicine have hydro linkage, imine bond in spacer arms, colchicines moiet

Canadian Autonomy

The Fight for Freedom Neham Marwah CHC2D1 Ms. Ballantyne January 15 2011 Some may ask themselves, to what extent has the 20th century contributed to Canada’s autonomy? Canadian autonomy came as a result of the events that occurred within the 20th century. Without these vital events they would have never gained full independence from Britain to become their own nation. The main events that influenced their autonomy are their brave and fearless fighting in WWI, their mid-war self-success and great contributions in WWII and the great assistance Canada served nations post war.Canada showed bravery and fearlessness to new challenges in the First World War that proved that Canadians were able to walk on their own. Canada was new to the war life, and although they only participated because of their attachment to Britain they participated with full force. Citizens all around Canada joined to serve in WWI, ready to fight for their nation. The first battle Canadian soldiers took part in was Ypres in 1915 and they joined the French-Algerian troops in this battle. (Newman, 105) The position of the Canadian troops was surrounded by German trenches, which made them an easier target. Newman, 105) Little did the Canadians know that the Germans were about to release a treacherous weapon for the first time in history—chlorine gas. (Newman, 105) The Canadians were taken by surprise, but French officials had been warned prior to the attack, but they failed to instruct the Canadians about this new weapon or any method of defending themselves against it. (Newman, 106)The French-Algerians saw the gas and ran leaving an open space in their formation for Germans to penetrate through. (Newman, 106) Canadians were hit with the chlorine gas, but they held their position unlike their allies. Newman, 106) They waited three days under harsh attack, until British reinforcements came to relieve them. (Newman, 106) Canadians came out of the battle with injuries and lost members bu t they were recognized as strong and courageous fighters. (Newman, 106) Ypres may have been the first battle Canadians fought in, but The Battle of Vimy Ridge was the one that really changed the outlook on Canadians. German soldiers were confident that no one would take over Vimy Ridge, and they had an advantage as they were on a hill that had a great view of the whole field, this made hiding difficult for the Canadian soldiers. Newman, 117)Canadians corps fought alone in this battle, under the command of British general Julian Byng. (Newman, 119) Under Byng’s command was Canadian born Major-General Arthur Currie was the commander of the First Canadian Division; they decided to use a technique called â€Å"the creeping barrage. † (Newman, 119) The plan devised by Currie was very well thought out and the hard work and dedication of the Canadian soldiers helped them win the battle. (Newman, 119) Although Canadians number had been cut by 3500, (Newman, 119) by the end of the battle they held their heads high.This attack showed everyone that Canadians were capable of coming up with a successful battle plan and able to carry out their instructions and achieve the task at hand. Arthur Currie became the commander of the Canadian corps, (Newman, 119) eliminating the involvement of British officers in the Canadian army. It was a huge step for Canadians to finally have something that was completely theirs; they were no longer being pushed around and told what to do by British officers. Throughout the war, August 8 through to November 11 became known as â€Å"Canada’s 100 Day† because of their success within the time period.As WWI was coming to a close, Lloyd George invited Robert Borden to the Paris Peace Conference to represent Britain. (Newman, 128) Borden rejected his offer and insisted that after all of Canada’s sacrifice in the war, they should earn their own seat, as an independent country. (Newman, 128) Canada suffered many casu alties in the war that led to their first step to independence. They were running their own, strong army, and they were doing it well, without the help of Britain. All of their fight, and dedication through the war process showed nations around them, their ability to take charge of a situation, and get through a hassle.In the mid-war years Canada showed its ability to become a self dependent nation and survive without collaborating with the nations around it. Canadian contributions in WWII were not obvious, but were definitely there. Canada showed its potential as an independent country that can survive through tough situations staying intact. Very few countries were hit by the consequences of the depression as hard as Canada; 1 in 5 Canadians became dependant on the government for survival. (Canadian Encyclopaedia, Web) Canada was seriously affected by the collapse in world rade; 33% of its national income came from exporting resources, and because of the depression other countries would not buy. (Canadian Encyclopaedia, Web) Canadian goods had dropped to an extreme low which led to many people becoming homeless and being unable to support their families. There were very few people who had jobs, so when WWII started, munitions factories were being re-opened and there were more jobs that brought Canada out of poverty. Canada started over and built its economy from the ground up, making it stronger than its previous structure.It was wartime yet again, but this time Canada knew the consequences, it joined WWII in its own right and not to accompany Britain. Canadian corps was ordered to capture Ortona, which became known as one of the best battles fought by Canada. (Marwah, Battles Notes)The Germans defending Ortona were very strong fighters and were rewarded for their previous battles, and they also had the advantage of being entrenched in the hills. (Marwah, Battles Notes) Canadian corps took Ortona house by house and within one week they had it captured. The c apture of Ortona helped the allies take over Rome, without which they could have never won the war. Marwah, Battles Notes) After this success, Canadians got the difficult task of liberating the Netherlands. The Dutch were facing starvation as they were being controlled and used for slave labour by Nazi’s under Hitler’s command. (Marwah, Battles Notes) Canadians struggled with their task to kill the Nazi’s, and after months of hard labour, they had finally freed the Dutch. The Netherlands were, are, and always will be grateful for the assistance of the Canadian troops and their struggle to fight for Dutch freedom. Canadians continued their assistance in D-Day.There were 5 divisions called in to land along an 80 km form, and Canadians were the 3rd division and got Juno Beach. (Marwah, Battles Notes) They defeated the defending Germans and moved farther inland than any other allied troops. (Marwah, Battles Notes) The casualties they suffered in this battle were muc h fewer than they had feared. (Marwah, Battles Notes) Canadians succeeded in many aspects of WWII, but they did not win all of their battles. When 50,000 Japanese soldiers sprung out to attack Hong Kong, (Marwah, Battles Notes) Canadians were ordered to come to their defence. 0% of the Canadian soldiers had never shot a gun in their practice and very unready for this battle. (Marwah, Battles Notes) The total number of their defence force was a mere 14000 men, they did not have air protection and Canada itself was outnumbered 10-1. (Marwah, Battles Notes) When Hong Kong surrendered every Canadian was either killed or captured and used as slaves to build. (Marwah, Battles Notes) The ability to find strength within your own home is difficult, but when Canada was put through the test they passed without a problem.Canada contributed many forms of success in WWII, but there were sacrifices that came with their glory. Canadians put their selves in danger to protect others, and their protec tion has made them accepted in many parts of the world. Canada became known for its separate achievements, and not the ones that attached it to Britain. WWII had ended, but the rein of Canadian contributions continued to pour in far after their assistance in the World Wars. The Cold War was beginning and the United States and United Nations were working on creating the atomic bomb, (Newman, 244) trying to keep up with the Soviet Union’s advancements in weaponry.They were having difficulty coming across a substance without which the bomb could not be made—uranium. (Newman, 244) It just so happened that all of the uranium refineries were under the Nazi control, all except one located in Canada. Canada provided the UN and US the uranium to build the atomic bomb and provided a safe-working environment away from battlefields. (Newman, 244) Canada participated on its own, and while working with the UN and US, was looked at as an equal. Canada was a huge factor in the reason US won the cold war, although Canada is not the most powerful nation in the world, they assisted in getting their partners to glory.Canada’s involvement in the production of the atomic bomb got them in tussles further into the future. Russian, Igor Gouzenko worked in the Soviet Union embassy in Ottawa and he announced that there were Russian spies located in Canada, US, and the UN trying to find information about their production of the atomic bomb. (Marwah, Cold War Notes) An organization called NATO (North Atlantic Treaty Organization) was created and Canada, along with Britain, France and 8 other countries were taking part in it. Each of the countries who are involved in the organization must send army, navy, air force units to a new NATO defence force. Marwah, Cold War Notes) They put together their militaries together to make a sort of super army; it was made to intimidate the Soviet Union from taking over Western Europe. (Marwah, Cold War Notes) Canada was able to recru it the biggest intimidation towards the Soviet Union—the United States. (Marwah, Cold War Notes) Canada was seen on a world-scale when they got the US to join NATO; (Marwah, Cold War Notes) the fact that they recruited the most powerful country in the world really had everyone appreciate their effort and dedication.When the United States turned to Canada for help with the creation of NORAD, Canadians rose to the occasion. (Marwah, Cold War Notes) US was quite frightened of the SU’s ability to drop nuclear bombs on North America, so they had Canada help them develop a system that could warn them of enemy air bombing planes. (Marwah, Cold War Notes) Nations around the world looked and saw the US look to Canada for assistance, and support. Canada became known for their own successes and not their achievements with Britain.Canada’s contributions post war helped them become recognized as an independent nation; for the reason that most of their achievements were separ ated from Britain, the 2 countries were not interconnected. The events in the 20th century contributed to Canadian autonomy and independence in numerous ways like their brave and fearless fighting in WWI, their mid-war self-success and great contributions in WWII and the great assistance Canada served nations post war. Canada fought courageously in its first world war. They held their positions when hit with the first gas attack in history, while their allies fled to protect their own lives.In the battle of Vimy Ridge they won their fight when no other allies could, and they were able to lead their own army, a huge step towards their independence. They contributed great successes in WWII; they became heroes around the world, endangering themselves to free the Netherlands. They assisted the most powerful nation in the world and led them to success and prosperity in the cold war. Although Canada was in the background, their presence was noticed. They were the backbone of every success and triumph made in the 20th century.They made their mark wherever they could, the mark representing their independent nation— Canada. Works Cited â€Å"Canada Flag. † Photograph. Pastyme With Good Companye. 15 Feb 2008. Web. 15 Jan 2011. Hillmer, Norman. â€Å"Statute of Westminster. † The Canadian Encyclopaedia. James Marsh . Web. 14 Jan2011. Marwah, Neham. â€Å"Battles of World War 2. † 26 Nov 2010. Class Notes. Marwah, Neham. â€Å"Cold War Events. † 02 Jan 2011. Class Notes. Newman, Garfield. Canada: A Nation Unfolding. Toronto: McGraw, 2000. Print. Struthers, James. â€Å"The Great Depression. † The Canadian Encyclopaedia. James Marsh . Web. 14 Jan 2011.

Different types of play Essay

The activity called playing is a form of enjoyment that provides pleasure, excitement and competition. A person playing more often than not is enjoying himself and having fun. Games are the factors of playing that creates the whole essence of the word. Studying two â€Å"types† of games can help provide more understanding regarding this subject matter. The Traditional Games that have been active from different nations during the course of time, and the technology-based Video games, particularly in China and Europe are the two main aspects of this paper. II. TRADITIONAL GAMES Traditional games are the games that nations have produced due to people’s love for enjoyment and leisure. These are the games that were inspired by the times and have been kept alive through the passing of the knowledge of the game from generation to generation. A. TRADITIONAL GAMES IN ASIAN COUNTRIES Traditional games very much vary due to the differences of cultures and nationalities. Taking a look at examples of two different Asian countries can help assist compare and contrast traditional games. Two nationalities that have interesting traditional games are China and the Philippines. 1. ) China Due to China’s rich history, it has produced so many different traditional games throughout the years of the civilization’s existence. Here are some of the games (The Chinese Historical and Cultural Project, 2007). â€Å"Chinese Yo-Yo or Pull-Bell† The bamboo â€Å"empty bell† is represented in Records of Scenes at the Capital from the Ming dynasty (1386-1644 A. D. ): The two ends are circular saucer shapes. In the center is a horizontal bit of wood. Mount it on a string and twirl with a vibrating motion. It emits a humming sound. This was a game played by girls and boys during the springtime, when the willow leaves turns green. It became specifically famous in the North. A poem was even made about it. â€Å"Kites† Different folk tales about the beginning of the kite do exist. A Sung Dynasty statement makes their initial appearance in the Warring States era. But Lin K’un of the Yuan dynasty perceived that the kite was created in the Han dynasty to faze the opponents by the eerie sounds of connected whistles. History displays that the kite was also utilized to call for help. In Taiwan, kite flying is incorporated with the season of autumn. Cut bamboo, which is strong and light, is the conventional material for creating the frame of the kite. â€Å"Jump Rope† The jump rope dates back 1,500 years to say the least in China. It was named â€Å"jumping one hundred threads† due to the rope’s appearance displaying like a hundred different ropes as it circled in the air. During the Spring Festival in the South, this was the time that â€Å"jump rope† was most famous. It can be created with the utilization of different materials such as cotton and grass, straw and cotton combinations with wax coating. Group and single jumping are both popular in China as well as in the Wes. â€Å"The Shuttlecock (Chien-tsu)† The Shuttlecock developed out of an ancient military exercise It was famous during the time of the Han and T’ang dynasties. Subsequent to the Sung dynasty, the game was named Chien-tsu, the Chinese term for â€Å"arrow† which sounds just exactly like the word for â€Å"shuttlecock†. Consisting of a small, weighted round base with tassels or feathers at a single end, the Shuttlecock is usually kicked with the heel, the toe, instep and outer side of the foot, and the same with the knee. This game was most appropriate for cold weather because this energetic exercise warmed the body. The Tawainese government during the year 1975 included this game in physical education programs of their elementary schools, and it somehow brought back the popularity of the game. 2. ) Philippines The Philippines, despite having a diverse history due to different colonial periods, has produced such enjoyable and challenging traditional games. Most of these games were usually played during town â€Å"fiestas† (feasts) while some are just the usual pastime of Filipino children. The following are samples of Filipino traditional games (Filipino Games, 2008). â€Å"Agawang sulok† Agawang sulok – catch and own a corner – The â€Å"it† or tagger stands in the center of the ground. The participants in the corners will try to exchange places by running from one base to another. The â€Å"it† must persevere to protect a base or corner by running to any of the corners when it’s left vacant. â€Å"Araw-lilim† Araw-lilim – sun and shade – The tagger or it attempts to touch or tag any of the participants who directly in contact with the sunlight. A player saves himself or herself from being tagged by simply staying within the shade. The tagged player will in turn become the next game’s tagger. If there are five or more players participating, two or three taggers can be allowed as the taggers at the same time. â€Å"Bulong-pari† Bulong-Pari – whisper it to the priest – It is composed of an it and two teams. Team A’s leader goes to the priest and whispers one of the names of Team B’s players. Then he goes back to his place and the priest shouts out, â€Å"Lapit! † (â€Å"Approach! †). One of team B’s players must approach the priest, and if it happens to be the one whom the leader of team A whispered, the priest will then say, â€Å"Boom† or â€Å"Bung! † The participant then falls out of line and stays somewhere close, serving as the priest’s prisoner. â€Å"Luksong-tinik† Luksong-tinik – jump over the thorns – Two players acts as the base of the tinik (thorn) by placing their left or right feet together (soles touching gradually building the tinik). Players shall set a starting point, providing a runway for the participants to attempt a higher jump, so as not to hit the tinik. The other players of the team starts jumping over the tinik, then the other team members follow. â€Å"Langit-lupa† Langit-lupa – heaven and earth – An â€Å"It† chases after participants who are permitted to run on level ground (lupa) and climb over objects (langit). The â€Å"tagger† may tag participants who stay on the ground, but not those who are standing in the â€Å"langit† (heaven). The player who gets tagged then becomes â€Å"It† and the game continues. â€Å"Patintero† Patintero or harangang taga – try to cross my line without letting me to touch or catch you – The group’s members who is it stands on the water lines. The middle perpendicular line allows the â€Å"it† appointed on that line to cross the lines occupied by the â€Å"it† that the parallel line intersects, thus adding up to the opportunities of the runners to be cornered. â€Å"Palosebo† Palo-sebo – greased bamboo pole climbing – The challenge of this game includes a bamboo pole that is greased that players must accomplish to reach the top by climbing. Usually played during town fiestas, more often in the provinces, the game’s objective is that for the participants to attempt to be the first person to reach the prize which is usually a little bag placed at the peak of the bamboo pole. The bag normally has money or toys inside. â€Å"Piko† Piko – hopscotch – The participants stand behind the edge of a box, and each must have to throw their cue ball. The first to play is dictated depending on the agreement of the players (e. g. nearest to the moon, wings or chest). The one who had success in throwing the cue ball closest to the point or place that they have agreed upon will be the first to play. The next closest is second, and so on and so forth. â€Å"Sipa† Sipa – game of kick – The thing being utilized to play the game is also named â€Å"sipa†. It is consisted of a washer with colorful threads, commonly plastic straw, connected to it. The sipa is then thrown above for the participant’s toss utilizing his/her foot. The participant should prevent the sipa to reach the ground by hitting it several times using his/her foot, and sometimes the portion just above the knee. The participant must count the number of times he/she was able to kick the sipa. The player with the most number of kicks shall win the game. â€Å"Sungka† Sungka – The game’s objective is to amass stones or cowrie shells in the participant’s home base (bahay) by ceaselessly distributing the shells around smaller holes until the participant have no more shells to use. The player who gathers the most number of shells in his or her bahay wins the game. â€Å"Ubusan lahi† Ubusan lahi – game of conquer – A player attempts to conquer the members of a group (as in claiming the members of another’s clan). The player tagged from the main group then transforms as an ally of the â€Å"it†. The more players, the better it is. The game shall begin with just a single it and then try to conquer and tag other participants. Just as soon as one player is tagged by the tagger, he or she then will assist the â€Å"it† to tag the other remaining members until no other player is left on the original group. B. TRADITIONAL GAMES IN EUROPEAN COUNTRIES 1. ) England There are also many famous traditional games present in England, one example of it is the game â€Å"Skittles†. â€Å"Skittles† Skittles or Nine Pins has existed in the Inns of England for a long time. Generally, participants take turns to stroke balls of wood down a lane at the end of which are several skittles also made of wood, to try to knock them all over. Across England there are a number of skittle games. Undoubtedly, Skittles has been one of England’s most popular games. Different books have made mention of this game. Seemingly, for numerous centuries up until today, a bunch of the different games of Skittles are still being played. 2. ) Scotland Scottish people are considered as Highlanders, their traditional games are called the Highland games which they held throughout the year. This is their way of celebrating Celtic culture and Scottish heritage. The common facets of the games almost are epitomes of Scotland. They use the bagpipes, the kilt and the heavy events. Held in Dunoon, Scotland every August, the Cowal Highland Gathering, (better known as the Cowal Games), is the biggest Highland games in Scotland, appealing to around 3,500 competitors and somewhere in the region of 15-20,000 of international crowd (Grondin, 2006). III. VIDEOGAMES A video game is a game that regards interaction with a user interface to create visual feedback on a video device. The term video in video game usually referred to a raster display device. But with the famous use of the term â€Å"video game†, it now connotes any type of display device (Newman, 2004). The electronic systems utilized to play video games are named as platforms; sample of these are video game consoles and personal computers. These platforms range broadly, showing from big computers to little handheld devices. Video games that are specialized such as arcade games, while previously common, have gradually declined in use as home video game consoles have grown to fame and notoriety (Garrat, 2004). Moreover, Video games have changed the landscape of playing games, or the more common term of today, gaming. Almost being a more comfortable way of playing, Video games provide a person with the chance of enjoying himself at home. The genre of Video games has evolved throughout the years. Starting off with the Atari System and evolving to the Nintendo Wii and XBOX 360s of today, Video games have changed and made an impact to the youth of today’s generation (Silberman, 2007). It can be said that Video games have transformed a lot on people, almost affecting their way of life and their perception of play. A. VIDEOGAMES IN ASIAN COUNTRIES A lot of countries in Asia have many addicted people with regards to Video games. The following two countries can be considered as one of the top countries in Asia who have a large following for Video games. 1. ) Korea In South Korea, most people are linked to Video games due to the influences of their history. A sense of integration and correlation with regards to what people need to accomplish in Video games somehow make Koreans feel more attached to the game. Online games are the most popular among Korean citizens and most of them seem to like playing as an organized group different from Americans who loves to play in a solo way. Coordination and cooperation among Korean players somehow makes them much different from other nations (Crego, 2003; Lachlan, 2003). They consider their country as a game nation who accepts different styles of games, especially online ones. The passion for Video games has made Koreans stand out as one of the most addicted nations in terms of Video games. 2. ) China Another interesting country to look at regarding video games would definitely be China. A country with a magnanimous population combined with the huge territory, China has been also expanding in terms of technology development and economic growth. The popularity of Video Games is really high, but it has not yet reached its full potential due to the low Internet penetration within the country. Improvement of this matter can help China be more acquainted with Video games. China has a large market and it draws attention of corporations that create games due to that reason. China is different from Korea in terms of Video Games due to their different favorites. It is predicted that if in the future, 10% of Chinese people would be playing online games, it would showcase that there will be more people playing games online in China than the whole population of any single country in Europe (Lachlan, 2003). B. VIDEOGAMES IN EUROPEAN COUNTRIES Video games in Europe are not as popular compared to Asian countries. The drive for online games is just not as fierce unlike in China or Korea. In Europe, Video Games are not as big as compared to China or Korea. Video games in Europe does not become a sensation to the whole of the population. IV. COMPARISON & CONTRAST There is a huge difference with regards to the Traditional games compared to Video games. The Traditional Games somehow creates an image of a more cultural approach while Video games showcase a more technological approach (Smith, 2007). Another major difference regarding the two is that Video Games need power or energy and online games need Internet to provide full satisfaction. Without electricity, Video games won’t even exist. Traditional games tend to become more substantially formed for exercise as compared to the usual Video games, with exception to the Nintendo Wii (Hanson, 1999; Lachlan, 2003). There is a huge difference with regards to different nations’ perceptions about Video games, and it may be influenced by the country’s moral characteristics or traditional aspects. The difference with regards to Asian countries to European countries is that Asian countries freely accept the Video games and allows it to become a huge phenomenon in their respective countries, unlike in Europe. V. CONCLUSION All in all, it can be concluded that there are huge differences regarding Video games and Traditional games. For one, the physicality factor differs a lot. In traditional games, physical exercise is more utilized than in Video games. The latter promotes some sort of laziness while the former encourages fitness and health. It may not be disregarded that both are fun to play and that’s the reason why they both exist in the world today (Smith, 2007). But Video games have displayed both positive and negative sides. The positive side is that it helps educate people towards the advancement of technology. It promotes modernity and futuristic possibilities. These Video games even take the players to different sights and sounds. Only a Video game could provide varying places of fantasy, past, future and other surrealistic worlds or universe. Video games expand man’s creative thinking. But despite all of these positive factors that Video games can create, there are also the negative implications that go along with it. Violence has been a concern with regards to Video games. Due to the freedom of ideas and the creative side of gaming companies, there are huge risks of exposing the youth to violence with the use of these Video games. Many killings are attributed to Video game addictions. The effect of Video games to a person’s mind can be magnanimous. Today, there are so many different violent games that somehow scare many nations. This seems to be a wrong path for children who love to play Video games. The influence of Video games to children can be surmountable and be hard to analyze. The school killings in the United States somehow showcase the suspects as attributed to love for video games with violent content. Overall, Video games are not bad, they just need to be utilized and maximized for the good because they can even influence the youth for education. Video games used as academic tools are a big help for educators and students alike. Tradition and modernization must coincide for a better future. The traditional games should not be regarded as a threat to children’s development. Instead it should serve as the basis for people’s concept of play and parents must ensure proper guidance and child-rearing. The video games should be inspired by these traditional games that have lasted for centuries and has proven that they are fun that’s why they last. Hopefully this lasting impression could still be present in the next generations to come. Traditional games and Video games may sound different but they both posses the access to fun and enjoyment in terms of playing and they can help improve people’s socialization, fine motor and psychomotor, intellectual, leadership, time management, problem solving, decision making, and planning skills. REFERENCES Crego, R. (2003). Sports and Games of the 18th and 19th Centuries. Wesport, CT: Greenwood Press. Lachlan, K. (2003). Popular Video Games: Quantifying the Presentation of Violence and Its Context. Journal of Broadcasting & Electronic Media, 47, 58. Newman, J. (2004). Videogames. London: Routledge. Silberman, L. (2007). Incorporating Video Games into Physical Education: Between Their Popularity and Their Efficient Delivery of Information, Video Games May Help to Enhance Students’ Motivation, Understanding, and Performance in Sports. Journal Title: JOPERD–The Journal of Physical Education, Recreation & Dance, 78, 18. The Chinese Historical and Cultural Project (2007). Traditional Games. [Electronic Version]. Retrieved May 12, 2008, from http://www. chcp. org/games. html Hanson, G. (1999, June 28). The Violent World of Video Games. Insight on the News, 15, 14. Garrat, P. (29, August 2004). Videogames: Play To Win. Mail on Sunday, 48. Grondin, K. (18, June 2006). Fun and Games †¦ Scottish Style Residents Bask in Music, Traditional Competitions. Daily Herald, 10. Smith, K. (15, July 2007). Don’t Give a Childtoys, Says Expert; CHILD’S PLAY: But Traditional Games or Role Play Can Be Better Fun Than Toys. The Mail on Sunday, 41. Filipino Games (Mga Larong Filipino). Retrieved May 12, 2008, from http://www. seasite. niu. edu. /Tagalog/Filipino_Games/mga_larong_pilipino. htm

ESL Tips and Quiz Possessive Nouns and Adjectives