Comprehensive Review of Cancer Treatment Approaches and Modalities

This report provides a comprehensive overview of cancer treatment approaches, beginning with an introduction to the disease, its pathophysiology, and the significance of addressing it as a major public health concern. The report details the search strategy employed to gather relevant evidence from various electronic resources and literature, focusing on the modalities for cancer treatment. It then delves into the cellular and molecular mechanisms of cancer, including the cell cycle, genetic alterations, oncogenes, and tumor suppressor genes. The core of the report explores the common treatment methods, including surgery, chemotherapy, and radiation therapy, detailing different surgical techniques such as laser surgery, cryosurgery, and electrosurgery. The report also examines the role of surgery in diagnosis, staging, and treatment, providing a detailed account of different surgical approaches. The report highlights the importance of different treatment modalities and their potential for improving patient outcomes. The report's conclusion emphasizes the importance of staying informed about the latest advances in cancer treatment and the need for personalized treatment plans.

APPROACHES FOR THE TREATMENT OF CANCER
1.0. Introduction
Cancer (malignant tumors or neoplasm) is a generic term for a large group of diseases that can
affect any part of the body. One defining feature of cancer is the rapid creation of abnormal cells
that grow beyond their usual boundaries, and which can then invade adjoining parts of the body
and spread to other organs, the latter process is referred to as metastasizing. Metastases are the
major cause of death from cancer (The point, 2015). It is considered as a major public health
problem worldwide and is the second leading cause of death in the United States; leading cause
of death worldwide, accounting for 8.2 million deaths in 2012 (Cancer, 2015). The most
common causes of cancer death are cancers of lung (1.59 million deaths), liver (745 000 deaths),
stomach (723 000 deaths), colorectal (694 000 deaths), breast (521 000 deaths) and esophageal
cancer (400 000 deaths) (Cancer, 2015). The values reflect the intensity of the disease on the
survival of life of victims and gave an insight to apply an adequate treatment. Therefore, the
focus has been given to review the available modalities of treatment. The present paper describes
the pathophysiology, available treatment modalities along with novel methods and possibilities
to explore for newer modes of treatment.
2.0. Search strategy
The available and popular sources were used to search for the evidences. The sources, diverse
online electronic resources including BNI (British Nursing Index), CINAHL (Cumulative Index
to Nursing and Allied Health Literature), EMBASE (the Excerpta Medica database), Pubmed,
The DARE (Database of Abstracts of Reviews of Effects), HTA (Health Technology Assessment
Database) and NHS (Economic Evaluation Database). In addition, the available text books,
magazines and articles from news papers from library have been searched to find out the relevant
literature on the modalities for the treatment of cancer. The search was made for past 30 years to
collect the relevant sources and link the evidences to the current context. Adequate measures
were made to channel the quest for the pertinent sources. The keywords utilized for the pursuit
incorporate ‘pathophysiology of cancer, treatment of cancer, novel methods for prevention of
cancer, etc. The outcome of the search for the relevant sources has been depicted in subsequent
sections.
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3.0. Cancer Pathology
In the cell cycle, dividing cells undergo one mitosis (M) after another, passing through G1,S
(DNA synthesis phase), and G2 phases. Some cells leave the cycle temporarily, entering a G0
state from which they can be rescued by appropriate mitogenic stimuli. Other cells leave the
cycle permanently, entering terminal differentiation.
Any population of cells can grow in number by any one of three mechanisms including (i)
shortening the length of the cell cycle, (ii) decreasing the rate of cell death and (iii) moving G0
cells into the cell cycle. All three mechanisms operate in normal and abnormal growth. In most
tumors, all three mechanisms are important in determining the growth of the tumor, which is best
characterized by its doubling time. Doubling time of tumors range from as little as 17 days for
Ewing sarcoma to more than 600 days for certain adenocarcinomas of the colon and rectum.
However, the fastest growing tumor is probably Burkitt’s lymphoma, with a mean doubling time
of less than 3 days.
Cancer is a multi-step process in which multiple genetic alterations must occur, usually over a
span of years, to have a cumulative effect on the control of cell differentiation, cell division and
growth. Among human tumors, heritable mutations are an exception. Most alterations are
acquired in somatic life in the form of chromosomal translocations, deletions, inversions,
amplifications or point mutations. Certain oncogenic viruses play important roles in a few human
tumors E.g., human papilloma-virus in cervical cancer and skin tumors.
The application of molecular biological techniques in the field of tumor virology, cytogenetic,
and cell biology led to the discovery of the transforming genes of tumor viruses, the genes
activated at the breakpoints of non-random chromosomal translocations of lymphomas and
leukemia (Carlos and Harlan, 1994). Oncogene products are positive effectors of transformation.
They impose their activity on the cell to elicit the transformed phenotype and can be considered
positive regulators of growth. To the transformed cell, they represent a gain in function. Tumor
suppressor gene products are negative growth regulators and their loss of function results in
expression of the transformed phenotype.
The normally functioning cellular counterparts of the oncogenes, called proto-oncogene are also
important regulators of biological processes. They are localized in different cell compartments,
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are expressed at different stages of the cell cycle, and appear to be involved in the cascade of
events that maintain the ordered procession through the cell cycle.
In addition, the cell cycle is regulated by external mitogens (e.g. growth factors, peptide and
steroid hormones, lymphokines), which activate a process called signal transduction by which
specific signals are transmitted within the cell to the nucleus. The process is also mediated by
non integral membrane associated proteins belonging to the tyrosine kinase, RAS gene families,
and members of the MAPK family. Signals generated by mitogenic stimulation can lead to the
expression of specific genes coding for proteins localized in the nucleus. Certain members of the
nuclear oncogene protein family have been shown to be transactivators of specific RNA
transcripts.
4.0. Types of treatment in practice
The common methods in practice for the treatment of cancer include surgery, chemotherapy, and
radiation therapy. Surgery is often the first treatment option if the tumor can be taken out of the
body. Sometimes only part of the tumor can be removed. Radiation, chemotherapy, or both
might be used to shrink the tumor before or after surgery. Surgery also plays a key role in
diagnosing cancer and finding out how far it may have spread. The details are discussed in
subsequent sections
4.1. Surgery
Surgery is used to prevent, diagnose, stage, and treat cancer. Surgery can also relieve (palliate)
discomfort or problems related to cancer. Sometimes, one surgery can take care of more than one
of these goals. In other cases, different operations may be needed over time. Surgery can be
explored to estimate the intensity of cancer. In most cases, the only way to know if a person has
cancer and what kind of cancer it is by collecting a small piece of tissue and testing it. The
diagnosis is made by looking at cells from the sample with a microscope or by doing other lab
tests on it. The entire procedure is referred as biopsy. Another mode of surgery (staging surgery)
is done to find out how much cancer there is and how far it has spread (Rungruang and
Alexander, 2012). During this surgery, the area around the cancer including lymph nodes and
nearby organs is examined. This is important because it provides information to guide treatment
decisions and predict how people will respond to treatment. The curative or primary surgery is
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usually done when cancer is found in only one part of the body, and it’s likely that all of the
cancer can be removed. In this case, surgery can be the main treatment. It may be used alone or
along with other treatments like chemotherapy or radiation therapy, which can be given before or
after the operation. Another type of surgery, debulking surgery is used to remove some, but not
all, of the cancer for instance ovarian cancer (Schorge et al., 2010). It’s sometimes done when
taking out the entire tumor would cause too much damage to nearby organs or tissues. For
example, it may be used for advanced cancer of the ovary and some lymphomas. In these cases,
the doctor may take out as much of the tumor as possible and then treat what’s left with
radiation, chemotherapy, or other treatments. Palliative surgery is used to treat problems caused
by advanced cancer (Gray and Adnan, 1997); correct a problem that’s causing discomfort or
disability. For example, some cancers in the belly (abdomen) may grow large enough to block
off (obstruct) the intestine. If this happens, surgery can be used to remove the blockage.
Palliative surgery may also be used to treat pain when the pain is hard to control by other means
(Hosoya and Lefor, 2011). Palliative surgery helps ease problems caused by cancer and helps
people feel better, but it’s not done to treat or cure the cancer itself. Supportive surgery is done to
help make it easier for people to get other types of treatment. For example, a vascular access
device such as a Port-A-Cath® or Infusaport® is a thin, flexible tube that can be surgically
placed into a large vein and connected to a small drum-like device that’s placed just under the
skin. A needle is put into the drum of the port to give treatments and draw blood, instead of
putting needles in the hands and arms each time.
Reconstructive surgery is used to improve the way a person looks after major cancer surgery. It’s
also used to restore the function of an organ or body part after surgery. Examples include breast
reconstruction after mastectomy or the use of tissue flaps, bone grafts, or prosthetic (metal or
plastic) materials after surgery for head and neck cancers. Preventive or prophylactic surgery is
done to remove body tissue that’s likely to become cancer-even though there are no signs of
cancer at the time of the surgery. Sometimes an entire organ is removed when a person has a
condition that puts them at very high risk for having cancer there. The surgery is done to reduce
cancer risk and helps prevent the chance of cancer, but it doesn’t guarantee cancer prevention.
For example, some women with a strong family history of breast cancer have an inherited change
in a breast cancer gene (called BRCA1 or BRCA2). Because the risk of breast cancer is very
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high, removing the breasts (prophylactic mastectomy) may be considered. This means the breasts
are removed before cancer is found. .
The advanced surgical techniques can also be utilized to facilitate the surgery of complex cases.
The newer surgical techniques are less invasive, use different types of surgical instruments, and
lead to less pain and shorter recovery times. Some of these techniques as shown below
o Laser surgery utilizing a beam of light energy
o Cryosurgery: Utilizes a liquid nitrogen spray or a very cold probe to freeze and kill
abnormal cells. This technique is sometimes used to treat pre-cancerous conditions, like
those affecting the skin, cervix, and penis. Cryosurgery can also be used to treat some
cancers, like those in the liver and prostate. A scan (like an ultrasound or CT scan) might
be used to guide the probe into the cancer and watch the cells freeze. This limits damage
to nearby healthy tissue.
o Electrosurgery: A high-frequency electrical current can be used to destroy cells. This may
be done for some cancers of the skin and mouth.
o Radiofrequency ablation: In radiofrequency, ablation, or RFA, high-energy radio waves
are sent through a needle to heat and destroy cancer cells. RFA may be used to treat
cancer tumors in the liver, lungs, kidney, and other organs.
o Mohs surgery: Mohs micrographic surgery is also called microscopically controlled
surgery. It’s used to remove certain skin cancers by shaving off one very thin layer at a
time. After each layer is removed, the doctor looks at the tissue with a microscope to
check for cancer cells. This procedure is repeated until all the cells in a layer look normal.
Mohs surgery is used when the extent of the cancer is not known or when as much
healthy tissue as possible needs to be saved, such as when treating skin cancers near the
eye.
o Chemosurgery is an older name for surgery like this and refers to certain drugs that may
be put on the tissue before it’s removed. Mohs surgery does not use chemotherapy drugs.
o Laparoscopic surgery: A laparoscope is a long, thin, flexible tube that can be put through
a small cut to look inside the body. It’s sometimes used to take pieces of tissue to check
for cancer. In recent years, doctors have found that by making small holes and using
special long, thin instruments, the laparoscope can be used without making a large cut.
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This can help reduce blood loss during surgery and pain afterward. It can also shorten
hospital stays and allow people to heal faster. Laparoscopic surgery is used commonly
today for many other operations. Laparoscopic surgery can be used in cancer treatment,
but not for all cancers. Doctors can safely and effectively to use laparoscopic surgeries
for some cancers of the colon, rectum, liver, prostate, uterus, and kidney.
o Thoracoscopic surgery: A thoracoscope is a thin tube with a tiny video camera on the end
that can be put through a small cut into the chest after the lung is collapsed. This allows
the doctor to see inside the chest. Tissue samples of any areas of concern on the lining of
the chest wall can be taken out, fluid can be drained, and small tumors on the surface of
the lung can be removed. This type of surgery leads to less cutting and has even been
used to remove parts of the lung that contain cancer. Studies have shown that for early-
stage lung cancer, results using this approach are much the same as removing part of the
lung through a cut in the side of the chest.
o Robotic surgery: Robotic surgery is a type of laparoscopic (or thoracoscopic) surgery
where the doctor sits at control panel and uses precise robotic arms to control the scope
and other special instruments. The advantages of this type of surgery are largely the same
as laparoscopic and thoracoscopic surgery: it can help reduce blood loss during surgery
and pain afterward. It can also shorten hospital stays and let people to heal faster. Robotic
surgery is sometimes used to treat cancers of the colon, prostate, and uterus. It has also
been cleared for use by the FDA in operating on other body systems. It’s not yet clear if
robotic surgery leads to better long-term results than operations where the surgeon holds
the instruments directly.
o Other forms of surgery: Doctors are always looking for new ways to remove or destroy
cancer cells. Some of these methods are blurring the line between what we commonly
think of as surgery and other forms of treatment. Researchers are testing many new
techniques, like using high-intensity focused ultrasound, microwaves, and even high-
powered magnets to try to get rid of unwanted tissue. These techniques are promising, but
still largely experimental. As doctors have learned how to better control the energy waves
used in radiation therapy, some newer radiation techniques that work almost as well as
surgery have been found. By using radiation sources from different angles, stereotactic
radiation therapy delivers a large precise radiation dose to a small tumor area. The
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process is so exact that this is sometimes called stereotactic surgery, even though no cut
is actually made. In fact, the machines used to deliver this treatment have names like
Gamma Knife® and CyberKnife®, but no knife is involved. The brain is the most
common site that can be treated using this technique, but it’s also used on some head,
neck, lung, spine, and other tumors.
4.2. Chemotherapy
The term chemotherapy refers to the use of drugs to kill cancer cells. Usually, the drugs are
given into a vein or they’re taken by mouth. Chemo drugs travel through the body in the
bloodstream, reaching cancer cells that may have spread (metastasized) from the tumor to other
places in the body. The chemotherapy is used to cure, control and palliation of cancer (Howie
and Jeffrey, 2013). Either single or multiple drugs are indicated for cancer chemotherapy.
Different drugs that work in different ways can work together to kill more cancer cells. This can
also help lower the chance that the cancer may become resistant to any one chemo drug. Chemo
may be used to shrink a tumor before surgery or radiation therapy. Chemo used in this way is
called neoadjuvant therapy. It may be used after surgery or radiation therapy to help kill any
remaining cancer cells. Chemo used in this way is called adjuvant therapy. It may be used with
other treatments if your cancer comes back. However certain factors prevailing in the use of
drugs that include the type of cancer, the stage of the cancer, the patient’s age, the patient’s
overall health, other serious health problems (such as heart, liver, or kidney diseases) and types
of cancer treatments given in the past. The chemotherapy is associated with diverse side effects
that include, short-term side effects of chemo can include nausea and vomiting, loss of appetite,
hair loss, and mouth sores. Because chemo can damage the blood-producing cells of the bone
marrow, patients may have low blood cell counts. Low blood counts can cause certain side
effects, such as higher risk of infection (from a shortage of white blood cells), serious bleeding or
bruising after cuts or injuries (from a shortage of blood platelets), extreme tiredness or fatigue
(sometimes from low red blood cell counts), cancer care teams carefully watch for and manage
chemo side effects. Because everyone’s body is different, people notice different effects from
chemo. Most chemo side effects go away after treatment ends. For instance, hair lost during
treatment nearly always grows back after treatment. In the meantime, most patients are able to
use wigs, scarves, or hats to cover, warm, or protect their heads.
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4.3. Radiation therapy
The mode of therapy utilizes high-energy rays (like x-rays) to kill cancer cells and shrink tumors.
The radiation may come from outside the body (external radiation) or from radioactive materials
put right into the tumor (internal or implant radiation). Getting external radiation is much like
getting an x-ray. The radiation itself is painless, but tissue damage may cause side effects.
Radiation therapy is one of the most common treatments for cancer. It uses high-energy particles
or waves, such as x-rays, gamma rays, electron beams, or protons, to destroy or damage cancer
cells. Other names for radiation therapy are radiotherapy, irradiation, or x-ray therapy. Radiation
can be given alone or used with other treatments, such as surgery or chemotherapy. In fact,
certain drugs are known to be radio sensitizers. This means they can actually make the cancer
cells more sensitive to radiation, which helps the radiation to better kill cancer cells. There are
also different ways to give radiation. Sometimes a patient gets more than one type of radiation
treatment for the same cancer. Radiation therapy uses special equipment to send high doses of
radiation to the cancer cells. Most cells in the body grow and divide to form new cells. But,
cancer cells grow and divide faster than many of the normal cells around them. Radiation works
by making small breaks in the DNA inside cells. These breaks keep cancer cells from growing
and dividing, and often cause them to die. Nearby normal cells can also be affected by radiation,
but most recover and go back to working the way they should. Unlike chemotherapy, which
exposes the whole body to cancer-fighting drugs, in most cases, radiation therapy is a local
treatment. It’s aimed at and affects only the part of the body being treated. The goal of radiation
treatment is to damage cancer cells, with as little harm as possible to nearby healthy cells. Some
treatments use radioactive substances that are given in a vein or by mouth. In this case, the
radiation does travel throughout the body. Still, for the most part, the radioactive substance
collects in the area of the tumor, so there’s little effect on the rest of the body.
The long-term side effects of radiation therapy include, damage to victim’s body; radiation can
damage to normal cells, and sometimes this damage can have long-term effects. For instance,
radiation to the chest area may damage the lungs or heart. In some people this might affect a
person’s ability to do things. Radiation to the abdomen (belly) or pelvis can lead to bladder,
bowel, fertility, or sexual problems in some people. Radiation in certain areas can also lead to
fluid build-up and swelling in parts of the body, a problem called lymphedema. A long-term
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problem linked to radiation treatment is the possible increased risk of getting a second cancer
many years later. This is caused by the radiation damage to healthy tissues. The risk of this
happening is small but real.
From the evidences, it can be understood that the link between radiation and cancer was noted
many years ago in studies of atomic bomb survivors, workers exposed to radiation on their jobs,
and patients treated with radiation therapy. For instance, young women who had radiation to the
chest for the treatment of Hodgkin disease were later found to be at increased risk for breast
cancer and some other cancers. Some cases of leukemia are also linked to past radiation
exposure. The risk of leukemia increases within a few years of exposure, peaks about 5 to 9
years after the radiation, and then slowly declines.
Radiation treatments are much like x-rays and are not painful. The most common side effects are
skin irritation and severe tiredness (fatigue). Fatigue is especially common when treatments go
on for several weeks. It’s a feeling of extreme tiredness and low energy, which often does not get
better with rest.
4.4. Miscellaneous modes of treatment
In addition to cited modes of treatment, other kinds of treatment including hormone therapy,
stem cell or bone marrow transplant, immunotherapy, and targeted therapy are in practice.
Hormone therapy is sometimes used to treat certain kinds of prostate and breast cancers.
Immunotherapy is treatment designed to boost the cancer patient’s own immune system to help
fight the cancer. Targeted therapy is treatment that targets the cancer cells and causes less
damage to healthy cells.
4.5. Novel methods of treatment
Rationale: Despite of the diverse modes, there exist an unusual toxic effect of these modes on
individual as the modes show non-selective cytotoxic effect. The type of treatment a person gets
depends on the cancer type and stage (how far the cancer has spread), the age of the patient, and
other medical problems and treatments the person has had. Each drug or treatment plan has
different side effects. It’s hard to predict what side effects will occur, even when patients get the
same treatment. Some effects can be bad and others fairly mild. Some people have a tough time
with cancer treatment, but there are also many who manage quite well and are even able to work
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throughout treatment. Often people diagnosed with cancer have never had any symptoms or pain.
For others, the symptoms have just started and are not too bad yet. But once the treatment starts,
they often begin to feel pretty sick. It’s true that chemo, radiation, and surgery can cause
distressing and sometimes serious side effects. But most of them can be treated and will go away
after treatment ends, and cancer treatment can be life-saving. If cancer is not treated at all,
symptoms tend to become worse and worse. There are times when every cancer patient questions
their commitment to the difficult journey of treatment and its side effects. Sometimes they can
get discouraged by the uncertainty of treatment and wonder if it’s worth it. This is normal. It may
help to remember that every year cancer treatments get more and more effective, and doctors
keep learning better ways to control treatment side effects.
4.5.1. Barriers in Tumor-directed Therapies/Strategies
The success of treating tumors by systemic therapy depends on various characteristics of the
tumor. Besides the importance of intrinsic drug activity and the potential targets within the tumor
cells, drug pharmacokinetics and whole body distribution, site of delivery and the ability of site-
specific targeting (affinity) are important features. In the following sections tumor cell-directed
targeting and intracellular delivery of drugs will be discussed. This includes crucial factors such
as tumor structure and physiology as well as physiological, cellular, molecular, biochemical and
pharmacokinetic barriers. To understand the role barriers, it is required to know in brief about the
structure and physiology of tumor.
4.5.2. Tumor structure and physiology
The successful delivery of cytotoxic agents, either as small molecules or associated with
polymers or liposomes, to a solid tumor depends on the relationship between the tumor cells and
the blood vessels supporting their growth. Therefore the first requirement for effective delivery is
a fully functional vasculature with respect to perfusion function. In solid tumors the criterion of
adequate perfusion is rarely met. Solid tumors comprise of sheets or nests of neoplastic cells
interspersed within a supporting stroma. The stoma component of the tumor is composed of
fibroblasts, inflammatory cells, and blood vessels, and may represent as much as 90% of the
mass of a tumor, depending on the tumor type (Klagsbrun and Moses, 1999). The supporting
stroma plays a critical role, in particular in the formation of new blood vessels in the growth of
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solid tumors. It is not possible for a tumour to grow in excess of 1–2 mm in diameter without
evoking a new blood supply. Neovascularization is necessary for growth of the tumor in order to
maintain the supply of nutrients and to remove the resultant catabolites. This process of new
vessel formation, or angiogenesis, is the result of a complex programme of proteolytic and
migratory events involving the endothelial cell. There is much evidence to support the
observation that this process is mediated by growth factors produced by tumor cells or by
immune competent effector cells infiltrating the tumor parenchyma, or both. As a result of the
intense local angiogenic pressures, the vasculature of many tumors appears abnormal. This
abnormality occurs at the level of the vessel wall itself which is often characterized by an
interrupted endothelium and/or an incomplete basement membrane. Abnormalities of vessel
architecture on a macroscopic scale are also frequently observed. Pre-existing arterioles and
venues inevitably incorporated into the growing tumor mass
There are certain barriers in tumor-directed therapies including physiological barriers with
respect to perfusion, cellular and biochemical barriers (Multi-drug Resistance, P-glycoprotein, P-
gp) and pharmacokinetic barriers with respect to distribution patterns of cytotoxic drugs. The
regularly used modes of treatment either influenced by either one or more of the barratries.
Hence the safety and efficacy with conventional modes of therapy is questionable. Therefore
advanced modes of drug delivery are desired. The advanced and recent modes of treatment are
provided below
o Monoclonal antibodies (MAb) against tumor-associated antigens or growth factors using
their intrinsic activity or used as carriers to target cytotoxic drugs, radionuclide and
toxins
o Pro-drugs in conjunction with enzymes or enzyme-MAb conjugates
o Synthetic copolymers as drug carriers
o Liposomes as carriers for drug delivery
4.5.3. Monoclonal Antibody-mediated Therapeutics
MAbs have been used in a natural, fragmented, chemically modified, or recombinant form in a
variety of settings. They have been coupled to drugs, toxins, enzymes, radio nuclides, cytokines,
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super antigens and drug-filled liposome. As the specificity and availability of the target epitope
expressed by the tumor cells are important determinants tumor-associated antigens for
therapeutic outcome
4.5.4. Immunotoxins (ITs)
ITs are hybrid molecules consisting of MAbs linked to powerful toxins (or toxin subunits)
purified from plants, fungi, or bacteria (Thrush et al., 1996). These toxins inhibit protein
synthesis after internalization, leading to death of the targeted cell. Small quantities of ITs when
compared with unconjugated MAbs, are needed for effective target cell killing. In fact, a single
toxin molecule in the cytosol can kill a target cell, and, unlike chemotherapeutic agents, ITs will
kill both resting and dividing cells E.g., The toxin α-Sarcin obtained from fungi shows inhibitory
activity on ribonuclease for 28 S RNA
4.5.5. Antibody-directed enzyme prodrug therapy (ADEPT)
The approach involves the use of antibody–enzyme conjugates directed against tumor-associated
antigens that achieve in situ activation of subsequently administered pro-drugs (Fig-1). Pro-drugs
are inactive drug precursors that are not readily taken up by cells and hence are less toxic to
healthy cells. The pro-drug can be converted locally in the tumor into the active drug by a
specific enzyme which is covalently linked to tumor-specific antigen-targeted MAbs. When the
active form of the drug is released, it will then distribute to the nearby tumor cells, resulting in
cell death. A number of such pro-drug/MAb–enzyme conjugates have been developed and tested
in vitro and in vivo (Jackson, et al., 1999). E.g., ADEPT comprising of Beta-lactamase as an
enzyme, cephalosporin vinca alkaloid as the pro-drug and desacetylvinblastine hydrazide as the
active form of drug
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