Chapter 2 Review of Literature

2.1 General overview of cancer

Cancer is an intricate interplay of separate genetic and epigenetic irregularities that lead the
advancement of regular cells into invasive cancer cells. Cancer emerges through the production
of hereditary, epigenetic, and alternative cellular alterations in a step-by-step progression of
tumorigenesis whereby cancerous cells obtain boundless proliferation capacity, self-reliance in
growth stimuli, and resilience to ant proliferative and programmed cell death hints (Sugimura).

Every tumour displays distinct permutations of these alterations, as unveiled by complete-

genome sequencing and worldwide examination of epigenetic control (Maherali, Sridharan et al.
2007). Moreover, tumours develop to acquire assistance from neighbouring stromal cells, allure
fresh blood vessels to transport nourishment and oxygen, elude immune recognition, and
ultimately spread to distant organs (Hanahan and Weinberg 2000).

In addition to them, tumour cells also need to overcome various stress conditions such as
metabolic strain, proteotoxic strain, mitotic strain, oxidative strain, and DNA damage strain (Luo
J Fau - Solimini, Solimini Nl Fau - Elledge et al.). Operational interactions among these
circumstances foster the neoplastic state and inhibit cancerous strain. For instance, the
application of glycolysis enables cancer cells to adjust to oxygen deprivation and acidify its
surroundings to elude the immune monitoring. Elevated mitotic strain encourages aneuploidy,
which results in proteotoxic strain that necessitates compensation from the heat shock response
pathway (Hanahan and Weinberg 2011).

Heightened levels of responsive oxygen molecules lead to amplified levels of genetic material
harm that typically triggers ageing or programmed cell death but is surpassed by cancerous cells
(Figure 1) (Masutani and Fujimori 2013). It is comprehended that numerous of these phenotypic
characteristics can be induced by genetic modifications that encompass the acquisition-of-
functional mutation, augmentation, and upregulation of pivotal oncogenes alongside the
deprivation-of-functional mutation, eradication and epigenetic hushing of pivotal tumour
suppressors (Hanahan and Weinberg 2000).

This outcome leads to cancer cells to attain distinct characteristics primarily by reactivating and
altering numerous preexisting cellular processes typically employed during the growth. In

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general, these programmes regulate synchronised processes such as cell growth, movement,
orientation, programmed cell death, and specialization during embryonic development and tissue
equilibrium (Greenman, Stephens et al. 2007).

Collectively, cancer cells thus undergo transformation via fortuitous mutations and epigenetic
modifications that modify these routes, succeeded by the clonal assortment of cells that can
endure and multiply under conditions that would be physiologically detrimental.In spite of
numerous years of systemic drug exploration and advancement of valuable chemotherapeutic
substances (Chabner and Rothenberg 1991)

along with several significant triumphs in the care and control, cancer still persists as one of the
foremost reasons for illness and death with substantial health load globally. Management of
cancer is intricate due to the presence of a diverse range of distinct DNA alterations that trigger
or aid in the development of tumours, alongside the mechanisms through which cells withstand
pharmaceutical interventions. Expanding comprehension of the molecular causation of cancer
implies that approaches that restrict DNA harm and enhance the likelihood of DNA mending by
obstructing abnormal growth will diminish cancer occurrence (Bertram 2000).

Despite numerous diverse methods such as radiation therapy, surgical intervention, hormonal
therapy, and so forth being employed to address cancer, the resemblance between tumours and
regular cells hinders the detection of such tumor-specific objectives. Only a handful of cancer-
specific focused medications are utilised in the medical facility up until now (Qurishi, Hamid et
al. 2011). Cancer is one of the most examined ailments presently, with a substantial quantity of
exploration dedicated to discovering triumphant antineoplastic treatments.

Alterations in the genomes of cancer cells hinder signaling pathways that hold a pivotal role in
cellular growth, propagation, revascularization, viability, programmed cell death, and
dissemination. Stimulation of these signaling pathways results in the increase of a cluster of
transcriptional factors that trigger epithelial to mesenchymal transition in cells (Takebe, Warren
et al. 2011).

Certain signaling pathways are indispensable for embryogenesis, which assumes pivotal
functions in the diversity of tumour advancement and reaction to treatment in a range of human

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malignancies (Schmid, Bieber et al. 2011). Consequently, through exploring the diverse
pathway-oriented methodologies, researchers might potentially elucidate the pathological
foundation of cancer, which will optimistically result in enhanced therapy. These routes are the
focal point which showcases an assortment of aiming the signaling pathways in cancer treatment.

2.2 Epidemiology of cancer

“Cancer is a significant global public health issue. One in 4 demises in the United States is
caused by malignancy. Every year, the American Cancer Society approximates the figures of
novel cancer instances and fatalities anticipated in the United States in the present year and”
assembles the most up-to-date information on cancer occurrence, fatality, and endurance (Siegel,
Naishadham et al. 2013).

In USA over 1.6 million fresh instances of cancer will be identified in 2014 and the most
prevalent cancers are prostate in males and breast in females; lung and colorectal cancers are the
subsequent and third most prevalent cancers in both males and in females. Furthermore,
leukemia additionally contributes to the highest number of cancer fatalities in youngsters,
constituting nearly one-third of cancer-related deaths among males and females aged 0-14 years
(Siegel, Naishadham et al. 2012) (Society 2002).

Table 1 additionally displays the anticipated figures of fatalities transpiring as a result of

malignancy projected for the year 2014. It is approximated that approximately 585,720
“Americans will perish from cancer this year, corresponding to nearly 1600 demises per day.

Tumours of the lung, bronchus, prostate, colorectal in males and tumours of the lung, bronchus,
breast, colorectal in females persist to be the most prevalent origins of cancer demise in 2014.
These” 4 malignancies comprise approximately 50% of the overall cancer fatalities among males
and females (Fig. 2). Moreover, as individuals in developing nations embrace the western way of
life, such as tobacco usage, increased intake of saturated fat and energy-rich meals, and
decreased levels of physical exertion, frequencies of malignancies prevalent in western nations
will escalate if precautionary actions are not extensively implemented. By 2050, the worldwide
cancer load is anticipated to increase to 27 million fresh cancer instances and 17.5 million cancer
demises. In financially advanced nations, the three most frequently diagnosed cancers are

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prostatic, pulmonary, and gastrointestinal among males and mammary, gastrointestinal, and
pulmonary among females. In addition to the regional disparities in overall cancer rates,
disparities based on gender have also been discovered, and the most commonly diagnosed
cancers by gender differ significantly among nations. The most frequently diagnosed malignancy
among males is pulmonary carcinoma in the majority of Eastern Europe and Asia; prostatic
carcinoma in America, Australia, Western and Northern Europe, and hepatic carcinoma in
certain regions of West Africa; sarcoma in central areas of Africa; oesophageal carcinoma in
East Africa; and urinary bladder carcinoma in Egypt.

Table 2.1: Epidemiology of Cancer

Authors Focus Findings

Siegel, Cancer incidence, Over 1.6 million new cancer cases in 2014;
Naishadham et al. mortality, and survival prostate and breast cancers most prevalent in
(2013) in the United States males and females
Siegel, Cancer statistics in the Leukemia contributes to the highest number of
Naishadham et al. United States cancer fatalities in children aged 0-14 years
(2012)
Society (2002) Projected cancer Estimated 585,720 Americans will die from
fatalities for 2014 cancer in 2014; lung, bronchus, prostate, and
colorectal cancers mostcommon causes of death
Various studies Impact of Western Increased cancer incidence due to tobacco use,
lifestyle on cancer high-fat diets, and decreased physical activity;
incidence global cancer burden expected to rise by 2050

2.3 Etiology and mechanisms of carcinogenesis

Tumour advancement is linked with physiological reactions and genetic modifications that have
three crucial outcomes. Firstly, for macroscopic tumour expansion to transpire, sufficient oxygen
provision must be accomplished through the tumour vascularization that arises from heightened
production of angiogenic substances and diminished production of anti-angiogenic substances.

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Furthermore, neoplasm cells adjust “their metabolism to diminished oxygen accessibility by

enhancing glucose transportation and glycolysis to uphold ATP generation despite the decreased
effectiveness of anaerobic metabolism in comparison to oxidative metabolism. Thirdly,
neoplasm cells alter the equilibrium between pro and anti-cell” death elements to foster viability
both under unfavorable ecological circumstances and in reaction to radiation or pharmacotherapy
during therapy (Semenza 2002).

Additionally, a crucial aspect is the pace of cellular proliferation, which is impacted by

hormones, development, cytotoxicity, and inflammation (Ames Bn Fau - Gold, Gold Ls Fau -
Willett et al. ; Ames, Gold et al. 1995).

Table 2.2: Etiology and Mechanisms of Carcinogenesis

Authors Focus Findings

Semenza (2002) Tumor advancement and Tumors require vascularization, altered
physiological reactions metabolism, and balance between pro and
anti-cell death elements for growth
Ames Bn Fau - Gold, Impact of hormones, Cellular proliferation influenced by various
Gold Ls Fau - Willett growth, cytotoxicity, and factors; hormone-dependent tumors
et al. (1995) inflammation affected by hormonal changes

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2.4 DNA Lesions

DNA is incessantly assaulted by responsive entities that can impact its configuration and
operation profoundly. Structural alterations “to DNA primarily arise from modifications in its
bases that mainly occur due to their exposure to diverse reactive species. Receptive oxygen
species (ROS) and Responsive nitrogen species (RNS)” can induce DNA nucleotide alterations,
DNA helix fracture, inter- and intra-helix connections, impairment to tumor-inhibitor genes,
heightened manifestation of protooncogenes and DNA–protein connections (Fig. 2) (Jena 2012).
These architectural alterations are implicated in mutation, carcinoma, and myriad other ailments
(Weitzman and Gordon 1990). Nevertheless, the progression of human malignancy relies on
numerous additional elements, encompassing the magnitude of DNA impairment, antioxidant
safeguards, DNA mending mechanisms, the efficacy of elimination of oxidised nucleosides prior
to their integration into DNA, and the cytotoxic consequences of ROS (reactive oxygen species)
in substantial quantities as well as their growth enhancing affiliations (Wiseman and Halliwell
1996). Truly, these organisms can function at various stages in multiphase carcinogenesis.

Table 2.3: DNA Lesions

Authors Focus Findings

Jena (2012) Impact of reactive ROS and RNS induce DNA alterations, leading
species on DNA to mutations, cancer, and other diseases
Weitzman and DNA damage and repair DNA damage repair mechanisms, antioxidant
Gordon (1990) mechanisms defenses, and ROS effects on carcinogenesis
Wiseman and Reactive oxygen species ROS can act at various stages of carcinogenesis,
Halliwell (1996) in carcinogenesis affecting DNA and promoting cancer
progression

2.5 Impairment in cell cycle checkpoints during tumor genesis

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Appropriate advancement through the cellular cycle is supervised by checkpoints that detect
potential abnormalities during DNA replication and chromosome partitioning. Cellular cycle
detention enables cells to adequately mend these imperfections, consequently obstructing their
transmission to the ensuing progeny cells. The DNA harm checkpoint safeguards cells from the
perpetual assault by the exogenic as well as indigenous genotoxic substances that provoke
various modifications in the DNA structure. These modifications are detected by a signalling
pathway that ultimately results in cyclin dependent kinase (CDK) suppression and cell cycle
cessation (Fig. 2) (Bartek, Lukas et al. 2004). If restoration is ineffective due to extreme DNA
harm or hereditary imperfections in either the checkpoint or the DNA restoration apparatus, cells
may enter senescence or experience apoptosis. In contrast, aggregation of DNA modifications
may cause genetic instability resulting in cellular metamorphosis and tumor genesis (Kastan and
Bartek 2004).

Table 2.4: Impairment in Cell Cycle Checkpoints During Tumor genesis

Authors Focus Findings

Bartek, Lukas Cell cycle checkpoints Cell cycle checkpoints detect abnormalities,
et al. (2004) and DNA damage allowing repair or triggering apoptosis if damage is
irreparable
Kastan and Genetic instability and Accumulation of DNA alterations leads to genetic
Bartek (2004) tumor genesis instability and cancer

2.6 Defense Systems, chronic inflammation and cancer development

The immune system's principal role in mammals is to maintain tissue homeostasis, protect
against invading or infectious microbes, and eliminate damaged cells. Consequently, the
enormous frequency with which cancer develops in humans is astounding. Disruption of the
links between innate and acquired immune cells may occur when tissue balance is continually
disturbed. Excessive tissue remodelling, loss of tissue structure from tissue destruction, protein
and DNA changes from oxidative stress, and an increased risk of cancer can result from harmful

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cycles initiated within tissues when the immune system is not properly engaged or disengaged
(de Visser, Eichten et al. 2006).

It is hypothesised that tumour cells evade immune scrutiny through the mechanisms that
neoplastic microenvironments promote polarised persistent protumorigenic inflammatory states
rather than ones that depict sudden antitumor immune reactions (Balkwill, Charles et al. 2005),
(Zou 2005). Furthermore, aggregations of persistently stimulated myeloid inhibitory cells and
governing T cells are discovered in the bloodstream, lymphatic glands, and malignant tissues.
Collectively, resistant conditions such as these can incapacitate tumor-eradicating CD8+ CTL
(persistent T lymphocyte) reactions and empower conditions of immune favouritism that nurture
cancerous cells to elude antitumor resistance while concurrently capitalizing on stimulated
immune cells that amplify cancer progression (Serafini, De Santo et al. 2004).

Table 2.5: Defense Systems, Chronic Inflammation, and Cancer Development

Authors Focus Findings

de Visser, Immune system's role in Disruption of immune cell connections can lead
Eichten et al. cancer to cancer development due to tissue imbalance
(2006) and remodeling
Balkwill, Immune evasion by Tumors evade immune surveillance by promoting
Charles et al. tumors pro-tumorigenic inflammatory states
(2005)
Zou (2005) Chronic inflammation Persistent inflammation supports tumor
and cancer progression progression and immune evasion
Serafini, De Immune suppression in Accumulation of immune-suppressive cells in
Santo et al. cancer cancer promotes tumor growth and evades
(2004) immune response

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2.7 Involvement matrix metalloproteinase’s in cancer development

Several different investigations conducted by various researchers have consistently documented

and observed a notable increase in the manifestation of matrix metalloproteinase’s (MMPs)
within human malignant tissue. This heightened presence of MMPs has been found to be closely
correlated with an unfavorable prognosis, indicating a potential link between the two. In the field
of biology, it has been observed that matrix metalloproteinase’s (MMPs) play a crucial role in
maintaining the balance of tissues. These MMPs have a wide range of effects on various
biological processes, including the alteration of both soluble and insoluble components of the
extracellular matrix (ECM).

Moreover, they also have an impact on the molecules responsible for cell-to-cell and cell-to-
matrix adhesion. The combined effect of these modifications is the alteration of important By
modifying these intricate mechanisms, matrix metalloproteinase’s (MMPs) also play a
significant role in the development and progression of various pathological circumstances,
including but not limited to rheumatoid arthritis, a chronic autoimmune disorder characterized by
joint inflammation and damage; coronary artery illness, a condition that affects the blood vessels
supplying the heart and can lead to heart attacks and other cardiovascular complications; and
malignancy, a broad term encompassing various types of cancer that arise due to uncontrolled
cell growth and invasion (John and Tuszynski, 2001).

These pathological conditions are complex and multifaceted, involving a multitude of factors and
processes, and the involvement of MMPs adds another layer of complexity to their pathogenesis.
Understanding the intricate interplay between MMPs and these diseases is crucial for developing
targeted therapeutic strategies and improving patient outcomes. In addition to the aforementioned
points, it is worth noting that neoplasm cells, which are abnormal cells that form tumours, are
believed to utilize the matrix disintegrating capacity of these proteases to effectively spread and
metastasize to distant and remote locations within the body. This ability to break down the
extracellular matrix, which is the structural framework that surrounds and supports cells, allows
neoplasm cells to invade nearby tissues and organs, as well as enter the bloodstream or lymphatic
system, ultimately leading to the establishment of secondary tumours in different parts of the
body.

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This process of dissemination is a crucial aspect of the progression and aggressiveness of

neoplastic diseases, as it enables the cancer cells to evade local control mechanisms and establish
a foothold in new environments. By harnessing the proteolytic activity In order to effectively
facilitate the intravasation and extravasations processes of a tumour cell, it becomes necessary
for the collagen-abundant extracellular matrix (ECM) and basement membrane to undergo a
disintegration process.

This disintegration is crucial as it allows for the seamless movement of the tumour cell within
and outside of the blood vessels, enabling it to spread and metastasize to other parts of the body.
By breaking down the collagen-rich ECM and basement membrane, the tumour cell gains the
ability to navigate through the surrounding tissues and penetrate the blood vessel walls,
ultimately leading to its dissemination and the potential formation of secondary tumours. Hence,
the disintegration of these structural components plays a pivotal role in the invasive nature of
tumour cells, allowing them to overcome barriers and establish a foothold in new locations
throughout the body.

Multiple investigations conducted by various researchers and scientists have consistently

demonstrated a strong correlation between elevated concentrations of MMP-2 and MMP-9, two
specific types of matrix metalloproteinase’s, and an increased likelihood of metastasis, the spread
of cancer cells from the primary tumour to other parts of the body.

These findings have been replicated across different studies, providing robust evidence to
support the notion that heightened levels of MMP-2 and MMP-9 play a significant role in
promoting the metastatic process.

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Table 2.6: Involvement of Matrix Metalloproteinase’s in Cancer Development

Authors Focus Findings

John and Role of matrix Elevated MMPs in malignant tissues
Tuszynski metalloproteinase’s (MMPs) in associated with poor prognosis; MMPs play
(2001) tissue balance and disease roles in rheumatoid arthritis, coronary artery
disease, and cancer
Multiple MMPs in tumor spread and Neoplasm cells use MMPs for invasion and
studies metastasis metastasis; MMP-2 and MMP-9 levels
correlate with increased metastasis risk

2.8 Tumor progression: the angiogenic and metastatic cascade

After a growing mass continues to expand, it becomes medically detectable as cancer. But
revascularization is necessary for a neoplasm to grow beyond its initial little size of a non-
vascular tumour (Folkman 1990; Holmgren, O'Reilly as well as others 1995). Crucial to cancer
progression is the tumor's capacity to undergo the angiogenic shift, in which it changes from a
non-angiogenic to an angiogenic phenotype. According to research conducted by Naumov,
Akslen et al. (2006),

tumours with a higher percentage of angiogenic cells are more likely to metastasize and are also
more aggressive from a medical standpoint (Fig. 2). Several factors accelerate the shift to the
angiogenic phenotype. One of them is the increased expression of angiogenic proteins by both
cancer cells and stromal cells. using vascular precursors produced from bone marrow to reduce
the expression of innate angiogenesis suppressors and in certain cancers (Folkman 2007). Ingber
(2009) states that the two leading causes of death in cancer patients are abnormal coagulation
and hemorrhaging, which can be caused by the release of molecules that impact normal
physiologic functions or by the symptomatic, clinically detectable, and potentially fatal growth
of neoplasms that accompany the transition to angiogenesis. Typically, when tumours do not
undergo revascularization, they do not grow larger than a microscopic ball and do not
disseminate. Although most people may survive while tumours are in this dormant condition, if
they become neovascular, they can quickly grow to a deadly size.

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Table 2.7: Tumor Progression: The Angiogenic and Metastatic Cascade

Authors Focus Findings

Folkman (1990); Role of Revascularization is necessary for tumor growth
Holmgren et al. angiogenesis in beyond a microscopic size; angiogenic switch
(1995) tumor growth crucial for cancer progression
Naumov, Akslen et Angiogenic Tumors with a higher percentage of angiogenic
al. (2006) phenotype and cells are more likely to metastasize and are more
metastasis aggressive

2.9 Dietary factors responsible for cancer causation

Present consciousness of the significance of nourishment in the causation of human cancer has
sparked revitalized curiosity for investigating impacts of diet on tumorigenesis. Nutrition can
impact cancer in animals by influencing the commencement or subsequent preneoplastic phase
of tumorigenesis, but it has a diminished impact on tumour expansion. Dietary limitation has a
widespread suppressive effect on tumor genesis. Nutritional fat, conversely, has a tendency to
foster tumor genesis, albeit exclusively specific kinds of tumours, like breast tumours.

Both caloric limitation and nutritional fat seem to operate mainly during the preneoplastic phase
and their impacts on hormone-dependent tumours may be facilitated through alterations in the
hormonal milieu. Nevertheless, numerous organic edibles, particularly fruits and veggies,
encompass significant amounts of compounds that possess chemo preventive capabilities against
the progression of cancer. Such compounds comprise vitamins, trace minerals, and a plethora of
other molecules with ant oxidative characteristics. Several epidemiological and experimental
investigations have demonstrated that vitamin C and E, Alpha-carotene and the vital trace
element selenium can diminish the likelihood of cancer. Vegetables, fruits, legumes, cereals and
green tea have numerous botanical constituents particularly photochemical that safeguard against
DNA harm. Numerous of these compounds obstruct distinct cancer-causing agent routes.

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Table 2.8: Dietary Factors Responsible for Cancer Causation

Authors Focus Findings

Various studies Impact of diet on Nutrition affects cancer initiation and preneoplastic
tumor genesis phase; dietary restrictions suppress tumorigenesis,
while certain fats promote it
Vitamins, trace Chemo Fruits, vegetables, legumes, cereals, and green tea
minerals, preventive contain compounds that protect against DNA
photochemical capabilities damage and cancer

2.10 Other major risk factors

Insufficient physical exertion, which refers to the lack of regular exercise and physical activity,
has been identified as a major factor that significantly contributes to the development of certain
malignancies. This sedentary lifestyle, characterized by a lack of movement and prolonged
periods of sitting or inactivity, has been shown to have detrimental effects on overall health and
well-being. In addition to insufficient physical exertion, another contributing factor to the
development of malignancies is corpulence, commonly known as obesity or being overweight.

The prevalence of obesity has been steadily increasing in recent years, and it is now recognized
as a global health concern One of the primary factors that can significantly contribute to the
development of skin cancer, particularly melanoma, is prolonged exposure to the powerful rays
of the sun. Furthermore, it is important to note that smoking poses a significant risk to one's
health due to its profound oxidative strain on the body. The act of smoking introduces a
multitude of harmful substances into the respiratory system, including a wide range of mutagens
and rodent carcinogens found within the smoke itself. These mutagens and carcinogens have the
potential to cause detrimental effects on the body's cells and genetic material, increasing the risk
of developing various types of cancers. Therefore, it is crucial to be aware of the harmful
consequences associated with smoking and to take proactive measures to avoid or quit this
detrimental habit. One of the harmful components found in cigarette smoke, which primarily
consists of nitrogen oxides, has been identified as oxidizers. These oxidizers have been found to

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deplete the body's natural antioxidants, as highlighted in a study conducted by Fraga, Motchnik,
and colleagues in 1996.

Consuming in toxicating beverages, such as alcoholic drinks, can have detrimental effects on
the human body, particularly on the liver, leading to a multitude of health issues that can range
from mild irritation to severe scarring and even the development of hepatic carcinoma, a type of
liver cancer. Alcohol, a widely consumed beverage, has been extensively studied and found to
have a profound impact on human health. One area where its detrimental effects are particularly
evident is in the development of various types of cancer. Among these, oral and esophageal
carcinoma are known to be significantly influenced by alcohol consumption, as highlighted by
the comprehensive research conducted by Pöschl and Seitz in 2004.

Moreover, emerging evidence suggests that alcohol may also play a role in the development of
colorectal carcinoma, further emphasising the need for a thorough understanding of the
relationship between alcohol and cancer. By delving deeper into the intricate mechanisms
underlying these associations, scientists aim to provide valuable insights that can inform public
health strategies and empower individuals to make informed decisions regarding their alcohol
consumption habits. Persistent infections, which are defined as infections that persist for an
extended period of time without being completely eradicated, have been found to play a
significant role in the development of malignancies worldwide. In fact, studies have shown that
these persistent infections contribute to approximately one-third of all cases of malignancy on a
global scale.

This alarming statistic highlights the profound impact that these infections can have on human
health and underscores the importance of understanding and effectively managing them.
Hepatitis B and C viruses, which are known to cause chronic liver inflammation, have been
identified as major contributors to the development of hepatic carcinoma, as highlighted in a
study conducted by Ocama, Opio, et al. in 2005.

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Table 2.9: Other Major Risk Factors

Authors Focus Findings

Various studies Insufficient physical Lack of exercise and obesity contribute to cancer
activity and obesity development
Fraga, Motchnik Smoking and oxidative Smoking depletes antioxidants and introduces
et al. (1996) stress mutagens and carcinogens, increasing cancer risk
Pöschl and Seitz Alcohol consumption Alcohol consumption linked to oral, esophageal,
(2004) and cancer and possibly colorectal cancers
Ocama, Opio et Persistent infections and Chronic infections like hepatitis B and C viruses
al. (2005) cancer contribute significantly to global cancer
incidence

2.11 Treatment regimes of cancer

The biological objective of cancer prevention is to intercept the mechanisms implicated in cancer
initiation and advancement in order to hinder progression to the invasive phase. However, there
is no straightforward manner to anticipate beforehand which proteins will produce cancer
medication targets, measures such as recent endeavours to comprehend cancer at the systems
level appear to be of importance. Furthermore, a comprehension of the accumulating hereditary
and alternative molecular modifications that typify gradually sophisticated, pre-cancerous lesions
will provide objectives for potential, precautionary interventions. The objective of cancer
treatment is, consequently, to either invert these characteristics or aim at them as tumor-specific
weaknesses, ideally through the combined

utilization of a relatively limited quantity of medications. It is widely comprehended that cancer

cells have extensively reconfigured pathways for proliferation and endurance that underlie the
malignant characteristic.

Therefore, a crucial aspect of effective treatment is the recognition of pivotal, operational hubs in
the cancer-causing web whose suppression will lead to system breakdown, namely, the

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termination of the cancerous condition through programmed cell death, tissue decay, ageing, or
specialization (Luo, Solimini et al. 2009).

Moreover, remedial substances aiming for these junctions must exhibit an adequately extensive
remedial aperture with which to eliminate neoplasm cells while preserving regular cells. To
enhance the focused treatment, it is crucial to comprehend the potential systemic impacts of
aiming at a specific pathway and how suppression of one pathway may affect other pathways in
the aimed cancer cell.

Table 2.10: Treatment Regimes of Cancer

Authors Focus Findings

Luo, Solimini Biological objective Intercepting mechanisms of cancer initiation and
et al. (2009) of cancer prevention progression is crucial; targeting pivotal cancer
pathways for treatment
Various Cancer treatment Effective treatment requires recognizing and targeting
studies strategies operational hubs in cancer pathways, while minimizing
harm to normal cells

2.12 Chemotherapy for the treatment of cancer

In the premature 1900s, the renowned German scientist Paul Ehrlich established the notion
regarding formulating medications to address contagious ailments. He was the individual who
originated the phrase ‘‘chemotherapy’’ and established it as the utilization of chemicals to
address illness (DeVita and Chu 2008).

Flora possess an extensive chronicle of utilization in the management of malignancy. Their

utilization resulted in the exploration of numerous innovative chemotherapeutic categories
exhibiting a variety of cytotoxic capabilities (Table 2). Furthermore, there are a multitude of
approaches in the management of the pharmacological agents employed presently. In general,
chemotherapy is administered with a healing purpose, combined-modality chemotherapy entails
treating a patient with a variety of distinct medications concurrently (Qurishi, Hamid et al. 2011).

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In neoadjuvant chemotherapy of preoperative management, preliminary chemotherapy is

intended to reduce the size of the primary tumour, nevertheless adjuvant chemotherapy in
postoperative care. Palliative chemotherapy is administered without remedial purpose, but
merely to diminish tumour burden and enhance life span. Present chemotherapy protocols
employ medication therapy in cycles (Hirsch 2006; Wagner, Unverzagt et al. 2010).

Over half of all individuals diagnosed with cancer undergo chemotherapy nevertheless;
disadvantages are frequently linked to the utilization of antineoplastic substances, such as
inadequate durability and selectivity and a substantial prevalence of drug-resistant tumour cells.
Partially, these can be surmounted to a certain extent by integrating them into the suitable
pharmaceutical administration systems (Malhotra and Singh 2010).

Unfavorable side and unwelcome consequences of chemotherapy in cancer include harm “to the
epithelial surfaces, swelling, sterility and down regulation of the immune system, which can lead
to lethal infections (Busch 1993). Furthermore, medications that eradicate cancer cells typically
diminish the quantity of platelets in the bloodstream, which may lead to contusions and
hemorrhaging.

Moreover, one of the primary constraints of cancer chemotherapy is the emergence of multidrug
insusceptibility. Due to efflux being a noteworthy contributor for multidrug resistance in cancer
cells, ongoing investigations are focused on obstructing distinct efflux mechanisms like ATP
binding cassette transporters. Management of cancer is additionally intricate due to the reality
that there is such a multitude of distinct sources, triggers, and pathologies that contribute to
heterogeneous tumour formation, as well as mechanisms by which cells” withstand medications
(Deng 2002).

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Table 2.11: Chemotherapy for the Treatment of Cancer

Authors Focus Findings

DeVita and Chu History and concept of Chemotherapy involves using chemicals to
(2008) chemotherapy treat disease; significant history in managing
cancer
Qurishi, Hamid et al. Approaches in Chemotherapy administered with curative,
(2011) chemotherapy neoadjuvant, adjuvant, and palliative
intentions; cycle-based treatment common
Hirsch (2006); Chemotherapy protocols Chemotherapy protocols involve cycles;
Wagner, Unverzagt and challenges challenges include drug resistance and side
et al. (2010) effects
Malhotra and Singh Side effects and drug Chemotherapy often leads to side effects like
(2010) resistance in epithelial damage and immune suppression;
chemotherapy drug resistance is a major challenge

2.13 Role of radiotherapy in cancer treatment

Radiation therapy persists as a significant constituent of cancer management with roughly 50%
of all cancer patients undergoing radiation therapy throughout their disease progression; it plays
a role in 40% of remedial intervention for cancer (Baskar, Lee et al. 2012).

The primary objective of radiation therapy is to deprive cancer cells of their proliferation
capability. Elevated vitality radiation (ionising or particle) harms hereditary substance of cells
and consequently obstructing their capacity to partition and multiply (Jackson and Bartek 2009)
(Table 3). There are two methods to administer radiation to the site of the tumour. Extrinsic
beam radiation is administered from the exterior of the body by directing intense energy beams
towards the site of the neoplasm and is the prevailing method in the medical environment.
Intrinsic irradiation or endobrachytherapy is administered from within the organism by
radioactive substances, enclosed in tubes or kernels directly into the neoplasm location.

This particular treatment method is commonly used in the routine management of gynaecological
and prostate neoplasms, which are types of cancer that affect the reproductive organs.

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Chapter 2 Review of Literature

Additionally, it is also employed in situations where re-treatment is deemed necessary, based on

the observed limited scope consequences of the treatment (DeNittis 2013). Radiotherapy, which
is a highly effective and widely used treatment modality, has been found to have even more
utility when combined with other treatment approaches. In particular, it has been successfully
used in conjunction with alternative modalities such as surgical intervention, cytotoxic therapy,
and immune-based therapy. This means that radiotherapy can be used in combination with these
other treatments to enhance their effectiveness and improve patient outcomes. By utilizing a
multi-moda If radiation therapy is utilized before surgery, also known as neoadjuvant therapy, its
primary goal is to effectively reduce the size of the tumour, thereby improving the chances of a
successful surgical outcome.

If employed as an adjunctive therapy after the operation, radiation treatment will effectively
target and eliminate any remaining minuscule neoplasm cells that may have been inadvertently
left behind during the surgical procedure. In the research study conducted by Baskar, Lee et al.

in 2012, an extensive analysis was performed to compile a comprehensive list of prevalent

malignancies that are commonly treated using radiation therapy. The findings of this study,
which are presented in Table 4, shed light on the various types of cancers that can be effectively
managed through the application of radiation therapy. This valuable information serves as a
valuable resource for healthcare professionals and researchers alike, providing them with a
deeper understanding of the role that radiation therapy plays in the treatment of malignancies.

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Chapter 2 Review of Literature

Table 2.12: Role of Radiotherapy in Cancer Treatment

Authors Focus Findings

Baskar, Lee et Importance of radiation Radiation therapy is significant in cancer treatment,
al. (2012) therapy involved in 50% of cancer cases, contributes to
40% of cancer cures
Jackson and Mechanisms and methods Ionizing radiation damages DNA, inhibiting cell
Bartek (2009) of radiation therapy division; external beam radiation and
brachytherapy are common methods
DeNittis Combination of Radiotherapy combined with surgery, cytotoxic,
(2013) radiotherapy with other and immune-based therapy enhances treatment
treatments effectiveness

2.14 Cancer Immunotherapy

Progress “in cellular and molecular immunology in the previous two decades have granted
immense understandings into the essence and repercussions of connections between tumours and
immune cells proposing approaches through which the immune system could be utilized for
treatment of established malignancies (Prendergast and Jaffee 2007).

Cancer immunotherapy endeavours to utilize the exceptional potency and precision of the
immune system for the management of malignancy (Table 5). Even though cancer cells are less
immunogenic than pathogens, the immune system is evidently capable of identifying and
eradicating tumour cells. Nevertheless, tumours often disrupt the growth and operation of
immune reactions by evading immune assault through a plethora of supplementary mechanisms
of immune inhibition (Blattman and Greenberg 2004).

Among paracrine agents, adenosine, prostaglandin E2, tumour growth factor (TGFβ) and
vascular endothelial growth factor (VEGF) exert numerous direct and indirect
immunosuppressive activities.” These arbitrators may operate in the repression of dendritic cells

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Chapter 2 Review of Literature

(DCs), indirectly restraining T-cell infiltration into the tumour site or directly repressing
effectors T-cell stimulation (Mellman, Coukos et al. 2011).

To conquer the immune suppression phenomenon in cancer cells, one of the initial tactics
utilised was the delivery of enhancers directly into solid tumours to provoke inflammation and
enlist immune executor cells (Yamamoto, Sato et al. 2003).

Nevertheless, numerous tumours thwart this approach ineffectual by generating TGFβ proteins
to hinder initiation of the immune reaction (Gorelik and Flavell 2001). Utilising the curative
chemoattractants and stimulators is still basic, but manifestation of substances such as auxiliary
lymphoid-tissue chemokine or the TNF superfamily constituent BRIGHT in cancer locations has
been demonstrated to transform these surroundings into exceedingly immunogenic formations
(Homey, Müller et al. 2002).

ILLUMINATION is a 29 kilodalton category II transmembrane protein generated by stimulated

T cells that also interacts with the receptor for the lymphotoxin αβ (LTαβ) but does not create
complexes with either LTα or LTβ. IFNα directly restrains tumour cell proliferation, enhances
antigen presenting cell (APC) development, and notwithstanding certain toxicity is currently
employed to manage chosen malignancies in the clinic, like renal cell carcinoma and chronic
myelogenous leukemia (CML) (Marroquin, Westwood et al. 2002).

Systemic delivery of Toll similar receptor (TLR) stimulants or antibodies to CD40 has led to
robust stimulation of DCs and tumour reactions in animal prototypes and is presently being
examined medically (Blattman and Greenberg 2004). Additional perspectives on how to
efficiently regulate APC quantity and operation should result in remedial advantages.

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Chapter 2 Review of Literature

Table 2.13: Cancer Immunotherapy

Authors Focus Findings

Prendergast and Advances in cancer Understanding tumor-immune interactions has
Jaffee (2007) immunotherapy led to approaches utilizing the immune system
for cancer treatment
Blattman and Challenges in cancer Tumors evade immune attacks through
Greenberg (2004) immunotherapy immune suppression mechanisms; enhancing
immune response is crucial for efficacy
Mellman, Coukos Role of paracrine agents in Adenosine, prostaglandin E2, TGFβ, and
et al. (2011) immune suppression VEGF suppress immune response, aiding
tumor evasion
Yamamoto, Sato Enhancing immune Delivery of immune enhancers into tumors to
et al. (2003) response in cancer provoke inflammation and immune cell
recruitment
Gorelik and Tumor suppression of Tumors produce TGFβ to hinder immune
Flavell (2001) immune initiation reaction initiation
Homey, Müller et Transforming tumor Use of chemokines and TNF superfamily
al. (2002) environments into members to enhance immune response in
immunogenic sites tumors
Marroquin, IFNα in cancer therapy IFNα inhibits tumor proliferation and
Westwood et al. enhances APC development, used clinically
(2002) for specific cancers
Blattman and Systemic delivery of Toll-like receptor stimulants and CD40
Greenberg (2004) immune stimulants antibodies activate DCs and tumorresponses,
currently under clinical examination

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