CHE 101 Term Paper

8/2/2019 CHE 101 Term Paper

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CHE 101 : CHEMISTRY

Term Paper

Topic : Anti-Cancer Drugs

NAME : Vipul Kalia

SEC : B1901

REG NO.: 10900153

ROLL NO. : A 03

D.O.A : 11/02/2010

D.O.S : 20/04/2010

Submitted To : Dr. Ashish Kumar


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A cknowledgement

I convey my most heartfelt and sincere gratitude to my respected Chemistry teacher Dr. Ashish

Kumar for his guidance and sincere and dedicated help extended to me in order to achieve my goal

successfully by providing me with adequate information and required inputs, which were of great

help.

I would also like to thank him for providing me technical knowledge in order to complete my

project work successfully.

I would also like to thank dear God who has always inspired and encouraged me.

I also extend my sincere thanks to all those who in their slightest manner helped me in direction of

completing my project successfully.

Contents

1) What is cancer?

2) What causes cancer?

i) Genes the DNA type

ii) Carcinogens

iii) Other medical factors

3) What are the symptoms of cancer?

4) How is cancer diagnosed?

5) What are anti-cancer drugs?

6) Categories of anti-cancer drugs

i) Stop the synthesis of pre DNA molecule building blocks

ii) Directly damage the DNA in the nucleus of the cell

iii) Effect the synthesis or breakdown of the mitotic spindles

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7) Some anti-cancer drugs

i) Methotrexate

ii) 5-Fluorouracil

iii) Hydroxyurea

iv) Merceptopurine

v) Intercalating agents

8) Chemistry of cisplatin

9) Synthesis of cisplatin

10) How cisplatin works?

11) Side-effects of cisplatin

12) How to prevent cancer?

13) References

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What is cancer?

Cancer is a class of diseases characterized by out-of-control cell growth. There are over 100

different types of cancer, and each is classified by the type of cell that is initially affected.

figure showing lump formed due to cancer

Cancer harms the body when damaged cells divide uncontrollably to form lumps or masses of

tissue called tumors (except in the case of leukemia where cancer prohibits normal blood function

by abnormal cell division in the blood stream). Tumors can grow and interfere with the digestive,

nervous, and circulatory systems, and they can release hormones that alter body function. Tumors

that stay in one spot and demonstrate limited growth are generally considered to be benign.

More dangerous, or malignant, tumors form when two things occur:

1. a cancerous cell manages to move throughout the body using the blood or lymph systems,

destroying healthy tissue in a process called invasion

2. that cell manages to divide and grow, making new blood vessels to feed itself in a process

called angiogenesis.

When a tumor successfully spreads to other parts of the body and grows, invading and destroying

other healthy tissues, it is said to have metastasized. This process itself is called metastasis, and the

result is a serious condition that is very difficult to treat.

In 2007, cancer claimed the lives of about 7.6 million people in the world. Physicians and

researchers who specialize in the study, diagnosis, treatment, and prevention of cancer are called

oncologists.

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What causes cancer?

Cancer is ultimately the result of cells that uncontrollably grow and do not die. Normal cells in the

body follow an orderly path of growth, division, and death. Programmed cell death is called

apoptosis, and when this process breaks down, cancer begins to form. Unlike regular cells, cancer

cells do not experience programmatic death and instead continue to grow and divide. This leads to

a mass of abnormal cells that grows out of control.

1) Genes - the DNA type

Cells can experience uncontrolled growth if there are damages or mutations to DNA, and therefore,

damage to the genes involved in cell division. Four key types of gene are responsible for the cell

division process: oncogenes tell cells when to divide, tumor suppressor genes tell cells when not to

divide, suicide genes control apoptosis and tell the cell to kill itself if something goes wrong, and

DNA-repair genes instruct a cell to repair damaged DNA.

Cancer occurs when a cell's gene mutations make the cell unable to correct DNA damage and

unable to commit suicide. Similarly, cancer is a result of mutations that inhibit oncogene and tumor

suppressor gene function, leading to uncontrollable cell growth.

2) Carcinogens

Carcinogens are a class of substances that are directly responsible for damaging DNA, promoting

or aiding cancer. Tobacco, asbestos, arsenic, radiation such as gamma and x-rays, the sun, and

compounds in car exhaust fumes are all examples of carcinogens. When our bodies are exposed to

carcinogens, free radicals are formed that try to steal electrons from other molecules in the body.

Theses free radicals damage cells and affect their ability to function normally.

3) Genes - the family type

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Cancer can be the result of a genetic predisposition that is inherited from family members. It is

possible to be born with certain genetic mutations or a fault in a gene that makes one statistically

more likely to develop cancer later in life.

4) Other medical factors

As we age, there is an increase in the number of possible cancer-causing mutations in our DNA.

This makes age an important risk factor for cancer. Several viruses have also been linked to cancer

such as: human papillomavirus (a cause of cervical cancer), hepatitis B and C (causes of liver

cancer), and Epstein-Barr virus (a cause of some childhood cancers). Human immunodeficiency

virus (HIV) - and anything else that suppresses or weakens the immune system - inhibits the body's

ability to fight infections and increases the chance of developing cancer.

What are the symptoms of cancer?

Cancer symptoms are quite varied and depend on where the cancer is located, where it has spread,

and how big the tumor is. Some cancers can be felt or seen through the skin - a lump on the breast

or testicle can be an indicator of cancer in those locations. Skin cancer (melanoma) is often noted

by a change in a wart or mole on the skin. Some oral cancers present white patches inside the

mouth or white spots on the tongue.

Other cancers have symptoms that are less physically apparent. Some brain tumors tend to present

symptoms early in the disease as they affect important cognitive functions. Pancreas cancers are

usually too small to cause symptoms until they cause pain by pushing against nearby nerves or

interfere with liver function to cause a yellowing of the skin and eyes called jaundice. Symptoms

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also can be created as a tumor grows and pushes against organs and blood vessels. For example,

colon cancers lead to symptoms such as constipation, diarrhea, and changes in stool size. Bladder

or prostate cancers cause changes in bladder function such as more frequent or infrequent

urination.

As cancer cells use the body's energy and interfere with normal hormone function, it is possible to

present symptoms such as fever, fatigue, excessive sweating, anemia, and unexplained weight loss.

However, these symptoms are common in several other maladies as well. For example, coughing

and hoarseness can point to lung or throat cancer as well as several other conditions.

When cancer spreads, or metastasizes, additional symptoms can present themselves in the newly

affected area. Swollen or enlarged lymph nodes are common and likely to be present early. If

cancer spreads to the brain, patients may experience vertigo, headaches, or seizures. Spreading to

the lungs may cause coughing and shortness of breath. In addition, the liver may become enlarged

and cause jaundice and bones can become painful, brittle, and break easily. Symptoms of

metastasis ultimately depend on the location to which the cancer has spread.

How is cancer diagnosed?

Early detection of cancer can greatly improve the odds of successful treatment and survival.

Physicians use information from symptoms and several other procedures to diagnose cancer.

Imaging techniques such as X-rays, CT scans, MRI scans, PET scans, and ultrasound scans are

used regularly in order to detect where a tumor is located and what organs may be affected by it.

Doctors may also conduct an endoscopy, which is a procedure that uses a thin tube with a camera

and light at one end, to look for abnormalities inside the body.

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Extracting cancer cells and looking at them under a microscope is the only absolute way to

diagnose cancer. This procedure is called a biopsy. Other types of molecular diagnostic tests are

frequently employed as well. Physicians will analyze your body's sugars, fats, proteins, and DNA

at the molecular level. For example, cancerous prostate cells release a higher level of a chemical

called PSA (prostate-specific antigen) into the bloodstream that can be detected by a blood test.

Molecular diagnostics, biopsies, and imaging techniques are all used together to diagnose cancer.

After a diagnosis is made, doctors find out how far the cancer has spread and determine the stage

of the cancer. The stage determines which choices will be available for treatment and informs

prognoses. The most common cancer staging method is called the TNM system. T (1-4) indicates

the size and direct extent of the primary tumor, N (0-3) indicates the degree to which the cancer

has spread to nearby lymph nodes, and M (0-1) indicates whether the cancer has metastasized toother organs in the body. A small tumor that has not spread to lymph nodes or distant organs may

be staged as (T1, N0, M0), for example.

TNM descriptions then lead to a simpler categorization of stages, from 0 to 4, where lower

numbers indicate that the cancer has spread less. While most Stage 1 tumors are curable, most

Stage 4 tumors are inoperable or untreatable.

What are Anti-Cancer Drugs?

The drugs which are used to treat a cancer patient or cure cancer are known as Anti-cancerdrugs.

The available anticancer drugs have distinct mechanisms of action which may vary in their effects

on different types of normal and cancer cells. A single "cure" for cancer has proved elusive since

there is not a single type of cancer but as many as 100 different types of cancer. In addition, there

are very few demonstrable biochemical differences between cancerous cells and normal cells. For

this reason the effectiveness of many anticancer drugs is limited by their toxicity to normal rapidlygrowing cells in the intestinal and bone marrow areas. A final problem is that cancerous cells

which are initially suppressed by a specific drug may develop a resistance to that drug. For this

reason cancer chemotherapy may consist of using several drugs in combination for varying lengths

of time.

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Categories of Anti-Cancer Drugs

In general, chemotherapy agents can be divided into three main categories based on their

mechanism of action.

1) Stop the synthesis of pre DNA molecule building blocks:

These agents work in a number of different ways. DNA building blocks are folic acid,

heterocyclic bases, and nucleotides, which are made naturally within cells. All of these

agents work to block some step in the formation of nucleotides or deoxyribonucleotides

(necessary for making DNA). When these steps are blocked, the nucleotides, which are the

building blocks of DNA and RNA, cannot be synthesized. Thus the cells cannot replicate

because they cannot make DNA without the nucleotides.

Examples of drugs in this class include 1) methotrexate (Abitrexate),2) fluorouracil

(Adrucil), 3) hydroxyurea (Hydrea), and 4) mercaptopurine (Purinethol).

2) Directly damage the DNA in the nucleus of the cell:

These agents chemically damage DNA and RNA. They disrupt replication of the DNA and

either totally halt replication or cause the manufacture of nonsense DNA or RNA (i.e. the

new DNA or RNA does not code for anything useful).

Examples of drugs in this class include cisplatin (Platinol) and 7) antibiotics -

daunorubicin (Cerubidine), doxorubicin (Adriamycin), and etoposide (VePesid).

3) Effect the synthesis or breakdown of the mitotic spindles:

Mitotic spindles serve as molecular railroads with "North and South Poles" in the cell when

a cell starts to divide itself into two new cells. These spindles are very important because

they help to split the newly copied DNA such that a copy goes to each of the two new cells

during cell division. These drugs disrupt the formation of these spindles and therefore

interrupt cell division.

Examples of drugs in this class of 8) miotic disrupters include: Vinblastine (Velban),

Vincristine (Oncovin) and Pacitaxel (Taxol).

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Figure showing action of an anti-cancer drug

Some Anti-Cancer Drugs

1) Methotrexate:

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Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid

to tetrahydrofolic acid. At two stages in the biosynthesis of purines (adenine and guanine) and

at one stage in the synthesis of pyrimidines (thymine, cytosine, and uracil), one-carbon transfer

reactions occur which require specific coenzymes synthesized in the cell from 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.

2) 5-Fluorouracil:

5-Fluorouracil (5-FU; Adrucil, Fluorouracil, Efudex, Fluoroplex) is an effective

pyrimidine antimetabolite. Fluorouracil is synthesized into the nucleotide, 5-fluoro-2-

deoxyuridine. This product acts as an antimetabolite by inhibiting the synthesis of 2-

deoxythymidine because the carbon - fluorine bond is extremely stable and prevents the

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addition of a methyl group in the 5-position. The failure to synthesize the thymidine nucleotide

results in little or no production of DNA

Two other similar drugs include: gemcitabine (Gemzar) and arabinosylcytosine (araC). They

all work through similar mechanisms.

3) Hydroxyurea:

Hydroxyurea blocks an enzyme which converts the cytosine nucleotide into the deoxy

derivative. In addition, DNA synthesis is further inhibited because hydroxyurea blocks the

incorporation of the thymidine nucleotide into the DNA strand.

4) Mercaptopurine:

Mercaptopurine, a chemical analog of the purine adenine, inhibits the biosynthesis of adenine

nucleotides by acting as an antimetabolite.

In the body, 6-MP is converted to the corresponding ribonucleotide. 6-MP ribonucleotide is a

potent inhibitor of the conversion of a compound called inosinic acid to adenine Without

adenine, DNA cannot be synthesized.

6-MP also works by being incorporated into nucleic acids as thioguanosine, rendering the

resulting nucleic acids (DNA, RNA) unable to direct proper protein synthesis.

5) Intercalating Agents:

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Intercalating agents wedge between bases along the DNA. The intercalated drug molecules

affect the structure of the DNA, preventing polymerase and other DNA binding proteins from

functioning properly. The result is prevention of DNA synthesis, inhibition of transcription

and induction of mutations.

Examples are cisplatin, carboplatin etc.

Chemistry of Cisplatin

Cisplatin orcis-diamminedichloroplatinum(II) (CDDP) is a platinum based chemotherapy drug

used to treat various types of cancers, including sarcomas, some carcinomas and germ cell tumors.

It was the first member of a class of anti-cancer drugs.

Cisplatin was actually first created in the mid 19th Century and is also known as Peyrone's

chloride. (The disoverer was Michel Peyrone.) It wasn't until the 1960s that scientists started

getting interested in its biological effects, and cisplatin went ito clinical trials for cancer therapy in

1971. By the late 1970s it was already widely used and is still used today despite the many newer

chemotherapy drugs developed over the past decades.

The chemical forumla is Pt(NH3)2Cl2. Molecular weith is 300.045. Cisplatin is soluble in water

and delivered to the body in aqueous form. Cisplatin is administered intravenously as short-term

infusion in physiological saline for treatment of solid malignacies.

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Synthesis of Cisplatin

The synthesis of cisplatin is a classic in inorganic chemistry. Starting from potassium

tetrachloroplatinate(II), K2[PtCl4], the first NH3 ligand is added to any of the four equivalentpositions, but the second NH3 could be added cis or trans to the bound ammine ligand. Because Cl

has a larger trans effect than NH3, the second ammine preferentially substitutes trans to a chloride

ligand, and therefore cis to the original ammine. The trans effect of the halides follows the order I -

>Br->Cl-, therefore the synthesis is conducted using [PtI4]2 to ensure high yield and purity of the

cis isomer, followed by conversion of the PtI2(NH3)2 into PtCl2(NH3)2, as first described by Dhara.

How cisplatin works?

The way that cisplatin operates is by forming a platinum complex inside of a cell which binds to

DNA and cross-links DNA. When DNA is cross-linked in this manner, it causes the cells to

undergo apoptosis, or systematic cell death. One of the methods it uses causes apoptosis through

cross-linking is by damaging the DNA so that the repair mechanisms for DNA are activated, and

once the repair mechanisms are activated and the cells are found to not be salvageable, the death of

those cells is triggered instead.

Side-effects of Cisplatin

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Cisplatin has a number of side-effects that can limit its use:

Nephrotoxicity(kidney damage) is a major concern when cisplatin is given. The dose is

reduced when the patient's creatinine clearance is reduced. Adequate hydration and diuresis

is used to prevent renal damage. The nephrotoxicity of platinum-class drugs seems to be

related to reactive oxygen species and in animal models can be ameliorated by free radical

scavenging agents. This is a dose-limiting toxicity.

Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction studies

before and after treatment.

Nausea and vomiting: cisplatin is one of the most emetogenic chemotherapy agents, but

this is managed with prophylactic antiemetics in combination with corticosteroids.

Ototoxicity (hearing loss): unfortunately there is at present no effective treatment toprevent this side effect, which may be severe. Audiometric analysis may be necessary to

assess the severity of ototoxicity. Other drugs (such as the aminoglycoside antibiotic class)

may also cause ototoxicity, and the administration of this class of antibiotics in patients

receiving cisplatin is generally avoided.

Alopecia (hair loss): this does not generally affect patients treated with cisplatin.

A patent application was filed in December 2009 for the use of a product called CV247 in

combination with Cisplatin. Early tests show that this combination may allow Cisplatin doses to be

reduced by about 80%, thus reducing the impact of dose-related side-effects.

How to prevent cancer?

Cancers that are closely linked to certain behaviors are the easiest to prevent. For example,

choosing not to smoke tobacco or drink alcohol significantly lower the risk of several types of

cancer - most notably lung, throat, mouth, and liver cancer. Even if you are a current tobacco user,

quitting can still greatly reduce your chances of getting cancer.

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Skin cancer can be prevented by staying in the shade, protecting yourself with a hat and shirt when

in the sun, and using sunscreen. Diet is also an important part of cancer prevention since what we

eat has been linked to the disease. Physicians recommend diets that are low in fat and rich in fresh

fruits and vegetables and whole grains.

Certain vaccinations have been associated with the prevention of some cancers. For example, many

women receive a vaccination for the human papilloma virus because of the virus's relationship with

cervical cancer. Hepatitis B vaccines prevent the hepatitis B virus, which can cause liver cancer.

Some cancer prevention is based on systematic screening in order to detect small irregularities or

tumors as early as possible even if there are no clear symptoms present. Breast self-examination,

mammograms, testicular self-examination, and Pap smears are common screening methods for

various cancers.

References

1) http://www.elmhurst.edu/~chm/vchembook/655cancer.html

2) http://www.elmhurst.edu/~chm/vchembook/655cancer2.html

3) http://rex.nci.nih.gov/NCI_Pub_Interface/raterisk/risks64.html

4) http://www.medicalnewstoday.com/info/cancer-oncology/whatiscancer.php

5) Everyones guide to cancer therapy: How Cancer is treated by Malin Dollinger

6) Cancer by H.C Southworth

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http://www.elmhurst.edu/~chm/vchembook/655cancer.htmlhttp://www.elmhurst.edu/~chm/vchembook/655cancer.htmlhttp://www.elmhurst.edu/~chm/vchembook/655cancer2.htmlhttp://www.elmhurst.edu/~chm/vchembook/655cancer2.htmlhttp://rex.nci.nih.gov/NCI_Pub_Interface/raterisk/risks64.htmlhttp://rex.nci.nih.gov/NCI_Pub_Interface/raterisk/risks64.htmlhttp://www.medicalnewstoday.com/info/cancer-oncology/whatiscancer.phphttp://www.elmhurst.edu/~chm/vchembook/655cancer.htmlhttp://www.elmhurst.edu/~chm/vchembook/655cancer2.htmlhttp://rex.nci.nih.gov/NCI_Pub_Interface/raterisk/risks64.htmlhttp://www.medicalnewstoday.com/info/cancer-oncology/whatiscancer.php

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