CHE 101 : CHEMISTRY Term Paper Topic : Anti-Cancer Drugs NAME SEC : Vipul Kalia : B1901

REG NO.: 10900153 ROLL NO. : A 03

D.O.A D.O.S : 11/02/2010 : 20/04/2010

Submitted To : Dr. Ashish Kumar

Acknowledgement
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) ii) iii) Genes the DNA type Carcinogens 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) ii) iii) Stop the synthesis of pre DNA molecule building blocks Directly damage the DNA in the nucleus of the cell Effect the synthesis or breakdown of the mitotic spindles 2

7) Some anti-cancer drugs i) ii) iii) iv) v) Methotrexate 5-Fluorouracil Hydroxyurea Merceptopurine 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

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.
4

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

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
6

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.

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 to other 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-cancer drugs. 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 rapidly growing 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.
8

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).
9

Figure showing action of an anti-cancer drug

Some Anti-Cancer Drugs

1) Methotrexate:

10

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-2deoxyuridine. This product acts as an antimetabolite by inhibiting the synthesis of 2deoxythymidine because the carbon - fluorine bond is extremely stable and prevents the
11

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:

12

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 or cis-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.

13

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 equivalent positions, 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
14

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 to prevent 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.

15

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

16