Anticancer Drugs

Mansoura university

Faculty of pharmacy

Dept. of biochemistry

• Nada Mohammed Atta (806)

• Nada Ibrahim Zakaria (807)

• Nada Hassan Ramzy (808)

• Nada Saeed Abd Ellatif (809)

• Nada Tariq Ali (810)

Brief of Cancer

Cancer starts when cells in a part of the body start to grow out of control.

Cancer cell growth is different from normal cell growth. Instead of dying,

cancer cells continue to grow and form new, abnormal cells. Cancer cells

can also invade (grow into) other tissues, something that normal cells can’t

do. Growing out of control and invading other tissues are what makes a

cell a cancer cell.

Brief of Cancer

Cells become cancer cells because of DNA damage. DNA is in every cell and it

directs all its actions. In a normal cell, when DNA is damaged the cell either

repairs the damage or dies. In cancer cells, the damaged DNA is not repaired,

but the cell doesn’t die like it should. Instead, the cell goes on making new

cells that the body doesn’t need. These new cells all have the same damaged

DNA as the first abnormal cell does.

People can inherit abnormal DNA (it’s passed on from their parents), but most

often DNA damage is caused by mistakes that happen while the normal cell is

reproducing or by something in the environment. Sometimes the cause of the

DNA damage may be something obvious like cigarette smoking or sun

exposure.

In most cases, the cancer cells form a tumor. Over time, the tumors can

replace normal tissue, crowd it, or push it aside. Some cancers,

like leukemia, rarely form tumors.

"Drivers" of Cancer

The genetic changes that contribute to cancer tend to affect three main

types of genes…. proto-oncogenes, tumor suppressor genes and DNA repair

genes. These changes are sometimes called “drivers” of cancer.

Proto-oncogenes are involved in normal cell growth and division. However,

when these genes are altered in certain ways or are more active than normal,

they may become cancer-causing genes (or oncogenes), allowing cells to grow

and survive when they should not.

Tumor suppressor genes are also involved in controlling cell growth and

division. Cells with certain alterations in tumor suppressor genes may divide

in an uncontrolled manner.

DNA repair genes are involved in fixing damaged DNA. Cells with mutations in

these genes tend to develop additional mutations in other genes. Together,

these mutations may cause the cells to become cancerous.

How cancer spreads?

Cancer cells often travel to

other parts of the body where

they can grow and form new

tumors. This happens when the

cancer cells get into the body’s

bloodstream or lymph vessels.

The process of cancer spreading

is called metastasis.

What are the different types of cancer

treatment?

Surgery, chemotherapy, and radiation are the most common types of cancer treatment.

Chemotherapy is the use of drugs to kill cancer cells. However, when most people use the word chemotherapy they are referring specifically to drug treatments for cancer that destroy cancer cells by stopping their ability to grow and divide.

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.

Radiation therapy uses 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).

Other kinds of treatment you might hear about include hormone therapy, stem cell or bone marrow transplant, immunotherapy, and targeted therapy. 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.

1. Cytotoxic drugs (Drugs acting directly on

cells)

Alkylating agents

Alkylating agents involve reactions with guanine in DNA. These drugs add methyl or

other alkyl groups onto molecules where they do not belong. This in turn inhibits their

correct utilization by base pairing and causes a miscoding of DNA.

In the first mechanism an alkylating agent attaches alkyl groups to DNA bases. This

alteration results in the DNA being fragmented by repair enzymes in their attempts to

replace the alkylated bases.

A second mechanism by which alkylating agents cause DNA damage is the formation of

cross-bridges, bonds between atoms in the DNA. In this process, two bases are linked

together by an alkylating agent that has two DNA binding sites. Cross-linking prevents

DNA from being separated for synthesis or transcription.

The third mechanism of action of alkylating agents causes the mispairing of the

nucleotides leading to mutations.

Examples of alkylating agents: nitrogen mustards; alkyl sulfonates and triazenes.

Antimetabolites:

Methotrexate

Methotrexate inhibits folic acid reductase which is responsible for the

conversion of folic acid to tetrahydrofolic acid.

Tetrahydrofolic acid itself is synthesized in the cell from folic acid with

the help of an enzyme, folic acid reductase. Methotrexate looks a lot

like folic acid to the enzyme, so it binds to it thinking that it is folic

acid. In fact, methotrexate looks so good to the enzyme that it binds to

it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot

proceed because the coenzymes needed for one-carbon transfer

reactions are not produced from tetrahydrofolic acid because there is

no tetrahydrofolic acid. Again, without DNA, no cell division.

Vinca Alkaloids

Plant alkaloids like vincristine prevent cell division, or mitosis. There

are several phases of mitosis, one of which is the metaphase. During

metaphase, the cell pulls duplicated DNA chromosomes to either side

of the parent cell in structures called "spindles". These spindles

ensure that each new cell gets a full set of DNA. Spindles are

microtubular fibers formed with the help of the protein "tubulin".

Vincristine binds to tubulin, thus preventing the formation of spindles

and cell division.

2. Hormonal drugs

It involves the manipulation of the endocrine system through

exogenous administration of specific hormones, particularly steroid

hormones, or drugs which inhibit the production or activity of such

hormones (hormone antagonists). Because steroid hormones are

powerful drivers of gene expression in certain cancer cells, changing

the levels or activity of certain hormones can cause certain cancers to

cease growing, or even undergo cell death. Examples of drugs altering

hormonal milieu: Estrogen (fosfestrol).

3.Targeted drugs

What are targeted cancer therapies?

Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer.

Most targeted therapies are either small molecules or monoclonal antibodies.

Small-molecule compounds are typically developed for targets that are located inside the cell because such agents are able to enter cells relatively easily. Monoclonal antibodies are relatively large and generally cannot enter cells, so they are used only for targets that are outside cells or on the cell surface.

Targeted therapies differ from standard chemotherapy in several ways: Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells. Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells. Targeted therapies are often cytostatic (that is, they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumor cells).

How are targets for targeted cancer

therapies identified?

The development of targeted therapies requires the identification of good

targets (targets that play a key role in cancer cell growth and survival).

One approach to identify potential targets is to compare the amounts of

individual proteins in cancer cells with those in normal cells. Proteins that are

present in cancer cells but not normal cells or that are more abundant in

cancer cells would be potential targets, especially if they are known to be

involved in cell growth or survival. An example of such a differentially

expressed target is the human epidermal growth factor receptor 2 protein

(HER-2). HER-2 is expressed at high levels on the surface of some cancer cells.

Another approach to identify potential targets is to determine whether cancer

cells produce mutant (altered) proteins that drive cancer progression. For

example, the cell growth signaling protein BRAF is present in an altered form

(known as BRAF V600E) in many melanomas

What are the side effects of targeted

cancer therapies?

Scientists had expected that targeted cancer therapies would be less

toxic than traditional chemotherapy drugs because cancer cells are

more dependent on the targets than are normal cells. However,

targeted cancer therapies can have substantial side effects. The most

common side effects seen with targeted therapies are diarrhea and

liver problems. Other side effects seen with targeted therapies

include: Skin problems, Problems with blood clotting and wound

healing.

Example of targeted cancer therapy

(Angiogenesis Inhibitors)

What is angiogenesis?

Angiogenesis is the formation of new blood vessels. This process

involves the migration, growth, and differentiation of endothelial

cells, which line the inside wall of blood vessels. The process of

angiogenesis is controlled by chemical signals in the body. These

signals can stimulate both the repair of damaged blood vessels and

the formation of new blood vessels. Other chemical signals, called

angiogenesis inhibitors, interfere with blood vessel formation.

Normally, the stimulating and inhibiting effects of these chemical

signals are balanced so that blood vessels form only when and where

they are needed.

Why is angiogenesis important in

cancer?

Angiogenesis plays a critical role in the growth and spread of cancer. A

blood supply is necessary for tumors to grow. Tumors can cause this

blood supply to form by giving off chemical signals that stimulate

angiogenesis. Tumors can also stimulate nearby normal cells to

produce angiogenesis signaling molecules. The resulting new blood

vessels “feed” growing tumors with oxygen and nutrients, allowing

the cancer cells to invade nearby tissue, to move throughout the

body, and to form new colonies of cancer cells, called metastases.

Because tumors cannot grow beyond a certain size or spread without a

blood supply.

How do angiogenesis inhibitors work?

Angiogenesis requires the binding of signaling molecules, such as

vascular endothelial growth factor (VEGF), to receptors on the surface

of normal endothelial cells. When VEGF and other endothelial growth

factors bind to their receptors on endothelial cells, signals within

these cells are initiated that promote the growth and survival of new

blood vessels. Angiogenesis inhibitors interfere with various steps in

this process by binding to receptors on the surface of endothelial cells

or to other proteins in the downstream signaling pathways, blocking

their activities.

Do angiogenesis inhibitors have side

effects?

It can cause complications, such as wound

healing, heart and kidney function, fetal

development, and reproduction. Side effects of

treatment with angiogenesis inhibitors can

include problems with bleeding, clots in the

arteries (with resultant stroke or heart attack),

hypertension, and protein in the urine.

Examples of angiogenesis inhibitors drug

Pazopanib (Votrient) is used to treat kidney cancer and

advanced soft tissue sarcoma. It is a pill taken by mouth.

Bevacizumab (avastin ) a substance called a monoclonal

antibody produced in the laboratory, is used to treat

colorectal canaer , kidney cancer and lung cancer . It is

injected into a vein .

Nanotechnology and Cancer

Nanotechnology is one of the most popular areas of scientific research, especially with regard to medical applications

Once the diagnosis of cancer occurs, there's still the prospect of surgery, chemotherapy or radiation treatment to destroy the cancer. Unfortunately, these treatments can carry serious side effects. Chemotherapy can cause a variety of ailments, including hair loss, digestive problems, nausea, lack of energy and mouth ulcers.

But nanotechnologists think they have an answer for treatment as well, and it comes in the form of targeted drug therapies. If scientists can load their cancer-detecting gold nanoparticles with anticancer drugs, they could attack the cancer exactly where it lives. Such a treatment means fewer side effects and less medication used. Nanoparticles also carry the potential for targeted and time-release drugs.

A potent dose of drugs could be delivered to a specific area but engineered to release over a planned period to ensure maximum effectiveness and the patient's safety.

Gold particle

Drug molecule

tumor

References

Cancer.Net Editorial Board, 07/2014: Angiogenesis and Angiogenesis Inhibitors to Treat Cancer

Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clinical Therapeutics 2006; 28(11):1779–1802. [PubMed Abstract]

Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 2010; 13(1):1–14. [PubMed Abstract]

Cook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA: A Cancer Journal for Clinicians 2010; 60(4):222–243. [PubMed Abstract]

Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nature Reviews Clinical Oncology 2009; 6(8):465–477. [PubMed Abstract]

Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nature Reviews Cancer 2007; 7(6):475–485. [PubMed Abstract]

Siemann DW. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by Tumor-Vascular Disrupting Agents. Cancer Treatment Reviews 2011; 37(1):63–74. [PubMed Abstract]

References

Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in

melanoma with BRAF V600 mutations. New England Journal of Medicine 2012;

367(18):1694-1703. [PubMed Abstract]

Petrelli F, Borgonovo K, Cabiddu M, Lonati V, Barni S. Relationship between skin

rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR

tyrosine kinase inhibitors: A literature-based meta-analysis of 24 trials. Lung

Cancer 2012; 78(1):8-15. [PubMed Abstract]

Cai J, Ma H, Huang F, et al. Correlation of bevacizumab-induced hypertension

and outcomes of metastatic colorectal cancer patients treated with

bevacizumab: a systematic review and meta-analysis. World Journal of Surgical

Oncology 2013; 11:306.[PubMed Abstract]

Gore L, DeGregori J, Porter CC. Targeting developmental pathways in children

with cancer: what price success? Lancet Oncology 2013; 4(2):e70-78.[PubMed

Abstract]

Nanotechnology in cancer: National cancer institute

References

http://nano.cancer.gov/learn/impact/

Hormonal therapy (oncology): Wikipedia

http://en.wikipedia.org/wiki/Hormonal_therapy_(oncology)

Anticancer drugs: slide share

http://www.slideshare.net/avinashchirimalla/anti-cancer-drugs

http://www.slideshare.net/drdhriti/anticancer-drugs-drdhriti?related=1

Charles Ophardt, Professor Emeritus, Elmhurst College; Virtual Chembook: Anti-Cancer Drugs

What is cancer? National cancer institute

http://www.cancer.gov/cancertopics/what-is-cancer

What is cancer? American cancer society

http://www.cancer.org/cancer/cancerbasics/what-is-cancer

How could gold save my life? : Howstuffworks

http://health.howstuffworks.com/medicine/modern-technology/gold-nanotech1.htm