Historical theories of cancer causation from ancient Egypt to medieval times

Cancer: A deep study through ages

Oncology is the study of cancer. It's a field in which numerous doctors and scientists have worked all across the world. Their work in chemistry, physiology, anatomy and epidemiology transformed oncology into what it is today. Oncology is the fastest developing field in science with cancer understanding and technological breakthroughs. It is a quickly developing medicinal field with huge prospects.

Cancer and its definition

Cancer starts developing in a human body when human cells spiral out of control. There are numerous forms of cancer and yet they all commence from abnormal growth of cells. In the United States of America, cancer is the second cause of most deaths. One third of women and one half of women will stimulate cancer in their lifecycle. In this modern era, many people are suffering from cancer and many have had cancer in the past (ASCO, 2009).

Cancer and ancient civilizations

Through recorded history, humans and even animals have suffered cancer. It's not a huge surprise; people have noted and observed cancer. The earliest forms of cancer are found in bone tumors fossilized. The Egyptian mummies had cancer and manuscripts also mention the same symptoms and effects. Osteosarcoma has been observed in bones. This growth suggests bone cancer. Moreover, neck and head cancer has been observed in form of bony skull destruction (ASCO, 2009)

The oldest recorded form of cancer was found in Egypt which is as old as 3000 BC. The term cancer wasn't used for that matter. The description was found in Edwin Smith Papyrus and is a component of olden Egyptian book based on trauma surgery. It has noted down successfully eight cases of ulcers and tumors in breast. They were treated with cauterization by a tool known as fire drill. The diseases were finally written off as "Incurable" (ASCO, 2009).

The causes of cancer: A history

Cancer has confused, baffled and puzzled many an ancient physicians during the course of history. The Egyptians believed that the disease of cancer was primarily instiaged by gods as a form of wrath on them.

The humoral theory

Hippocrates thought a human body had four forms of body fluids namely:

Yellow bile

Phlegm

Black bile

Blood

A person was healthy when these four liquids coexisted in harmony. The belief was that misbalance could cause diseases. The excessive amount of black bile would stimulate cancer. The theory was accepted by the ancient Romans and taken in full regard by Galen's medical writings. They were unparalleled and unrivaled all through the middle ages. The writings remained in place for 1,300 years. During this dark period of time, the autopsies, studying human bodies, science and astronomy was banned for religious reasons, further hampering the research on cancer and related medical fields (ASCO, 2009).

The lymph theory

Among various other theories for the instigation of cancer, one of them was lymph. It was formed by a liquid in the body called lymph. Life was deemed as the movement of liquids in human body. It flowed in all parts of human body. Blood and lymph was the most imperative fluid in human body. Stahl and Hoffman thought that cancer was formed from fermentation and degenerating lymph's in terms of alkanet, acidity and density. The theory of lymph became limp with popularity. The Scottish surgeon in 1700's named John Hunter assumed that tumors came from lymph's secreted by blood continuously (ASCO 2009).

The theory of blastema

A German pathologist named Johannes Muller in 1838 showed that cancer consists of damaged cells and lymph was not the cause. He also assumed that cancerous cells were different from normal human cells. Muller thought that cancer cells came from elements such as blastema present in normal cells. Rudolph Virchow (1821-1902) was a popular German pathologist who came to the conclusion that cancer cells were derived from normal body cells too (ASCO, 2010).

The theory of chronic irritation

A practitioner named Virchow claimed that chronic irritation could probably cause cancer. He was wrong though that "cancer spreads like water." The German surgeon in 1860's named Karl Thiersch demonstrated that cancer usually spread by cancerous or malignant cells in the human body. The theory of unknown liquid was discarded (ASCO, 2010).

The trauma theory

As people and scientists began to understand cancer in the early late 1800's and 1900's, trauma was still thought to stimulate cancer. The belief was still propagated even though the experiment on lab animals failed wretchedly (ASCO, 2010).

Transmissible disease theory

Two doctors from Netherlands named Nicholas Tulp (1593?1674) and Zacutus Lusitani (1575?1642) came to the conclusion that cancer was transmissible. Their assumptions were made on breast cancer and studies on it. Tulp and Lusitani promoted the transmissible theory in 1652 and 1642. They assumed that cancer patients must be left alone and kept outside cities and prevent the spread of cancer everywhere (ASCO, 2010).

During the eighteenth and nineteenth century, people believed in dogmas that cancer was transmissible. In recorded history, France's cancer hospital was the first one to shift from city limits in 1779 as people thought it was contagious. The fact remains however that cancer in humans isn't contagious, there are agents which can stimulate cancer and elevate risks. They include parasites, viruses and bacteria (ASCO, 2010).

Cancer epidemiology

In the 18th century, there were three imperative observations that shot the cancer epidemiology to new heights. These are namely control of diseases, distribution and study of causes.

Then in 1713, an Italian doctor named Bernardino Ramazzini showed absence of cervical cancer and elevated presence in breast cancer in church nuns. Fingers were raised on their life of celibacy. The observation was apt, yet it assisted in finding the significance of hormones and identifying them. The alternations with pregnancy were also observed. The sexually transmitted infections were also taken in consideration and cancer risks were assimilated (Hajdu, part 1, 2011).

Percival Pott in 1775 from Saint Bartholomew Hospital, London explained cancer during chimney sweeping. He explained scrotum cancer which occurred due to soot gathering in scrotum's skin. More studies were done in this regard and many new occupational carcinogenic exposures were identified. Public health measures were taken for lessening a risk to cancer at workplace (Hajdu, part 1, 2011).

In 1620, a person named Thomas Venner from London warned about the hazardous effects of tobacco in his book released in 1620 titled Via Recta. He stated that "unhealthy usage of tobacco has a negative effect on brain as well as the eye. It weakens the limbs and heart." One and a half century later in 1761, tobacco was becoming quite popular as a recreational substance in those days, John Hill stated in his book called Cautions against the Immoderate Use of Snuff. These linkages and observations were the source of thorough research in cancer department in 1950's and 1960's. It clearly showed that smoking caused severe lung cancer and in turn promulgated the U.S. Surgeon General's report titled Smoking and Health in 1964 (Hajdu, part 1, 2011).

Epidemiologists are involved in finding the root causes of cancer such as tobacco, obesity and radiation. They are also busy in seeking ways to prevent cancer for instance devising a diet and a nice physical workout. The research is then sent to public health departments for recommendations and implementations (Hajdu, part 1, 2011).

The molecular biologists are tasked with finding the causes of cancer and ways to prevent them. This enables them to work in molecular epidemiology. It's the study of genes and its interactions with external factors (Hajdu, part 1, 2011).

Cancer roots and modern science

Chemical and viral carcinogens

Two scientists at Tokyo University named Katsusaburo Yamagiwa as well as Koichi Ichikawa in 1915 transferred cancer in lab rabbits. It was the first experiment of its kind applying coal tar on rabbit's skin. At least one and a half century had passed when John Hill, a London clinician stated that tobacco was a carcinogen (a probable cause for cancer found in humans). Then, after few more decades of negligence, tobacco was found to the horror of many, as the primary source of chemical carcinogens for the mankind at large (Hajdu, part 1, 2011).

Today mankind stays off limits to substances which can cause cancer for instance: coal tar, benzene (a derivative), hydrocarbons, aniline (substance used in dye production), asbestos and few others. A variety of sources produce ironing radiation which includes our very own sun. It can cause cancer too. The government has taken a few steps in ensuring public awareness regarding cancer. These include:

Asbestos

Benzene

Hydrocarbons

Arsenic

Drinking water

Radiation (Hajdu, part 1, 2011).

In the year 1911, at Rockefeller Institute in New York City, a person named Peyton Rous found a new form of cancer known as sarcoma. It was present in chickens. It was later termed as Rous sarcoma virus. For his work in detecting a new breed of cancer he was bestowed with a Nobel Prize in 1968. Now many viruses are linked with human cancer which includes:

Infection from hepatitis B and hepatitis C viruses can cause liver cancer (Hajdu, part 1, 2011).

Epstein-Barr virus is a herpes virus. It can create infectious mononucleosis and has also been connected to nasopharyngeal cancer and non-Hodgkin lymphomas (Hajdu, part 1, 2011).

People who have been diagnosed with human immunodeficiency virus (HIV) can develop many other forms of cancer including non-Hodgkin lymphoma and Kaposi sarcoma (Hajdu, part 1, 2011).

HPVs commonly known as human papilloma viruses are linked with too many forms of cancers. Some of them exist in vagina, vulva, cervix and anus. Neck cancer and head cancer are also a case in point. Tongue and tonsils are an example of HPV here. It's a high risk situation. Now, a vaccine exists for averting HPV infection (Hajdu, part 1, 2011).

IARC is abbreviated as International Agency for Research on Cancer (IARC). It's a part of World Health Organization. It has now found at least 100 biological, physical and chemical carcinogens. The scientists were working to find out the development of cancer long before these associations came into existence. Now the research is discovering latest carcinogens and defines their cause for cancer. They also provide insight on ways to avert cancer (Hajdu, part 1, 2011).

During the 20th century, the scientists had everything to work on the disease of cancer which nevertheless continued to baffled them. They worked on biology and chemistry problems. Francis Crick and James Watson attained a Nobel Prize in 1962 for their efforts in determining the DNA's chemical structure. DNA is the basic form in genes (Hajdu, part 1, 2011).

DNA was responsible for the genetic code and gave specific orders to cells. The scientists could translate the code first and then began to comprehend how genes operated and how were they damaged by mutations (alterations in genes and changes). This modern study cleared many misconceptions and prejudices about cancer that were held quiet strongly before (Hajdu, part 1, 2011).

Scientists did know that cancer was a resultant of viruses, radiation, chemicals and sometimes it ran deep in family inheritance. DNA and genes understanding did increase with time, the scientists also learned that chemicals and radiation did affect the DNA sequences and altered them which resulted in cancer development. Then, the aim was to determine the location of a probable damaged gene (Hajdu, part 1, 2011).

Scientists did discover that defective genes were inherited in some cases and these inherited genes tend to get defective when chemical effects pull through with full force. In layman language, the factors that caused cancer (carcinogens) also damaged genes causing mutations. The mutation seems like inherited ones and can possibly cause various forms of cancer if left unattended (Hajdu, part 1, 2011).

It doesn't matter how the first mutation was formed (created or inherited), the cells formed due to such mutations also created groups of abnormal cells known as clones and duplicates of anomalous cell. The mutant clones became even more dangerous clones with the passage of time. The cancer became more and more hazardous. The genes were damaged and mutated.

There is a difference between normal tissue cells and cancer cells. Normal cells when damaged die while cancer cells after damage remain active. This major difference was a huge breakthrough for scientists after many centuries (Hajdu, part 1, 2011).

Early detection and cancer screening

For identifying a disease, screening tests are often done. Cancer doesn't have many symptoms for that matter. The Pap test is the first screening test for cancer identification. The name came from George Papnicolaou. The test was about researching on menstrual cycle. In 1923, Papanicolaou came out successfully with results in cervical cancer. The doctors were obviously skeptical at first. The American Cancer Society (ACS) came to his rescue and started promoting the test in the 1960's. The test was a massive hit (Hajdu, part 2, 2011).

After that, rate of cervical cancer in United States of America had gone down by seventy percent. In the late 1960's, modern mammography methods were invented. They were up for recommendation by ACS in 1976 (Hajdu, part 2, 2011).

The present American Cancer Society had methods for detection of cancer earlier in colon, rectum, breast, cervix, endometrium and prostate. They also advise on checkups from time to time. The age factor and gender are taken in account. The areas up for inspection include

Skin

Mouth

Thyroid

Lymph nodes

Ovaries

Testes

(Hajdu, part 2, 2011).

Immunotherapy

More synthetic understanding of cancer cells sciences has led to the growth of biological forces which imitates some of the signals used by the human body to control the extension of cells. Medical experiments have demonstrated that this cancer ailment which is known as BRM (biological response modifier) therapy is effective for various cancers (Hajdu, part 2, 2011).

Many of such biologic agents which exist in the body naturally can also be made artificially in a lab. Examples of such artificial agents are interleukins, cytokines or interferons. These agents or forces are given to cancer patients to mimic the natural immune response. This can be done by altering the growth of cancer cells or acting indirectly to aid strong cells which can control cancer (Hajdu, part 2, 2011).

Antigens, one of the most exciting implementations of biologic therapy came up by recognizing certain tumor targets aims as an antibody for these targets. This process was initially used to locate cancer cells and diagnose cancer and then it was used to attack these cells. During the 1970s, scientists could do the mass production of monoclonal antibodies by using this technology which targeted more specifically the chemical mechanism of cancer cells. More advancement of these methods by usage of recombinant DNA technology increased the effectiveness and minimized the side effects. In the last few years of the decade starting from 1990, the very first antibodies which were approved to treat breast cancer were structured and are known as rituximab (Rituxan) and trastuzumab. These monoclonal antibodies are now used generally to treat various cancers and many new are researched (Hajdu, part 2, 2011).

Scientists are also doing research for vaccines to boost up the response of body's immune to cancer cells. For example, a study which took place in 2009 worked on customized vaccines which could be made with the tissues of the patient's tumor. Positive results were the outcome for patients who lived longer from those who didn't have these vaccines (Hajdu, part 2, 2011).

The FDA confirmed Sipuleucel-T (Provenge), in 2010, a vaccine for metastatic prostate cancer (cancer which grows and does not respond to hormone treatment). Provenge vaccine improves body's immune response and its capacity to destroy cancer cells unlike a preventive vaccine, on that is normally given to put off the disease. This healing process has been demonstrated to aid certain men, suffering from prostate cancer, to live longer, but it doesn't treat the disease. However, it's a vital step towards cancer treatment (Hajdu, part 2, 2011).

Clinical-Translational Advances

Damage caused by DNA remains for long during cancer treatment. The dangerous side effects of agents which stimulate DNA damage minimize the tolerance level for doses which results in the increasing degree of tumor death.

Transformation in genes which is needed for the diagnosis, signaling and restoring the damage caused by DNA can also lead to maximized damage or the inappropriate treatment of DNA damage and cancer cells (Harper et al., 2007). In order to compensate for the failing methods of DNA damage, more reliable pathways may be implemented, so that the tumor cells can survive. The implementation of the proper repair method has been recommended for the limited response of tumor cells to radio therapy.

If the methods to repair DNA damage for the survival of tumor cells can be identified, radio and chemo therapy will be much more efficient. Thus it can be said that intending both checkpoint and repair methods together may kill tumor cells over healthy ones. Below, we list down some players in the DNA damage response pathway that may open up to some pharmacological interventions.

The major and leading Kinase which is liable for the implementation of various cell cycle checkpoints next to DSB induction is ATM. Particulars of ATM mediated signaling network were drawn attention by a latest research demonstrating that more than hundreds of phosphorylatin events depends on ATM kinase (Matsuoka et al., 2007).

Very first instance when ATM was viewed as a response that can be an exciting target for chemotherapy was that cells from cancer suffering patients, with disorder of genomic instability which results through ATM mutation, were extensively sensitive to radiation (Savitsky et al., 1995). Furthermore, caffeine which is also a recognized inhibitor of ATM could stretch cellular sensitivity towards radiation and drugs used in chemotherapy (Sarkaria et al., 1999; Sabisz et al., 2008), but because of its less potency it is not suitable as a clinical agent. LY294002 is one of the other ATM inhibitors which vastly inhibits the ATM kinase activity of PIKKS. Just like caffeine, extensive use of LY294002 is restricted because of its lacking specificity. Nevertheless it has been utilized as a study tool for inventions of more potent PIKK inhibitors.

As the process of screening of drug library which was based on LY294002 lead to the designing of highly particular miniature molecule ATP, it gave a stiff competition to ATM inhibitors (Hickson et al., 2004). This composition of inhibitor can effectively sensitize tumor cells towards radiation along with DSB-inducing chemotherapeutic agents, for example, camptothecin as well as etoposide. It is said that this inhibitor might be used as an efficient clinical treatment. Moreover there is a suggestion that inhibitors of ATM pathways could also sensitize cells, which lack in DNA repair pathways to potential cancer cures and its treatments. Confirmation of this proposal was firstly borne out when the process of screening identified ATM as an objective which disordered the extension of cells lacking in Fanconi anemia pathway (Kennedy et al., 2007). Inhibiton of ATM through SIRNA was toxic to cells with a flawed FA pathway. Inhibiton of ATM can also provide effective and thriving treatment in this context of cancers as FA genes are disrupted in this subset of cancers.

The check point kinases known as CHK1 and CHK in addition to ATM are also vital for cell cycle checkpoint commencement subsequent to the stimulation of DSBs. There are various indications and evidences which show that the combined treatment of tumor and genotoxic agents along with CHK1 and CHK2 inhibitors might have elevated therapeutic importance. Initial inhibitor of CHK!1 and CHK2 was UCN 01 and treating with this composition led to G2/Mcheckpoint flaws in IR-treated p53-deficient tumor cells (Graves et al., 2000), telling us that inhibition of kinases checkpoints might sensitize p53 deficient cells to chemo and radio therapy. This research encouraged the development and checking of CHK1 and CHK2 inhibitors that might conform anti-tumor qualities when bonded with other chemotherapeutics.

One potential dispute for the usage of UCN 01 in tumor treating process is the rising sensitivity of health tissues because of the wide spectrum of its targets. Extended myelosuppression was witnessed in phase 1 clinical experiments of UCN 01 with topotecan at lesser dosage as compared to the topotecan when used alone (Welch et al., 2007; Tse et al., 2007). With more precise inhibitors and biomarkers it is possible that more efficient therapeutic indexes could be attained in clinical settings.

Numerous precise inhibitors of CHK1 and also CHK2 kinases are developed along with AZD7762 (AstraZeneca), XL844 (Exelixis), and PF-00477736 (Pfizer). Even though all these composites containing CHK1 and CHK2 in different quantity PF-00477736 demonstrate the highest concentration of CHK1 as it shows the great resemblance with it.

It is also that noticed that treatment which consist PF-00477736 also pave way to strong inhibition of CHK1 auto-phosphorylation, unlike the other kinase inhibitors. It is not clear on what influences these differences in clinical settings will induce, but formerly it has been demonstrated that inhibitors of CHK1 may raise DNA damaging agents. These inhibitors are revealed to sensitize tumor cells and xenografts to anticancer damaging agents (Ashwell et al., 2008; Zabludff et al., 2008; Matthews et al., 2007; Blasina et al., 2008). Various clinical experiments using inhibitors of CHK1 and CHK2 as anti-tumor forces are held, Along with geno toxi forces together with gemcitabine, irinotecan, and cisplatin attacking various tumor subsets are presently under process. Collectively, these researches further support the power of CHK kinases inhibitors to cultivate the effectiveness of conventional chemo and radio therapy and boost up tumor destruction and cytotoxicity in a subset of cancers.

Recent studies have also suggested that checkpoint inhibitor is implemented as a vital method motivating radio resistance in cancer cells. One of the harmful human malignancies is glioblastma but its ailment is restricted due to radio resistance present in the subset of cancer cells. Noticeably the radio resistance of glioblastma cells can be inverted by adding particular Chk1 and Chk2 inhibitors (debromohymenialdisine; Bao et al., 2006), stressing on the potential of activation of CHK responses to beat the responses of tumor cells to radiotherapy.

Almost 50% of the human cancerous diseases contain the somatic mutation in the protein 53 gene and the inactivation of such protein is a vital phase during the process of tumorigenesis (Hoolstein et al., 1991).The reactivation and the function of mutated p53 in the cancer cells would be the highest achievement in the molecular based therapy. Efforts to use the p53 element as a chemotherapeutic target have focused on those sources and agents that can reactivate the function of p53 in tumors and that is due to the fact that there is a huge reduction of p53 in 50% of the cancer containing cells. (Vazques et al., 2008).

Presently there are two scientifically proven mechanisms that are causing an increase in the activity of p53 in tumors. These two main mechanisms are as follows:

1.

The primary mechanism includes the restoration of the wild-type functionality of protein 53 with the help of the process of recombinant adenovirus encoding p53. {Advexin, phase I-III clinical trials (Vousden and Lu, 2002)}; and the Gendicine, which was approved for further use in China and SCH 58500, phase I-III clinical trials (Snyder et al., 2004). The restoration of the tumor suppressor process of p53 mutant can also transpire by the utilization of the minisucule compounds (CP-31398 and PRIMA-1) or the short peptides {CDB3 and peptide 46 (Vazquez et al., 2008)}. As a result of the inadequate bio-availability of these small compounds, many problems have surfaced in their expansion. Though these elemental studies were encouraging but the mechanism of rescue by these small compounds is not clear-cut and is still unknown. Their therapeutic potential is limited to rescue as a result of the confined range of p53 mutants.

2.

The secondary mechanism includes the process of the stabilization of p53 with the help of small molecules that aim towards the active interplay between p53 and MDM2 (the E3 ligase is primarily accountable towards the ubiquitindependent degradation of p53). This involves the production of various elements such as nutlins, benzodiazepines, RITA, spiro-oxindoles, and quinolinols. These all outcomes take place at the preclinical development phases (Vazquez et al., 2008). In human cancer the mismanagement of the p53 gene is due to the Symbolic over-expression of MDM2 (Bond et al., 2005). This over-expression results in the embargo of p53 functionality and decreases its cohesion. This happens because MDM2 is a negative regulator of p53 and results in the alteration of the sub-cellular localization of such protein and its activities.

In the adjustment of the pathways and in the activation of the cell cycle checkpoints, DSB is very important. MRN complex is actually a main and the key component of the DSB. This complex is a very important component for the treatments of cancer. The deficiencies in the Mre11 and NBS1 which are the components of MRN complex can result in the origination of the radiosensitive human genomic instability syndromes (Girard et al., 2000). Results from the laboratory revealed that the use of a small peptide encompassing the evolutionary conserved region of NBS1, which is attached to ATM causes to rattle the synergy between ATM and NBS1. (Cariveau et al., 2007). It is also found that this peptide also helped in restricting those activities which were causing DNA damage signaling and radiosensitized the cells. This indicates that it is a necessary requirement in order to make a successful anticancer drug by targeting the NBS1:ATM interaction.

The forward genetic screen labeled as Mirin is used to analyze the distinguishing inhibitor complex of MRN. As shown by the most recent studies, Mirin plays a very vital role to prevent the MRN-reliant ATM activation and to abrogate the endonuclease activity of Mre11 component. The resultant aftereffect caused by the Mirin-dependent MRN inhibition is actually the reason for the avoidance of the HR recovery and G2/Mcheckpoint activation (Dupre et al., 2008).In the manifestation of the antitumor activity in xenograft models, a lot of research and study still needs to be effectively concluded.

To protect the cells from the tumor formation with the help of DSB repairing ability, Rad51 is an important necessity. After the formation of the tumor, Rad51 can also result in the advancement of resistance of the tumors to chemotheraphy (Christodoulopoulos et al., 1999; Henning et al., 2003). As shown by the studies, the tumor cells could stimulate the chemotherapy agents such as cisplatin by reducing the levels of Rad51 via antisense RNA and RNAi (Ohnishi et al., 1998; Collis et al., 2001).Thus it concludes that Rad51 is a promising target for the drugs to treat the tumor. To examine the inhibitory effect on the Rad51 activity in the recent studies, the short peptides containing the Rad51 interacting domain of the BRCA2 protein were used. (Ito et al., 2005) To bind the Rad51 and to restrict the DNA binding activities, a peptide of 28 cm acids was found. It especially restricts the formation of Rad51 nuclear foci and the development of the HR in the cells of Humans.

The further enhancements in the study and research of peptidomimics can create a tremendous effect in the development of the antitumor drugs by targeting the problematic components like Rad51 and HR in tumor. To rebuild various types of the damaged DNAs along with the DSBs, the single-stranded DNA binding plays a very crucial role and it is also vital to many of the different processes in which the ssDNA is exposed like DNA replication.

Two very simple types of SSBs were recently discovered named as hSSB1 and hSSB2 which helps in the rectification of the old concept which suggests that RPA is the only SSB involved in the process of repairing the DNA (Richard et al., 2009; Richard et al., 2008). In the DNA damage repair and replication, the cellular functionality of hSSB1 and RPA plays a very vital role and is best for the advanced cancer therapeutic target. Important chemicals were needed to be identified to inhibit the interaction of RPA with DNA by the examination and study. By utilizing the fluorescent-based reporter assay they have found many different inhibitory chemicals encompassing therapeutic potential (Andrews and Turchi, 2004). The modern drug discovery program that focuses on the ways to discover the potential therapeutic inhibitors also rely on the component of hSSB1 and its effective functionality.

The effective cancer treatment can take place by targeting HR and cell cycle checkpoint activation but it has also been proven that by targeting the pathways of NHEJ can also cause a positive impact on the treatment of cancer. Chemotherapeutic agents and DSBs induced by IR encounters sensitivity by the deficiency in Ku 70/80 or the catalytic subunit of DNA-PK (DNA-PKcs), (Lees-Miller et al., 1995; Ouyang et al., 1997). It thus concludes that DNA-PK may establish a good target for chemotherapy. In some cancers DNA-PK is upregulated which presents it as an important component for the growth and survival of the tumor. This activity of upregulation of DNA-PK was determined to hinder the apoptosis in B-cell chronic lymphocytic leukemia (Deriano et al., 2005).

To broad-spectrum the PIKK inhibitors wortmannin and LY294002, the initial investigations were carried out into the inhibition of DNA-PK.(Rosenzweig et al., 1997).For the development of more specific DNA-PK inhibitors, such as nonselective inhibitors were also represented to sensitize tumor cells to chemotherapeutic agents. Without causing any toxic effect, treatment with a flavone-based DNA-PK inhibitor IC87361 caused the radiosensitization of tumor in vitro and in vivo (Shinohara et al., 2005). A highly powerful and selective DNA-PK inhibitor NU7441 with an IC50 of 13nM was analyzed in a consecutive study (Zhao et al., 2006).The utilization of this powerful and effective agent caused the radiosensitivity and chemosensitivity of the tumor cell lines and resulted in the creation of xenograft models in the preclinical trials. Presently there are many other agents under the clinical trials that targets DNA-PK. (Martin et al., 2008).

It has been recently identified that HR is actually very important for DNA repair in the absence of Poly (ADP-ribose) polymerase (PARP-1) for the treatment of cancer. When the ssDNA breaks, it is readily repaired by the PARP-1 that is a member of the base excision pathway and its inhibition can result in the accumulation of the single strand breaks that converts themselves to DSBs during the process of replication. With a loss of BRCA1 and BRCA2, the prevention of PARP has proved to be synthetically lethal (Bryant et al., 2005; Farmer et al., 2005). The extreme decline in the survival and growth of tumor is due to the resulted exposure of BRCA2-deficient murine tumors to PARP-1 inhibitors (KU-0059436/AZD2281) (Hay et al., 2009). This inhibitor is proven to be a low level toxic and is considered to stabilize or deteriorate the chemotherapy-refractory ovarian, breast, or prostate cancers with BRCA1 or BRCA2 mutations. Outside of BRCA1- and BRCA2-defective tumors no particular activity was identified. Recently it was found in a study that AZD2281 inhibited PARP-1 and BRCA1 or BRCA2 mutations in ovarian, breast, or prostate cancers occurred along with the antitumor activity (Fong et al., 2009; Tutt et al., 2009; Audeh et al., 2009).

Inhibitors containing PARP-1 are presently under clinical trials as monotherapy for BRCA1- and BRCA2-deficient cancers affecting the female parts like breasts and ovaries (Martin et al., 2008). In cancer drug development and in the clinical findings, synthetic lethality is introduced as a new concept. This new concept supports the targeting of other relationships of synthetic lethality in DNA damage repair and reactive pathways.

Clinical experience with PARP inhibitors

In clinical trials PARP inhibitors have been examined as a single agent as well as in the combination. As a single agent it focuses on the patients with BRCA mutation and in the combination it acts with the DNA damaging therapies. In the patients of breast and ovarian cancer, the single agent activity was demonstrated by Olaparib along with germline mutations in BRCi (Fong et al., 2009; Audeh et al., 2010; Tutt et al., 2010).The response rate of 40% was specifically reported in those patients who have platinum sensitive disease with BRCA mutant ovarian cancer (Fang et al., 2010).

A demonstration of defected HR pathway is recently reported in half of the 489 analyzed tumors as a result of the research conducted by the Cancer Genome Atlas Research Project on the molecular aberrations in high grade serous ovarian adenocarcinoma (Cancer Genome, 2011). The study shows that those patients might benefit from the treatment with the PARP inhibitors who have sporadic abnormalities in the HR pathway hindering the DNA damage repair. The patients with TNBC and primary peritoneal cancers showed the similar abnormalities in DNA repair pathways. These abnormalities in DNA repair pathways resulted in the clinical trials which has investigated the use of PARP inhibitors in such patients (Gelmon et al., 2011; Dent et al., 2010; Lederman et al., 2011; Sandu et al., 2010).Tumors with microsatellite instability and the similar types of tumor with defects in other DNA repair pathways can also be affected by the inhibition of the BER pathway (Leichman et al., 2010).

The extent and period of the inhabitation has not yet been identified for the optimum clinical benefits regardless of the assessment of PARP inhibition in numerous clinical trials. (Kummar et al., 2009).This study on PARP inhibitor extended the scope of examination and identification that resulted in the discovery of higher PARP inhibitor doses. The results of these trials such as ICEBERG study have proposed the response of the dose for acquiring the clinical benefits from PARP inhibitors (Kaye te al, 2010; Audeh et al., 2010; Tutt et al., 2010).

Conclusions

As far as our understandability, study of the mechanism and the results of biochemical details are concerned, the DNA damage response is increasing and the possibility to maneuver this pathway for the establishment of innovative therapeutics will rise. This research will create a huge influence in the field of medical science in future. The availability of biomarker will ensure the success rate by identifying the patients with the specific checkpoint or DNA repair defects inclusive of the various defects identified in p53, HR, or FA pathways. It will help the patients who should be examined with a new and targeted therapy.

By the development of the tumor biomarkers, the responses will be more predictable to the adequate and targeted cancer treatments along with the cancer therapeutics. Furthermore to identify the more appropriate targets, the examination of the therapeutic and oncogenic impacts of checkpoint and repair inhibitors is guaranteed. The significance of the DSB signaling and repair pathways in radiosensitization and chemo of cancerous cells in the vitro has been perfectly elucidated but the disorder of the DSB response pathway and the correlation between the vivo clinical response to chemo and radiotherapy is yet to be explained.