Essay: Cancer and treatments

1.1 Background
Cancer is not a single disease, it is a pool of several ailments and disorder at the cellular and molecular level, and causes normal cells to act abnormally causing uncontrolled division. The uncontrolled and unchecked growth of the cells some time invades other neighboring tissues and can also spread to another part of the body by different means, such as lymphatic fluid and blood circulation; this is known as metastasis. The program cell death/program cell removal is the main processes by which the damaged cell removed from the body in an organized way. As soon as the cells become old they are destroyed and discarded in a well-programmed way known as apoptosis. Sometimes a mutation in genomic material more specifically hits the genes which are accountable for inhibition of apoptosis. As a result of this excessive cell division and reduced cell death, a mass of tissue is formed which is termed as a tumor. Some tumors are encapsulated and do not spread through the capsule; however, some are not capsulated and easily spread to the surrounding tissue as well as the rest of the body where they divide continuously and form ‘secondary tumors’– a process termed as metastasis. The latter is termed metastatic tumors or secondaries.
The cell in cancer has six distinctive characters as a consequence of an alteration in cell physiology. The important characters of cancerous cells are:
(a) A cancer cell has their own cell growth signals and they also a response to those weak signals which are normally ignored by the healthy cell.
(b) They might have a mechanism, which makes them nonresponding to the anti-proliferative signal.
(c) Cancerous cells are immune to programmed cell death that normally causes abnormal cells to die and be removed by the procedure of apoptosis.
(d) They have the capability for limitless replication.
(e) They have the capacity to initiate new blood vessel formation which can help the tumor growth.
(f) A cancer cell has the capacity by which they can invade tissue locally or any part of the body (Hanahan and Weinberg, 2000).
Cancer Statistics in India (Nandakumar A. 2009), estimated that around 25,00,000 individuals living with cancer in India. Every year about 7,00,000 fresh cancer patients are registered in India and cancer adds 5,56,400 deaths every year. Metastatic tumors can arise in any part of the body at any age, but around 71% of deaths due to cancer are in the age group between 30-69 years (Dikshit R, et al; 2012). According to the figures of national cancer registry program, around 50 % of all metastatic tumors related deaths in India are due to cancers of the oral cavity and lung cancer in males and breast and cervix cancer in females. Early stage detection and management could decrease the death rate related to different type of cancers (Sarnath D, Khanna A; 2014). Although, important advances in medical technologies for cancer diagnosis and management, it is perhaps the most advanced and complex disease and it bids a big challenge to the oncologists and researchers for treating this disease. One of the very important treatment strategies of cancer is chemotherapy, a treatment using anticancer drugs. It can be offered alone and also in conjugation with other medical approaches like radiation therapy and surgery. Nowadays, an enormous group of chemotherapeutic drugs is available as a result of extensive research in cancer treatment. Among which, cisplatin is considered to be a powerful chemotherapeutic agent extensively used in the handling of various solid tumors. This cytostatic agent has been in clinical use for three decades in the handling of a wide spectrum of tumors. This platinum-containing medicine act and kills cells primarily by inhibiting DNA synthesis and chromosomal damaging (Basu and Krishnamurthy 2010). The cancer inhibition property of cisplatin is assumed due to cisplatin and chromosomal interaction. (Liu et al. 2013). Upon treatment, it increases reactive oxygen species (ROS) formation and thereby causes an abnormal change in the redox status of cancer cells. Apoptosis in cisplatin-treated cells is accomplished by changes in ROS levels, changes in redox status, DNA damage, change in membrane potential in mitochondrial and involvement of signaling pathways. Cisplatin-induced DNA damaging and oxidative stresses remain the core source of apoptotic pathways in the cancerous cell. Various cisplatin-induced signals can trigger individual pathway through precise transcription factors that act as the crucial drug targets. Signaling pathways that control apoptosis have an important effect on critical cellular sensitivity to cisplatin (Torigoe et al. 2005; Kelland 2007). Even though its benefits, the cisplatin treatment is compromised due to, different toxicities, and immunosuppression. These three factors (cisplatin resistance, immunosuppression, and toxicity) remain to be the major obstacle to successful chemotherapy, but cisplatin is still used with curative intention, mainly for the management of various malignancies such as ovarian, testicular, head and neck, bladder, esophageal and lung cancer. Therefore, exploring alternative therapeutic medicine is required to reduce drug toxicity and provide immunomodulation in cisplatin treatment. Many new approaches have been established to reduce the appearance or the expansion of cancers through chemo-sensitization and chemo-protection. Co-administration of plant products with good anticancer activities would help in fixing the problem of cisplatin-host toxicity, and immunosuppression. Since the main target for cisplatin in the cell is believed to be chromosome and DNA, an enhanced cytoprotective effect is expected from a new combination of cisplatin with an herbal product which protects the cell from the damaging side effects of it (Marcu et al. 2003). In the recent past, herbs and herbal product are emerging as potential candidates among, alternative medicine which can act as immunomodulatory and chemoprotective against various induced toxicities and they are very cost effective.
1.2.1 Cause of cancer
There are two main classes of genes that play a chief role in normal cell cycle. The proto-oncogenes, which stimulate the growth of the cancer cell, and the tumor suppressor genes which inhibit the growth and expansion of the cancer cells. In the typical cell, both the genes coordinate and prevent unnecessary cell division. A transformation in tumor suppressor genes fails to regulate the cell division, whereas, an alteration in proto-oncogene starts excessive cell division; as a result of non-coordination between these genes a tumor may form. The mutations of these two genes along with a mutation in DNA repair genes play a substantial role in tumorigenesis (Lewin, 2004). The various molecules at the cellular level have a substantial role in inhibition of cell division such as, protein 53 (p53), pBR and intracellular controller of the cell division cycle (cdc), cycle cyclin-dependent kinases (cdk), have also shown its important role in cell replication and cancer formation (Meijer et al., 1997). When these inhibitors are genetically transformed by any factors, they cause cancer. Some molecules are sometimes transformed by carcinogens, such as radiation, infectious agents, tobacco, and certain chemicals. Generally, cancer of the lung is originated by the action of chemical constitutes in tobacco smoke. Polycyclic aromatic hydrocarbons (PAH) and Nitrosamines are the primary carcinogens in tobacco, besides fifty other identified carcinogens in it.
Ultraviolet (UV) long time exposure causes melanoma and other categories of cancers associated with the skin.
1.2.2 Mechanism of Cancer Development:
The human body has a well-established mechanism to control the cell and eliminate them when required. Any aberration in this system starts accumulating abnormal cell in the body which turned into cancer. The error in this mechanism leads to the damages in one or many genes in the cell causes genetic instability. Because of these genetic instabilities, the cell cannot regulate cell division, resulting in cancer, if the cells are not eliminated by the immune system. Cancer cells divide much faster rate than the typical cells, due to continuous cell division a pile of cell start accumulating in nearby cells forming a mass of tissue which is later known as a tumor. Histopathologically, cancer is characterized by many morphological changes, such as tissue architecture, cytological irregularities in the nucleus and cytoplasm and the incidence of unusual mitoses. The multiplying tissues in the body are vulnerable to the formation of cancer, there is a great challenge in cancer prevention and its cure.
Figure 1. The mechanism of cancer formation. There are many mutations necessary to arise in the DNA of an individual cell for cancer to develop. The tissues possibly will develop mutations in their ordinary cell (light blue), that allow the normal cell to grow faster. These mutated cells (light green) are not benign tumor cells yet, they must have another phase of mutation to form tumor cell. The genetic variability causes the mutated cells to grow rapidly and developed rapidly growing tumor cell (Dark blue). The untreated tumor cell developed a mutation which in turn cause the development of the malignant cell (dark red) or will spread to other organs through the bloodstream causes metastasis ( pale red).
1.3.1 Treatment of cancer
Due to the advancement of medical science along with biomedical research, now most of the cancers can be treated and some can be cured if detected early. Various approaches for the treatment of cancer are readily available these days, such as surgery (Liatsikos et al., 2012), immunotherapy (Rosenberg, 1986), hormonal therapy (Byar and Corle, 1988), chemotherapy (Blackburn, 1991) and radiation therapy (Pazdur, 2001). Treatment of malignancy is subject to the specific character of the malignancy, their location in the body. The surgical approaches are used in solid tumors along with the chemotherapy and radiotherapy, while chemotherapy alone is used in various types of cancers, including blood cancer etc. Certain agents are used for inhibiting the cancer growth and development in human population termed as chemotherapeutic agents (Blackburn, 1991; Pezzuto, 1997; Mann, 2002). Chemotherapy plays a noticeable role in the management of cancer treatment, Solid tumor, and localized tumors can be removed by surgical procedures but the treatment of metastatic tumors needs a well-established chemotherapy (Minko et al., 2004). Cells in cancer are very heterogenic and did not have any specific character. They are genetically unstable and have high mutation rates in them; hence different chemotherapeutic chemicals are in clinical use for management of cancer. To kill a cancerous cell with different genotypes, a combination of anti-cancerous agents are frequently used to target and kill these cancerous cells (Searcey, 2004).
1.3.2 Harmful effects of chemotherapy.
Side-effects remain the main drawback in chemotherapy, medicine can induce severe and sometimes lethal side-effects (Fennelly, 1995). Depend upon the characters and type of the malignant cell, a different type of drugs are chosen to target the cancer cell (Minko et al., 1999; Steeghs et al., 2007; Alder and Dimitrov, 2012). Numerous anti-neoplastic medicines are established to target highly multiplying cancer cells (Amin and Mousa, 2007). Anti-cancerous drugs also kill normal dividing cells along with the cancerous cell, such as hair follicles, gastrointestinal cells and blood cells (Rudolph et al., 1999). For this reason, we need a dose that can kill the cancerous cell, at the same time, lower the possibility of affecting normal cells and have limited side-effects. Many chemotherapeutic anticancer agents which are used by an oncologist in their clinical practice including mitoxantrone, 5-fluorouracil, indomethacin paclitaxel, vinblastine, etoposide, vincristine, camptothecin, carboplatin, cisplatin etc. However, these chemotherapeutic agents are linked with diverse kinds of adverse effects. There is a constant requirement for the development of the novel drugs which target the specific cells (Torchilin, 2000). Simultaneously, to improve drug therapy, drug transport systems can adjust routes of administration, bio-distribution, and removal of therapeutic candidate. Cisplatin is a unique, extremely effective chemotherapeutic drug known, and soon after its discovery and it showed its effectiveness in clinical trials, cisplatin had a key impact in cancer management.
1.4 Cisplatin
A new class of drug purely metal-based anticancer agent used to treat different types of cancer most commonly known as cisplatin (CDDP) or Cis-diammine-di-chloroplatinum(II). Cisplatin is commonly used against different types of cancers, such as ovarian, lungs, cancer of bladder, esophageal, colon, gastric, breast, testicular, melanoma, prostate cancer. Cisplatin is a platinum drug which is administrated intravenously with normal saline for the handling of several solid tumors. In platinum (II) based drugs cisplatin was the first platinum-based agent and after cisplatin, many more platinum-based chemotherapeutic agents have been in clinical use, such as carboplatin. The platinum compound has a square planar coordination in which Pt(II) is in the center and enclosed by two ammonia and two chloride ions. It has two isomers: trans- and cisplatin (CDDP) on the bases of confirmation of atoms around the platinum. The cisplatin is active complex having two ammonia and chlorine atoms in a cis location, and have a great anticancer activity. In platinum-based chemotherapy, Cisplatin (cis-diamminedichloroplatinum (II)) is one of the highly used antineoplastic chemotherapeutic drugs. It made a covalent bond between DNA, which resulted in platinum- DNA adducts (Jamieson and Lippard, 1999; Boulikas and Vougiouka, 2003). Michele Peyrone in 1845 characterized and synthesized cisplatin first time (Kauffman, 2010), and known as Peyrone’s salt thereafter. In 1893, Alfred Werner was the first person who proposed its configuration as square planar and differentiates between trans and cis isomers. In 1965, a researcher, Barnett Rosenberg produced a soluble complex which suppressed binary fission in E.coli, cell replication was stopped and cell uninterruptedly grows, bacteria developed as filaments up to 300 times their typical length (Rosenberg et al., 1965). Cis isomer was the main drug, which resulted in the filamentous growth of Escherichia coli cells. It was concluded by Rosenberg in his study that, the Pt(II) was effectively reducing the mass of sarcomas in rats, and shows its medical application as an effective antitumor agent in cancer management (Rosenberg et al., 1967). Many clinical trials of cisplatin were approved and carry out, as a consequence of these findings cisplatin emerges as highly effective broad spectrum natural antitumor agent against induced secondary tumor (Kociba et al., 1970).
Figure 2. Structure of cisplatin (cis-diamminedichloroplatinum (II))
Clinical studies show, that the cisplatin has a good anticancer activity in cancer of ovary (Wiltshaw and Carr, 1974) and testicular cancer (Hanna, N., & Einhorn, L. H., 2014).
In 1978, cisplatin approved by FDA, the USA as an anticancer agent. It shows good cancer management and inhibition in human malignancies including cervical (Robova, at al., 2010) cancer of bladder (Griffiths et al., 2011), and lungs cancer (Qin et al., 2012, Johnson, 2004).
1.4.1 Cisplatin biochemical mechanisms
Shortly after the administration of cisplatin to the patients, suggested that it entered the cell by passive diffusion.
Figure 3: Image shows the passive transportation of cisplatin through the cell membrane.
Cisplatin transported via carrier-mediated passage into the cell, as an active transportation. Na+K + -ATPase and others could assist the entry of cisplatin into the cytoplasm of the cell (Hall et al., 2008). The recent research works suggested the direct link between cellular copper and platinum (Nitiss, 2002; Sinani et al., 2007). Defect in the Ctr1 gene of copper transporter-1 (CTR1) in plasma membrane decrease cisplatin accumulation in yeast (Ishida et al., 2002; Safaei and Howell, 2005). The cisplatin maybe enters the cell by active influx through transporters along with passive diffusion, thus when reacting with water in an aqueous solution one or both the chloride ions in cisplatin exchanged by water, produced an “aquo” species [ (H20 2)/+ + Cl – ]. In an alkaline environment it may produce monochloro -monohydroxy platinum species [Pt(NH3) 2Ch + OH ~ Pt(NH3)2CI(OH) + Cl ]. For this reason, cisplatin is used with Isotonic and hypertonic saline solutions, high chloride ion concentrations in these fluids help to keep a larger amount of cisplatin as Pt(NH3) 2Cl. Human plasma has a good concentration of chloride ions which provide stability to cisplatin, chloride concentration decreased sharply when cisplatin cross the lipid membrane, and this promotes chloride ligands hydrolysis. As soon after the drug entered into the cytoplasm the platinum value increases to 42% which was 2% when it is in the plasma. The aquatic species then react with a range of intracellular components (Pinto and Lippard, 1985; Chu, 1994; Go and Adjei, 1999).
Figure 4. Active transportation of cisplatin through CTR 1, the formation of “aquo” species when reacted with water in an aqueous solution one or both the chloride ions in cisplatin replaced by water and formation of Cisplatin-DNA adduct.
Only 5-10% of cisplatin covalently bound with DNA in cell-cisplatin-association. In DNA fractions cell-associated cisplatin is found, the binding of cisplatin to proteins and other cellular constituents compromised 75-85% (Hrubisko et al. 1993). Soon entering to cytoplasm cisplatin reacts with the nucleophilic sites in the cell such as thiol-containing peptides, proteins, RNA, and cytoskeletal microfilaments, and (Jordan and Carmo-Fonseca, 2000). The antitumor action is due to the cisplatin- DNA adduct, formed due to the binding of cisplatin to nuclear of genomic DNA (Gonzalez et al., 2001). Cisplatin-DNA adducts may block the replication and prevent transcription in malignant cells ( Zhu et al., 2012). Cisplatin reacts with DNA and formed cisplatin-DNA adducts, the inter and intrastrand DNA crosslink suggested the central mechanism underlying its cytotoxic effect lead to apoptosis and cancer inhibition (Florea and Busselberg, 2011).
1.4.2 Cisplatin-induced toxicities
Despite its efficiency as an anticancer agent, it has lots of side effects in cancer patients (Siddik, 2003; Barabas et al., 2008). Due to its severe side effect, clinical use of cisplatin is restricted. Being nephrotoxic it can cause damage to Kidney. Cisplatin nephrotoxicity augmented with increasing time and a dose (Madias and Harrington, 1978). Main side effects include impaired renal function (revealed by raises in BUN, creatinine, and serum uric acid levels) along with myelosuppression, neurotoxicity, ototoxicity, hepatotoxicity etc. The significant variations were observed in hepatic metabolism when administrated with cisplatin at LD50. There was a rise in the activity of transaminases and alkaline phosphatase in serum, with an increase in lipid peroxidation and accumulation of malondialdehydes; also there was a change in the composition of phospholipids. (Vetoshkina and Dubskaia, 1993) (Dambska et al, 1994). The different dose of cisplatin may produce different toxicities in normal cells. The dose and organ injuries are as follows: Dose of cisplatin at 15mg/body wt causes a change in salivary gland, the dose at 19.5 mg/ body wt causes renal injury and at 19.7 mg/body wt causes damage to bone marrow. In the liver and kidney, there was a major increase in the activity of Ca¬(2+) in nitric oxide synthesis(NOS) during cisplatin treatment in rats. Lipid peroxidation in liver, kidney, and gastric mucosa increased by the action of cisplatin (Srivastava et al, 1996). Oxidative stress continues to play a major role in the initiation of induced toxicity. The cisplatin prompted oxidative stress largely act in the mitochondrion, cause subsequent damage in mitochondrial protein-SH, reduction in the mitochondrial membrane potential by inhibition of calcium uptake (Saad et al., 2004). There is a major need of chemoprevention which reduced toxicities of chemotherapeutic drugs. Herbs and medical plants can perform an imperative role as a cytoprotective medicine/ agent.
1.5 Role of herbs
In the present world, maximum population depends upon herbal medicine as their primary healer. Traditional medicine plays a decisive role in controlling of numerous diseases and disorder. Traditional medicinal physicians are practicing herbal medicine for generations and as a result of their therapeutic experience herbal medicine emerge as an alternative medical system. Plants have many active phyto constitutes used as a healer in many diseases and provide relief from pain (Okigbo et al. 2008). In many parts of the globe, the knowledge of medicinal plants passes from generation to generation and helps in the development of a traditional system of healing (Kinghorn, 2001). The use of chemical-based pharmaceuticals has led to unexpected side effects such as genetic variations, biomagnifications and even causes death in individuals receiving them.
The use of herbal medicine has several advantages, it is widely available and can be used in raw form, or as simply prepared formulations. Herbal plants contain minerals, sugar, proteins and other chemicals which interact with another active chemical in many ways, make it easily absorbable and digestible with rarer side effects and they are less toxicity to typical cells and tissues (Jellin et al., 2002). Supporters of traditional herbal medicine feel that medicine is most effective in its natural state which contains all the active ingredients rather than the processed synthetic drug.
1.5.1 Role of the drug as a chemoprotective agent.
Chemoprotective medicine or agents are certain drugs or herbal products that are used as a combination with chemotherapy to provide protection to the body from or reduce the harmful properties of the chemotherapeutical agent. Chemotherapy is one of the most persuasive tools used to battle cancer, but the side effects of the action can be as incapacitating as the disease itself. Many chemotherapeutic drugs targets cell replica mechanisms, which harm vital cells that also are in the procedure of cell division. Bone marrow cells, endothelial cells, and other cell types which divide quickly can be unintentionally killed by these therapies, the primary side effects include immunosuppression, nausea, hepatotoxicity and genetic instability. Chemoprotective agents are administered along with chemotherapeutic agents, which provides protection to vital cells from chemotherapy drugs, without interfering with the effectiveness of drugs. Since chemotherapeutic agents are regularly given concurrently and in cycles, several chemoprotective agents may be injected at just the once as well, and continue to be administered during each chemotherapy cycle. These treatments do not eliminate side effects. Rather, they protect the body from severe side effects.
1.5.2 Helicteres isora.
The botanical name of Marodphali is Helicteres isora, under the Sterculiaceae family. Helicteres isora is a member of a big genus comprised of tropical trees and shrubs, it has many medicinal properties and it is widely used in many diseases. The fruit of Helicteres isora more apparently looks like a screw and due to its screw-like appearance, it is commonly described as Enthani. In the different region, it is described with different names.
Table 1. Name of Helicteres isora in different languages.
Languages Name
Hindi Enthani, Gomathi, Marodphali, Marorphali,
Sanskrit Avartani, Murva, Avartaphala.
Marathi Kewad
Gujarat Maradashinghi
Tamil Balampari
Telugu Guvadarra
Kannada Pedamuri
Malayalam Ishwarmuri
Oriya Murmuriya
English East India screw tree
Table 2. The scientific classification of Marodphali (H. isora)
Division
Angiosperm
Class
Dicotyledon
Subclass
Archichlamydeae
Order
Malvales
Family
Sterculiaceae
Genus
Helicteres
Species
isora
1.5.3. Occurrence and distribution.
The plant is abundantly found in many parts of India namely in Jammu and Kashmir, and in some areas of Bengal, Assam, Gujrat and in the Andaman Islands. It occurs as undergrowth, especially as a secondary growth in forests. In some places as in the Siwalik tract in U.P., it forms dense, almost impassable thickets wrapper large areas. It is also distributed in Malaya, Philippines, Australia and West Indies (CSIR publications, 1969.).
1.5.4. Description.
It is a sub-deciduous bush found all over the world attaining a maximum height of 500 cm. There are dispersed stellate hairs on new branches making them rough. The leaves are a notch, ovate, soon acuminate and rough above and pubescent beneath. The flowers are sparse clusters or solitary with red reflexed petals. The fruits are greenish-brown in color and beaked and cylindrical with some spirally twisted carpels. The seeds are tubercle. In many medical formulations and in numerous herbal medicines fruits, seeds, bark, and roots of the plant are used. April to December is the flowering time depends on the geographical area and the fruiting from October to June.
1.5.5. Medicinal properties.
The root juice of Helicteres isora is claimed to be useful in diabetes, empyema, and provide protection in snake bite (Singh et al, 1984, Kirtikar and Basu, 1995). The roots and bark are anti-inflammatory, expectorant and are helpful in diabetes, scabies, gastropathy (Prajapati et al, 2003). The Helicteres isora fruit has a refrigerant effect, they are astringent and helpful in gripping of bowels (Chopra et al, 1956) and antispasmodic (Pohocha and Grampurohit, 2001 ). G. Kumar, et al in 2008, submitted that there was a major escalation in body weight, hexokinase activity and reduction in ACP, ALP, LDH, and glucose-6-phosphatase when injected with Helicteres isora bark extract in streptozotocin (STZ) diabetic rats orally. He concluded that Helicteres isora shows antidiabetic and hepatoprotective activity rats (G. Kumar, et al; 2008). In another study, the H. isora was reported to possess antihyperglycemic activity in alloxan-induced diabetic rats, while no such effect was observed in normal rats (Venkatesh et al, 2002).
Previous studies indicated that the plant Helicteres isora have not been pharmacologically evaluated so far for immunomodulatory and cytoprotective activity in contradiction of cisplatin-induced toxicity. In the light of therapeutic entitlements in favor of Helicteres isora and on the foundation of its traditional uses and scientific evidence, the present study was proposed to estimate the immunomodulatory and cytoprotective effect of Helicteres isora against cisplatin-induced cytotoxicity.
2.1. Introduction.
In today’s world, there is an increase in the numbers of cancer incidence and cancer-related deaths are reduced. In last few 50 years, the information about cancer, its prognosis, and management of disease significantly enhanced. Cancer sometimes a genetic instability in which some genes are mutated that control proliferation, differentiation, and death of cells. Cancer or malignant neoplasia, it is described as a disease of abnormal and uncontrolled cells. The normal cell converted into the malignant state through a mechanism recognized as carcinogens. It is a complicated, multistep process and a few normal cells are generated, which increased with increase in mutation and change in the pattern of expression of genes. The combination of many factors, such as chemical, physical, biological and genetic factors involved in the cancer formation (Minamoto et al. 1999). There are numerous known treatments of cancer and chemotherapy is among them.
2.2. Chemotherapy.
The practice of chemical agents to target the rapidly growing cell and in the management of cancer is known as chemotherapy. It destroys cancer cell in the body in an effective way, kills all malignant cells, which broken off from the primary tumor and shown their appearance in different portions of the body by lymph and blood circulation. Chemotherapy some time used alone and sometimes required conjugation with other therapy such as surgery and radiation for different types of cancer (Reichardt et al. 2003). Combinations of diverse chemotherapeutic agents are required to fight non-specific cancer. Certain chemotherapeutic agents are given in precise order depending on the category of cancer (Brennan et al. 1991). Chemotherapeutic agents are very effective in the handling of cancer, but they did not distinguish among normal and malignant cell causes many adverse side effects during treatment.
2.3. History of Chemotherapy.
The use of folic acid antagonist drugs and nitrogen mustards opened a new era of chemotherapy in the 1940s (Papac, R. J., 2001). The development and exploring cancer drug is a multi-crore industry. Since, the discovery of chemotherapy, new therapeutic methods have been established, a combination of chemotherapy using cisplatin with other anticancer agents is more effective than use alone ((Flaherty et al. 1993; Buzaid et al. 1994).
2.4 Cisplatin
Chemotherapy remains a spine in cancer treatment. In a current time lot of research is going on to discover a highly efficient chemotherapeutic agent for a number of different types of cancers. Cisplatin has good chemotherapeutic activities against different types of cancer, such as ovarian, Lung, and testicular cancer, etc. In 1845 the cisplatin compound (cis-[Pt(NH3)2(Cl)2] ) was first defined by Michele Peyrone, after that, it is synonymously recognized as Peyrone’s salt (Nair S. and Grampurohit N.D; 1996). A biophysical chemist in 1965, unintentionally discovered a cancer treatment, his name was Rosenberg. He has evaluated the outcome of electric fields on microorganism growth. He was trying to generate electric fields by using platinum electrodes, his experiment shows a very uncommon result, and the bacteria raised 300 times of their normal size (Rosenberg et al., 1965). He found that platinum electrodes were oxidizing in the test solution as result cisplatin is produced. Rosenberg and his coworkers in 1969, successfully verified in rat and mice that, cisplatin could treat tumors and shows a good antitumor action, against advanced tumors and those tumors, which shows resistant to other medicines (Rosenberg et al., 1969). Barnett Rosenberg and Loretta VanCamp in 1970, during their study, find that the platinum compounds, cis-platinum (IV) diamminotetrachloride, and cis-platinum (II) diamminodichloride, actively inhibiting the cell division and reduced Leukemia L1210 tumors in mice and small solid tumors.The platinum complexes were also shown 63 % to 100% antitumor activity in large solid Sarcoma in the animals, with no apparent permanent damage to the host, in different dose (Rosenberg and Loretta VanCamp 1970).
The structure of cisplatin was discovered by Alfred Werner in 1983 (Satake, T; 1999). At normal temperature and pressure, cisplatin remain stable, with the passage of time it is slowly transformed to trans- isomer which slowly losses its anticancer property. In saline solution at 1mg/ml cisplatin remain stable. It is a platinum-containing drug which is administrated intravenously for the handling of numerous solid tumors and metastasis ( Dasari, S., & Tchounwou, P. B., 2014). Platinum-based complexes characterized by a unique type of DNA-damaging cytostatic agents (Kostova, 2006). In clinical practice, cisplatin may cause certain toxicities in bodies such as Hepatotoxicity, nephrotoxicity, and Ototoxicity (Preston RJ et al 1987)
Table 3. Cisplatin.
Common name : Cisplatin, cisplatinum, or cis –diammine dichloro platinum (II) (CDDP)
IUPAC name : (SP-4-2)-diamminedichloridoplatinum
Structural name : cis – Diamminedichloroplatinum
Trade names : Platinol and Platinol-AQ
Molecular weight : 300.01
Molecular formula : Cl2H6N2Pt or (NH3 )2PtCl2
Colour : Deep yellow
Solid State/Form : Solid
2.4.1 Structure of cisplatin
Cisplatin is an independent, square planer coordination complex. In cisplatin, a core
Platinum atom is surrounded by two ammonia and two chlorine ions in the cis-
configuration.
[Cis- dichlorodiammine platinum (II)]
Figure 5. Structure of cisplatin
The cis position, the dissociable groups, and the complex being neutral are features of significance in cisplatin anticancer activity (Harrap, 1983). In 1971, cisplatin, the platinum coordinate complex was first time introduced as a new type of highly active broad-spectrum antitumor agent. After the discovery of cisplatin as a cytostatic agent, the development made in clinical and basic research has been transformed into an effective and more accurate medical therapy for numerous types of cancers and tumors. Many results indicated that cisplatin a platinum compound successfully cured the patients with testicular cancer with 100% cure rate and around 80% of the patients with progressive cancers can be cured (Einhorn, 1981). It has appeared as an important cytostatic drug in the treatment of numerous types of tumors and cancers. (Dentino e t a l 1978; Burchenal, 1978; Sarna and Sodhi, 1978; Burchenal et al., 1979; Loehrer and Einhorn, 1984; Ozols et al., 1985; Muggia, 1991; Prasad and Giri, 1994; Koberle e ta l., 1997).
2.4.2 Mechanism of cisplatin action
The cisplatin has a capacity to form covalent adducts with various cellular molecules, there are several indications to recommend that, its primary target is DNA repair. (Roberts and Pera Jr, 1983; Rosenberg, 1985; Zamble and Lippard, 1995). Cisplatin has the capacity to form a variety of DNA adducts in nucleus (Koberle et a l ., 1999; Zamble and Lippard, 1995), the most predominant about 90% of that’s the 1 2 intrastrand crosslink. The N7 positions of adjacent purine bases are a site for the formation of a covalent bond with the platinum. The DNA is relaxed and bent in the direction of the main groove in the 1, 2-intrastrand crosslink (figure 5.).
Figure 5. Cisplatin linkage with DNA
Scanning tunneling electron microscopic image of DNA revealed an intense structural perturbation of DNA by complex platinum with the typical curvature of the double helix of DNA (Zastawny et al., 1993). Many of the researchers suggested that the inhibition of DNA polymerases and RNA polymerases by these adducts is important to link in the cytotoxicity of cisplatin, but the fact is that trans isomer of cisplatin can also bind DNA and block replication (Brown, et al., 1993). Ali-Osman reported that higher level of DNA polymerase p (Pol P) and DNA ligase activity was associated with an increase in DNA repair (Ali-Osman et al., 1994). Although the DNA polymerase action of NER was initially recognized by Pol P, it is now supposed for accountable for other polymerases (Sancar, 1994). It was recently described that this polymerase is the solitary one that will proficiently bypass a cisplatin 1, 2-d (GPG) intrastrand crosslink, suggesting that increased expression of this protein will accelerate replicative bypass (Hoffman et al., 1995). Above mentions findings advocate that platinum adducts contribute as recognition elements for high mobility group (HMG) domain proteins and there is a big role of other factors. An understanding of the mode and manner of cisplatin action is unquestionably required in refining therapeutic methodologies that further boost the antitumor activity of the platinum drug. The understanding of the nature of the action is also critical for revealing mechanisms essential in drug-resistant phenotype, which drastically limits the clinical value of cisplatin. The ovarian cancer is an admirable example, which shows the limitation, which normally responds well to cisplatin-based treatment. It was revealed that the preliminary response rate of cisplatin was up to 70% is not long-lasting and only 15–20% in 5-year patient survival rate was shown in the results, mainly due to resistant developed in tumors by cisplatin therapy (Perez, et al., 1991). In another example, with small cell lung cancer, the drop rate can be as high as 95% (Giaccone, 2000) It is unquestionably a demonstration of the better sensitivity of platinum drugs on resistant cell, for example ZD0473 and oxaliplatin ((Kelland et al., 1999, Faivre et al., 1999) may reflect activating of autonomous pathways. The practice of such kind of agents in comparative research may demonstrate to be valuable for exploring cisplatin resistance mechanism. Cell death or cell survival will depend on the comparative strength of the signals produced and the crosstalk among the pathways involved.
Figure 7. Mechanisms involved in preventing the apoptotic signal (systematic cell death) in cisplatin-resistant tumor cells. Many mechanisms are usually observed in resistant cells, and this contributes to the multifactorial nature of cisplatin resistance image source Zahid H Siddik.,2003 nature journal
The DNA damage-repair mechanism plays a very fundamental role in the molecular mechanism in the drug action. Low-level repair observed in both the inter- and intrastrand crosslinks occurred more rapidly on vigorously transcribed genes (Jones el al., 1993). Huang in 1994, the cell deficient in DNA repair shown higher toxicity of cisplatin when compared to other cells (Huang el al,1994). J C Huang, D B Zamble and their colleagues in 1994 proposed that, DNA adduct made by the cisplatin, 1,2-intrastrand d(GpG) cross-link, and as well as the minor 1,3-intrastrand d(GpTpG) adduct, were both 1,2- and 1,3- intrastrand crosslinks are repaired by nucleotide excision repair (NER) pathway (Huang el al., 1994). Hanawalt in the same year also discovered that the NER pathway is closely connected to transcription (Hanawalt et al., 1994).
2.4.4 Cisplatin in Cell cycle checkpoints
A lot of the literature shown that DNA damaged due to the cisplatin involved in numbers of pathways. The leading pathway in cisplatin-induced DNA damage is stimulation of cell cycle checkpoints, which temporally promote a transient S-phase arrest. After the temporary inhibition of S-phase durable G2/M arrest caused by the inhibition of the Cdc2-cyclin A or B kinase (Shi et al., 1994; He et al., 2001; Shapiro and Harper, 1999). Meanwhile, the inhibitory outcome of DNA-cisplatin adducts on the G1-phase cyclin-dependent kinases (CDKs) is a next event in the categorization of checkpoint stimulation (He et al., 2001), and possibly enabled by the Cdk4 inhibitor (Shapiro et al., 1998). Most of the cell remains stuck in G2/ M and it is uncommon to the accumulation of cell in G 1 phase. Cell cycle halt and cytotoxicity association is complex and not completely interpreted. ( Zahid H Siddik;2003) If whatever, cell cycle arrest is due to the inhibitory cytotoxic process, which is an end that derives mainly from the demonstration that pharmacological revoke of the G2/M checkpoint rises due to cisplatin sensitivity in the cell (Demarcq et al., 1994; O’Connor and Fan, 1996). As a result, this is reliable with the idea that cell cycle arrest, as a generally accepted consequence of DNA damage and is essential to allow the nucleotide excision repair (NER) complex to eliminate the adducts and stimulate cell survival. Cells go through apoptosis only in that circumstance where there is high damage and repair is incomplete in that cell. Interesting p53 protein is collectively associated with DNA repair, checkpoint activation and apoptosis (Bullock and Fersht, 2001; Morgan and Kastan, 1997).
The basic aim of chemotherapy is to start apoptosis in tumor cells by exposure to antitumor agents. Cisplatin is a precise and effective inducer of apoptosis(systematic cell death) (Ormerod et al., 1996; Henkels and Turchi, 1997), but some tumor cells be unsuccessful to suffer apoptosis at clinically significant concentrations of chemotherapeutic agent due to the resistance acquired through continuing drug exposure or it can present itself as a fundamental phenomenon. It is challenging to describe the exact level of cisplatin resistance in patients but at least a double resistance is inferred from scientific studies, primarily responses have been detected when the typical medical dose of cisplatin is increased two times in drug-intensive treatment procedures (Ozols et al.,1984, 1988; Schilder and Ozols, 1992).
2.4.5 Cisplatin-induced toxicities.
The chemotherapeutic use of Cisplatin in cancer and tumor treatment has been connected with a number of toxic side effects, comprising nephrotoxicity (de Jongh, van Veen et al., 2003), hepatotoxicity and Cardiotoxicity (Al-Majed, 2006). Many cardiac actions have been reported in numerous case reports, including electrocardiographic changes, myocarditis, cardiomyopathy, arrhythmias, and congestive heart failure (Yousef, Saad, and El-Shennawy, 2009). Due to oxidative stress through the creation of reactive oxygen species (ROS), including antioxidant enzymes and nonenzymatic molecules may cause in a decrease in antioxidant defense, decreased glutathione, are most important alterations in the cisplatin toxicity (Kart, Cigremis et al., 2010).
2.4.6 Cisplatin-induced Hepatotoxicity
Some studies indicated that a high dose of cisplatin may cause hepatotoxicity and oxidative stress is the core reason for cisplatin-induced toxicity which might be due to reduction of reduced glutathione GSH (Al‐Majed, A. A. 2007, Yilmaz, et al., 2004), Cisplatin hepatotoxicity was revealed to be get worse by augmented expression of cytochrome P450-2E1 enzyme (Caro and Cederbaum, 2004). Yilmaz 2005 and Mansour 2006 in their studies reported that the rats treated with cisplatin have a decrease in the amount of antioxidant enzymes and there was a remarkable elevation in the hepatic malonaldehyde (MDA) (Yilmaz, et al., 2005; Mansour, Hafez et al., 2006). The transaminases are cytoplasmic in site and released into the circulation subsequently cellular damage. These are the most sensitive biomarkers directly involved in causing the damage to the cells and toxicity. Hepatotoxicity is marked with an elevation of the level of the hepatic enzyme in serum along with the rise of bilirubin level in impaired liver functions (Iseri, Ercan et al., 2007).
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