Chemotherapy Is Synonymous With Cancer Biology Essay

Cancer is normally referred to disease which normal cells undergo unnatural cell proliferation and distinction. These abnormalcies are due to mutants to cell cistrons, therefore bring forthing transforming genes and doing the tumour suppresser cistrons to lose its maps. Nowadays malignant neoplastic disease has become a common disease as many people have been diagnosed with it and is considered a major cause for mortality worldwide. World Health Organization has reported that malignant neoplastic disease has caused 7.4 million mortalities in 2004. In Peninsular Malaysia, about 70 000 new instances were reported from 2005-2008 ( MAKNA, 2006 ) . Colorectal malignant neoplastic disease is the 3rd most common malignant neoplastic disease worldwide and doing half a million of mortality yearly, as reported by World Health Organization ( WHO, 2009 ) . Colorectal malignant neoplastic disease has an about indistinguishable pathophysiology as other types of malignant neoplastic disease but the beginning starts at the colorectal of the human organic structure. In Malaysia, colorectal malignant neoplastic disease is the 2nd most common malignant neoplastic disease reported harmonizing to the National Cancer Registry ( NCR ) and the instances cover 13.2 % of overall malignant neoplastic disease instances that have been reported ( NCR, 2006 ) .

Nowadays chemotherapy is synonymous with malignant neoplastic disease, despite other malignant neoplastic disease directions, such as surgery and immunotherapy. Chemotherapy aims at interfering with cancerous cells patterned advance utilizing chemical agents. There are legion chemotherapy drugs available in the market for malignant neoplastic disease intervention. The chemotherapy drugs can be used as individual agent chemotherapy and combination chemotherapy, which means two or more chemotherapy drugs, are used together for direction of malignant neoplastic disease. However, chemotherapy drugs, either used as individual or in combination, present assorted inauspicious effects such as bone marrow suppression as stated by American Cancer Society ( ACS, 2010 ) , sickness and emesis ( de Boer-Dennert et al. , 1997 ) .

Therefore, farther drug find is conducted to detect new anticancer drugs that elicit less inauspicious effects, more selective and effectual agents ( Nam and & A ; Acirc ; Parang, 2003 ) . Research workers have turn to natural beginnings for this intent. Nature is abundance have such a broad biodiversity ( da Rocha et al. , 2001 ) . Plants with such diverseness have helped in drug find. For illustration, a well-known chemotherapy drug paclitaxel is isolated from bark of yew tree Taxus brevifolia and its derived functions docetaxel, has been isolated from the foliages of Taxus baccata ( da Rocha et al. , 2001 ) .

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Other than workss, micro-organisms besides play a major function in antineoplastic drug find from natural merchandises. Endophytes, which are micro-organisms found in workss and can be described to hold symbiosis interaction with its host ( Tadych and White, 2009 ) .

The aims of this survey are:

To turn and pull out selected endophytic Fungis ( PA1US1, PA1ML2 and PA1ML3 ) which have been isolated from Ixora congesta.

To find the anticancer activity of the endophytic infusions against colon malignant neoplastic disease cell lines.

To find the selectivity of endophytic infusions against colon malignant neoplastic disease cell lines as compared to a normal cell line.

Chapter 2

LITERATURE REVIEW

2.1 Cancer

The human organic structure is made up of legion cells. These cells proliferate, differentiate and dice in an oriented mode. The human cells undergo normal growing and ripening during the early old ages of life, and during tissue fix. However, there may be some abnormalcies during the procedure, ensuing in uncontrolled proliferation of cells. Therefore, malignant neoplastic disease is characterized by a alteration or divergence in the control mechanisms of cell endurance, proliferation and distinction ( Chu and Sartorelli, 2007 ) . Cancer cells are said to be normal cells holding damaged cistrons that straight regulates their cell rhythms. Familial changes or mutants of Deoxyribonucleic acid of the normal cells produce transforming genes, and do the loss of map of tumour stamp downing cistrons ( Hanahan and Weinberg, 2000 ) .

Cancer has been a major cause of decease worldwide as it accounted for 7.4 million deceases, which is 13 % of all deceases in 2004, as reported by World Health Organization. This has been rather a concern as the decease from malignant neoplastic disease is projected to increase by appraisal of 12 million deceases in twelvemonth 2030 ( WHO, 2009 ) . In Malaysia, about 70 000 instances were diagnosed between 2003 and 2005 ( MAKNA, 2006 ) and a sum of 21 773 instances were diagnosed among Malaysians in Peninsular Malaysia in 2006 ( NCR, 2006 ) . These informations show that malignant neoplastic disease will stay and intensify as the lead cause of mortality non merely in Malaysia, but worldwide.

Colon malignant neoplastic disease has been the 3rd most common malignant neoplastic disease following lung malignant neoplastic disease and chest malignant neoplastic disease, with more than 940 000 instances reported yearly world-wide doing about 500 000 mortality of all time twelvemonth ( WHO, 2003 ) . Even in the U.S. , colon malignant neoplastic disease is the 3rd most common malignant neoplastic disease among both work forces and adult females ( ACS, 2009 ) . Up to twelvemonth 2006, approximately 70 270 work forces and 68 857 adult females were diagnosed with colon malignant neoplastic disease and the mortality statistics were 26 801 in work forces and 26 395 in adult females, in the U.S. ( CDC, 2010 ) . In Malaysia, harmonizing to the National Cancer Registry, colon malignant neoplastic disease has become the 2nd most common malignant neoplastic disease with up to 13.2 % of overall malignant neoplastic disease instances ( NCR, 2006 ) . From these instances, Age Standardized Incidence Rate ( ASR ) for instances affecting Chinese were the highest, 21.4 per 100 000 population, and were lower in Malays and Indians with ASR of 11.3 per 100 000 and 9.5 per 100 000 severally ( NCR, 2006 ) .

2.1.1 Colon Cancer

Colon malignant neoplastic disease, as the name suggest, is a malignant neoplastic disease that starts in the country of the colon. It is suggested that the cause of colon malignant neoplastic disease is mutant of the adenomatous polyposis coli ( APC ) cistron. Patients that inherit a faulty APC allelomorph are diagnosed of holding familial adenomatous polyposis ( FAP ) syndrome which may do the development of many polyps, or adenomas beginning after pubescence ( Cappell, 2005 ) . Polyps can be defined as the benign branch of the liner of the colon and rectum ( NCSM, 2010 ) . These polyps may take to the formation of glandular cancer, necessarily ensuing in colon malignant neoplastic disease. Another pathogenesis of familial colon malignant neoplastic disease syndrome is familial nonpolyposis colon malignant neoplastic disease ( HNPCC ) ( Cappell, 2005 ) . This peculiar syndrome is caused by mutants of one of the mismatch fix cistrons, such as hMLH1 and hMSH2 cistrons. Mismatch fix cistrons are cistrons that encode for mismatch fix enzymes that recognize and right mistakes in nucleotide matching of complementary chromosome strands ( Cappell, 2005 ) . The accretion of the mutants further leads to mutant of the tumour suppresser cistrons and transforming genes, such as p53 cistrons which initiates the formation of colon malignant neoplastic disease ( Cappell, 2005 ) .

There are 5 phases involved in colon malignant neoplastic disease patterned advance. The phases and descriptions are shown in Table 2.1.1 and Figure 2.1.1

Table 2.1.1: Phases of colon malignant neoplastic disease.

Phases

Description

0

The malignant neoplastic disease is really early. It is found merely in the innermost liner of the colon or rectum.

I

The malignant neoplastic disease involves more of the interior wall of the colon or rectum.

Two

The malignant neoplastic disease has spread outside the colon or rectum to nearby tissues but non to the lymph nodes. ( Lymph nodes are little, bean-shaped constructions that are portion of the organic structure ‘s immune system. )

Three

The malignant neoplastic disease has spread to nearby lymph nodes but non to other parts of the organic structure.

Four

The malignant neoplastic disease has spread to other parts of the organic structure. Colorectal malignant neoplastic disease tends to distribute to the liver and/or lungs.

( Gani, 2009 )

Figure 2.1.1: Sites harmonizing to the phases of colon malignant neoplastic disease.

( Adapted from Gani, 2009 )

2.2 Chemotherapy

There are assorted ways for the direction of malignant neoplastic disease. Chemotherapy is one of them and is normally applied. Chemotherapy fundamentally refers to the usage of chemical agents to step in the patterned advance of malignant neoplastic disease. It is normally inserted into the organic structure, through unwritten path in the signifier of pills, or intravenously by injections. Therefore, chemotherapy is said to exercise systemic consequence to the organic structure of patients. The purpose of chemotherapy is to kill malignant neoplastic disease cells by interfering with the procedure of cell division because malignant neoplastic disease cells undergo active cell division as compared to most normal cells. The marks of the chemical agents are either the proteins involved during cell division, or straight damaging the Deoxyribonucleic acid of the cells ( Cancer Research UK, 2010 ) . Chemotherapy can be given as a individual agent or in combination chemotherapy. Single agent chemotherapy means utilizing a individual chemical agent from any categories of chemotherapy drugs for the direction of malignant neoplastic disease, while combination chemotherapy refers to the usage of several chemical agents, dwelling of several categories of chemotherapy drugs in regimen. For illustration, it is found that combination of Bevacizumab with Oxaliplatin, Fluorouracil, and Leucovorin ( FOLFOX4 ) improves survival extent of patients antecedently treated for metastatic colorectal malignant neoplastic disease ( Giantonio et al. , 2007 ) .

Chemotherapy is associated with legion side effects. These side effects occur because chemotherapy purposes and putting to deaths actively spliting malignant neoplastic disease cells, and exerts systemic consequence. Some normal organic structure cells besides divide actively which is indispensable for the organic structure to keep its map. The normal cells that are most likely to be damaged are bone marrow, cells of hair follicles, cells run alonging the digestive piece of land, and cells run alonging the generative piece of land ( ACS, 2010 ) . Patients that undergo chemotherapy may develop bone marrow suppression, hair loss, appetite and weight loss, irregularity, diarrhoea, liver and kidney harm, or even worse, lasting organ harm and secondary malignant neoplastic disease as long term side effects. However, sickness and emesis was found to be the two most distressful inauspicious effects of chemotherapy with the usage of serotonin adversary ( de Boer-Dennert et al. , 1997 ) .

Resistance of malignant neoplastic disease cells towards chemotherapy has long clip being researched intensively. Cancer cell opposition is non the consequence of a individual cistron change. Cancer cells besides contain multiple familial defects such as mutants, translocations and other types of defects. Epigenetic aberrances, such as change of DNA methylation may besides happen. Synergy by these defects may ensue in malignant neoplastic disease cell opposition as the cells try to keep homeostasis and to get by with the effects of chemotherapy or radiation therapy ( Perez-Plasencia and Duenas-Gonzalez, 1996 ) . Cancer root cell have the ability to self-renew indefinitely, while keeping their ability to bring forth both tumorigenic ( TG ) and non-tumorigenic ( NTG ) cells and it was discovered that colon malignant neoplastic disease cells developed after the exposure of chemotherapy agent, cyclophosphamide ( Dylla et al. , 2008 ) .

2.3 Drug Discovery from Natural Products

Research of new drugs is a ne’er stoping procedure. Although current drugs are supplying curative benefits, farther research must be conducted to happen alternate drugs that are more specific, have less inauspicious effects. This besides includes bettering ways to bring forth drugs in a more economical manner with higher output.

Drug find and development have evolved a long manner and integrated new technological promotions. Over centuries, natural merchandises have been the major beginning of new drugs. However, with the promotion of engineering, proteomics and genomics finds, high throughput showing, combinative chemical science and other engineerings have been implemented in current drug findings ( Sofia, 2004 ) .

Concentrating on anticancer agents, the purposes of drug find are to happen less toxic, more selective, and more effectual agents ( Nam and Parang, 2003 ) . The findings of new anticancer agents resolve around some facets, which are either detecting new compounds from natural beginnings or modifying construction of known anticancer agents ( Ma and Wang, 2009 ) . In the yesteryear, man-made merchandises such as alkylating agents were the lone chemotherapy agents of pick. However, man-made compounds exhibit enormous side effects as these agents are non malignant neoplastic disease cell specific, therefore wounding quickly spliting normal cells. Scientists have begun the hunt for selective anticancer agents that have less side effects when compared to the man-made compounds.

Even with all the engineerings and man-made compounds produced, natural merchandises have been a major beginning for drug find and development for over centuries. Analysis and apprehension of natural merchandises have become a discovery in the development of purified and defined compounds referred to as dose-controlled medical specialties ( Rishton, 2008 ) . It is analyzed that 60 % of approved drugs are derived from natural compounds ( da Rocha et al. , 2001 ) . Nature is a great beginning of happening new curative campaigner compounds because nature is copiousness and has great chemical diverseness ( da Rocha et al. , 2001 ) . There are three wide classs of beginnings of natural merchandises which are workss, Mariness and micro-organisms.

2.3.1 Natural Products in Plants

Plants have long been exploited as a beginning for drug find. Many people have used them as traditional medical specialties and for other intents such as dyes and nutrient additives for centuries. Even until today, medicative herbs are still being studied and used for handling assorted unwellnesss. It has been estimated by the World Health Organization that about 80 % of the universe & A ; acirc ; ˆ™s dwellers rely chiefly on traditional medical specialties for their primary wellness attention ( Newman et al, 2000 ) .

Now, as biotechnology evolved and entered the image in drug find, particularly associated with workss, more advantages are offered in footings of production graduated table and economic system, merchandise safety, easiness of storage and distribution ( Ma et al, 2005 ) . This gives chance for research workers and pharmaceutical companies to provide low-priced drugs and vaccinums.

However, deducing an agent from nature resources do non come without troubles. For case, see during the debut of drug paclitaxel, which is originally isolated from bark of yew tree Taxus brevifolia. Researchers and pharmaceutical companies were in struggle refering the environment because legion trees and woods will be chopped down if they were to run into the drug demand. Eventually, after some old ages, a semi-synthetic derived function of paclitaxel, docetaxel, has been isolated from a renewable beginning, which is the foliages of Taxus baccata.

Assorted natural merchandises from workss have been marketed around the universe. Examples of the merchandises are & amp ; Acirc ; Cynarin which is a works chemical found in the common Cynara scolymus ( Cynara Scolymus ) for liver jobs and high blood pressure ; quinine, which was discovered in a rain forest tree ( Cinchona ledgeriana ) as antimalaria ; and digoxin found in Digitalis lanata as cardiotonic ( Taylor, 2000 ) . Table 2.3.1 shows some anticancer agents that are undergoing Phase III/IV tests.

Table 2.3.1: Some anticancer agents of position Phase III/IV derived from natural resources and their malignant neoplastic disease intervention.

Anticancer Agents

Cancer Treatment

Vincristine

Leukemia, lymphoma, chest, lung, pediatric solid malignant neoplastic diseases and others

Vinblastine

Breast, lymphoma, germ-cell and nephritic malignant neoplastic disease

Paclitaxel

Ovary, chest, lung, vesica, and caput and cervix malignant neoplastic disease

Irinotecan

Colorectal and lung malignant neoplastic disease

( Adapted from district attorney Rocha et al. , 2001 )

2.3.2 Natural Products in Marines

Sea screens about 70 % of the Earth, doing it a valuable resource for drug find. Until now, Marine beginning is underexploited. Most drug find plans use samples merely near the surface parts. However, there are more diverse and abundant micro-organisms and makrofauna deep within the oceans. Such beings that have associated with post- and current drug find are marine bugs, algae and invertebrates. More than 15 000 structurally diverse natural merchandises with assorted and different bioactivities have been discovered since 1970 ( Baker et al, 2007 ) .

However, there are certain drawbacks in utilizing Marine as a beginning for new drug findings. As stated above, the inability to seek deep into the ocean for farther diverseness is a major drawback. Another drawback, as stated by Baker et Al ( 2007 ) is the inability of many of these beginnings to be propagated in a commercial scene or the trouble in retroflexing the production of the active molecule in an unreal environment.

Despite the declared drawbacks, there are successful findings of new compounds that lead to farther drug development. Examples of such compounds are salinosporamide A yielded from a marine actinomycete Salinispora tropica which inhibited human colon carcinoma HCT116 cells and exhibited utmost authority against several non-small cell lung, cardinal nervous system and chest malignant neoplastic disease cell lines ( Blunt et al, 2007 ) . Other illustrations of compounds that are undergoing clinical tests are Bryostatin derived from Bugula neritina in stage II for handling malignant neoplastic disease, IPL-550260 derived from a sponge in stage I for redness intervention, and Ziconotide derived from mollusc in stage III for intervention of neuropathic diseases ( Baker et al, 2007 ) .

2.3.3 Natural Products in Microorganisms

Microorganisms are immensely found in the environment and have structurally diverse bioactive substance. They have been quite an of import beginning in drug find procedure. Penicillin found by Alexander Fleming has become the foundation for development of microbic natural merchandise in drug find ( Challis, 2008 ) . Microorganisms have mostly contributed in development of antibacterial, such as penicillin, Mefoxins and other drug compounds. Nowadays, curative utilizations of metabolites from micro-organisms have been used in several drug categories such as immunosuppressive agents ( eg, cyclosporins and rapamycin ) , cholesterol-lowering agents ( eg, Mevacor and mevastatin ) , antihelmintic agents ( eg, ivermectin ) , antidiabetic agent ( acarbose ) , and anticancer agents ( eg, pentostatin, peplomycin, and epirubicin ) ( Chin et al, 2006 ) .

Among the drugs discovered from microbic beginnings approved by FDA are rosuvastatin Ca isolated from Penicillium citrinum and P. brevicompactum for direction of dyslipidemias ; daptomycin isolated from Streptomyces roseosporus for intervention of complicated tegument and tegument construction infections ; and caspofungin ethanoate from derivation of pneumocandin B0, a agitation merchandise of Glarea lozoyensis ( Chin et al, 2006 ) .

2.4 Endophytes

Endophytes, by and large can be defined as micro-organisms that live in workss. A more inclusive and widely accepted definition is endophytes are bugs that colonize life, internal tissue of workss without doing any immediate, open negative effects ( Strobel and Daisy, 2003 ) . Endophytes, which are a beginning of natural merchandises, are still ill exploited. The ground is automatons, combinative chemical science and molecular biological science has replaced the involvement of natural merchandises in drug development ( Strobel and Daisy, 2003 ) .

However, endophytes have shown as a promising beginning of new drugs in drug development. Endophytes have big biodiversity as one works can host a few types of endophytes, and there are legion workss around the universe. Endophytes can be described as holding mutualism with the hosts as they contribute to the wellness and growing development of the hosts in exchange of some privileges ( Tadych and White, 2009 ) . Some endophytes are said to be mutualists that protect the hosts and are responsible of versions of workss to emphasize. Recently endophytes have been the mark of new bioactive compounds and 2nd metabolites for drug development.

2.4.1 Anticancer Agents from Endophytes

In antineoplastic drug development, beginnings from endophytes have become a success and farther research are being done to better the findings of anticancer agents from the endophytes. A celebrated compound of anticancer agents that come from this beginning is paclitaxel. Paclitaxel is found in every yew ( Taxus ) species ( Strobel, 2003 ) . This compound has contributed to the promotion in malignant neoplastic disease intervention, particularly for breast malignant neoplastic disease patients ( Luck and Roche, 2002 ) . Endophytes Seimatoantlerium tepuiense and S. nepalense have been reported to bring forth paclitaxel. However, paclitaxel has some common side effects, which are neutropenia and peripheral neuropathy.

Some new compounds have been prospected to hold anticancer activity. Endophyte Pestalotiopsis microspora associated with the endangered tree Torreya taxifolia ( Florida Torreya ) produces antineoplastic agent, torreyanic acid which is more powerful than taxol and bring on cell decease by programmed cell death ( Priti et al, 2009 ) . These findings further strengthen the ground why endophytes can be a genuinely valuable beginning in detecting new and more enhanced intervention for malignant neoplastic disease.

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