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LECTURE 11 CANCER: DRUGS, IMMUNOCHEMISTRY and CHEMOCHEMISTRY More Than Pink Walk' raises funds to fight breast cancer – and ... https://www.cancer.gov/sites/g/files/xnrzdm211/files/styles/cgov_article/public/cgov_contextual_image/100/900/3/files/dividing-breast-cancer-cell-article-only.jpg?itok=7_RRcbFU

A dividing breast cancer cell.

Cancer is the name given to a collection of related diseases. In all types of cancer, some of the body’s cells begin to divide without stopping and spread into surrounding tissues.

Cancer can start almost anywhere in the human body, which is made up of trillions of cells. Normally, human cells grow and divide to form new cells as the body needs them. When cells grow old or become damaged, they die, and new cells take their place.

When cancer develops, this orderly process breaks down. As cells become more and more abnormal, old or damaged cells survive when they should die, and new cells form when they are not needed. These extra cells can divide without stopping and may form growths called tumors.

Many cancers form solid tumors, which are masses of tissue. Cancers of the blood, such as leukemia, generally do not form solid tumors.

Cancerous tumors are malignant, which means they can spread into, or invade, nearby tissues. In addition, as these tumors grow, some cancer cells can break off and travel to distant places in the body through the blood or the lymph system and form new tumors far from the original tumor.

Unlike malignant tumors, benign tumors do not spread into, or invade, nearby tissues. Benign tumors can sometimes be quite large, however. When removed, they usually don’t grow back, whereas malignant tumors sometimes do. Unlike most benign tumors elsewhere in the body, benign brain tumors can be life threatening. What are the differences between cancer cells and normal cells? Cancer cells differ from normal cells in many ways that allow them to grow out of control and become invasive. One important difference is that cancer cells are less specialized than normal cells. That is, whereas normal cells mature into very distinct cell types with specific functions, cancer cells do not. This is one reason that, unlike normal cells, cancer cells continue to divide without stopping.

In addition, cancer cells are able to ignore signals that normally tell cells to stop dividing or that begin a process known as programmed cell death, or apoptosis, which the body uses to get rid of unneeded cells.

Cancer cells may be able to influence the normal cells, molecules, and blood vessels that surround and feed a tumor, an area known as the microenvironment. For instance, cancer cells can induce nearby normal cells to form blood vessels that supply tumors with oxygen and nutrients, which they need to grow. These blood vessels also remove waste products from tumors.

Cancer cells are also often able to evade the immune system, a network of organs, tissues, and specialized cells that protects the body from infections and other conditions. Although the immune system normally removes damaged or abnormal cells from the body, some cancer cells are able to “hide” from the immune system.

Tumors can also use the immune system to stay alive and grow. For example, with the help of certain immune system cells that normally prevent a runaway  immune response , cancer cells can actually keep the immune system from killing cancer cells. How does cancer arise? Cancer is caused by changes to genes, the basic physical units of inheritance. Genes are arranged in chromosomes, long strands of tightly packed DNA. Cancer is a genetic disease—that is, it is caused by changes to genes that control the way our cells function, especially how they grow and divide.

Genetic changes that cause cancer can be inherited from our parents. They can also arise during a person’s lifetime as a result of errors that occur as cells divide or because of damage to  DNA  caused by certain environmental exposures. Cancer-causing environmental exposures include substances, such as the chemicals in tobacco smoke, and radiation, such as ultraviolet rays from the sun.

Each person’s cancer is a unique combination of genetic changes. As the cancer continues to grow, additional changes will occur. Even within the same tumor, different cells may have different genetic changes.

In general, cancer cells have more genetic changes, such as  mutations  in DNA, than normal cells. Some of these changes may have nothing to do with the cancer; they may be the result of the cancer, rather than its cause.

https://www.cancer.gov/sites/g/files/xnrzdm211/files/styles/cgov_article/public/cgov_contextual_image/900/300/files/DNA-structure-enlarge.jpg?h=1cb9984c&itok=5X1x6Ow5

Fundamentals of Cancer

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Cancer is a disease caused when cells divide uncontrollably and spread into surrounding tissues.

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Cancer is caused by changes to DNA. Most cancer-causing DNA changes occur in sections of DNA called genes. These changes are also called genetic changes.

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A DNA change can cause genes involved in normal cell growth to become oncogenes, which unlike normal genes, cannot be turned off, hence causing uncontrolled cell growth. Physicians who specialize in treating cancers are called Oncologists.

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 In normal cells, tumor suppressor genes prevent cancer by slowing or stopping cell growth. DNA changes that inactivate tumor suppressor genes can lead to uncontrolled cell growth and cancer.

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Within a tumor, cancer cells are surrounded by a variety of immune cells, fibroblasts, molecules, and blood vessels—what’s known as the tumor microenvironment. Cancer cells can change the microenvironment, which in turn can affect how cancer grows and spreads.

https://www.cancer.gov/sites/g/files/xnrzdm211/files/styles/cgov_article/public/cgov_contextual_image/2019-06/6-how-does-the-immune-system-interact-with-cancer.jpg?h=b48714fe&itok=48vDS3VD

Cells in our immune system can detect and attack cancer cells. But, some cancer cells can avoid detection or thwart an attack. Some cancer treatments help the immune system better detect and kill cancer cells.

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Each person’s cancer has a unique combination of genetic changes. Specific genetic changes may make a person’s cancer more or less likely to respond to certain treatments.

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Genetic changes that cause cancer can be inherited or arise from certain environmental exposures. Genetic changes can also happen because of errors that occur as cells divide.

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Most often, cancer-causing genetic changes accumulate slowly as a person ages, leading to a higher risk of cancer later in life.

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Cancer cells can break away from the original tumor and travel through the blood or lymph system to distant locations in the body, where they exit the vessels to form additional tumors. This is called metastasis.

 

What are "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 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.

Certain mutations commonly occur in many types of cancer. Consequntly, cancers are sometimes characterized by the types of genetic alterations that are believed to be driving them, not just by where they develop in the body and how the cancer cells look under the microscope.

How does cancer spread?

https://www.cancer.gov/sites/g/files/xnrzdm211/files/styles/cgov_article/public/cgov_contextual_image/900/300/files/metastasis-enlarge.jpg?itok=CBtbX_qG ENLARGE

In metastasis, cancer cells break away from where the first formed (primary cancer), travel through the blood or lymph system, and form new tumors (metastatic tumors) in other parts of the body. The metastatic tumor is the same kind of cancer as the primary tumor. A cancer that has spread from the place where it first started to another place in the body is called metastatic cancer. The process by which cancer cells spread to other parts of the body is called metastasis.

Metastatic cancer has the same name and the same type of cancer cells as the original, or primary, cancer. For example, breast cancer that spreads to and forms a metastatic tumor in the lung is metastatic breast cancer, not lung cancer.

Under a microscope, metastatic cancer cells generally look the same as cells of the original cancer. Moreover, metastatic cancer cells and cells of the original cancer usually have some molecular features in common, such as the presence of specific  chromosome  changes.

Treatment may help prolong the lives of some people with metastatic cancer. In general, though, the primary goal of treatments for metastatic cancer is to control the growth of the cancer or to relieve symptoms caused by it. Metastatic tumors can cause severe damage to how the body functions, and most people who die of cancer die of metastatic disease.  

Are there tissue changes that are not cancer?

Not every change in the body’s tissues is cancer. Some tissue changes may develop into cancer if they are not treated, however. Here are some examples of tissue changes that are not cancer but, in some cases, are monitored:

Hyperplasia occurs when cells within a tissue divide faster than normal and extra cells build up, or proliferate. However, the cells and the way the tissue is organized look normal under a microscope. Hyperplasia can be caused by several factors or conditions, including chronic irritation.

Dysplasia is a more serious condition than hyperplasia. In dysplasia, there is also a buildup of extra cells. But the cells look abnormal and there are changes in how the tissue is organized. In general, the more abnormal the cells and tissue look, the greater the chance that cancer will form.

Some types of dysplasia may need to be monitored or treated. An example of dysplasia is an abnormal mole (called a dysplastic nevus) that forms on the skin. A dysplastic nevus can turn into melanoma, although most do not.

An even more serious condition is carcinoma in situ. Although it is sometimes called cancer, carcinoma in situ is not cancer because the abnormal cells do not spread beyond the original tissue. That is, they do not invade nearby tissue the way that cancer cells do. But, because some carcinomas in situ may become cancer, they are usually treated.

Normal cells may become cancer cells. Before cancer cells form in tissues of the body, the cells go through abnormal changes called hyperplasia and dysplasia. In hyperplasia, there is an increase in the number of cells in an organ or tissue that appear normal under a microscope. https://www.cancer.gov/sites/g/files/xnrzdm211/files/styles/cgov_article/public/cgov_contextual_image/900/300/files/hyperplasia-dysplasia-cancer-progression-article.jpg?h=a6a6ac86&itok=PouWV9fw

Are there different types of cancer? There are more than 100 types of cancer. Types of cancer are usually named for the organs or tissues where the cancers form. For example, lung cancer starts in cells of the lung, and brain cancer starts in cells of the brain. Cancers also may be described by the type of cell that formed them, such as an epithelial cell or a squamous cell. Following are some categories of cancers that begin in specific types of cells.

Carcinoma

Carcinomas are the most common type of cancer. They are formed by epithelial cells, which are the cells that cover the inside and outside surfaces of the body. There are many types of epithelial cells, which often have a column-like shape when viewed under a microscope.

Carcinomas that begin in different epithelial cell types have specific names:

Adenocarcinoma is a cancer that forms in epithelial cells that produce fluids or mucus. Tissues with this type of epithelial cell are sometimes called glandular tissues. Most cancers of the breast, colon, and prostate are adenocarcinomas.

Basal cell carcinoma is a cancer that begins in the lower or basal (base) layer of the epidermis, which is a person’s outer layer of skin.

Squamous cell carcinoma is a cancer that forms in squamous cells, epithelial cells that lie just beneath the outer surface of the skin. Squamous cells also line many other organs, including the stomach, intestines, lungs, bladder, and kidneys. Squamous cells look flat, like fish scales, when viewed under a microscope. Squamous cell carcinomas are sometimes called epidermoid carcinomas.

Transitional cell carcinoma is a cancer that forms in a type of epithelial tissue called transitional epithelium, or urothelium. This tissue, which is made up of many layers of epithelial cells that can get bigger and smaller, is found in the linings of the bladder, ureters, and part of the kidneys (renal pelvis), and a few other organs. Some cancers of the bladder, ureters, and kidneys are transitional cell carcinomas.

Sarcoma

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Sarcomas are cancers that form in bone and soft tissues, including muscle, fat, blood vessels,  lymph vessels , and fibrous tissue (such as tendons and ligaments).

Osteosarcoma is the most common cancer of bone. The most common types of soft tissue sarcoma are  leiomyosarcoma Kaposi sarcoma malignant fibrous histiocytoma liposarcoma , and  dermatofibrosarcoma protuberans .

Leukemia

Cancers that begin in the blood-forming tissue of the bone marrow are called leukemias. These cancers do not form solid tumors. Instead, large numbers of abnormal white blood cells (leukemia cells and leukemic blast cells) build up in the blood and bone marrow, crowding out normal blood cells. The low level of normal blood cells can make it harder for the body to get oxygen to its tissues, control bleeding, or fight infections.  

There are four common types of leukemia, which are grouped based on how quickly the disease gets worse (acute or chronic) and on the type of blood cell the cancer starts in (lymphoblastic or myeloid).

Lymphoma

Lymphoma is cancer that begins in lymphocytes (T cells or B cells). These are disease-fighting white blood cells that are part of the immune system. In lymphoma, abnormal lymphocytes build up in lymph nodes and lymph vessels, as well as in other organs of the body.

There are two main types of lymphoma:

Hodgkin lymphoma – People with this disease have abnormal lymphocytes that are called Reed-Sternberg cells. These cells usually form from B cells.

Non-Hodgkin lymphoma – This is a large group of cancers that start in lymphocytes. The cancers can grow quickly or slowly and can form from B cells or T cells.

Multiple Myeloma

Multiple myeloma is cancer that begins in  plasma cells , another type of immune cell. The abnormal plasma cells, called myeloma cells, build up in the bone marrow and form tumors in bones all through the body. Multiple myeloma is also called plasma cell myeloma and Kahler disease.

Melanoma

Melanoma is cancer that begins in cells that become melanocytes, specialized cells that make melanin (the pigment that gives skin its color). Most melanomas form on the skin, but melanomas can also form in other pigmented tissues, such as the eye.

Brain and Spinal Cord Tumors

There are different types of brain and spinal cord tumors. These tumors are named based on the type of cell in which they formed and where the tumor first formed in the central nervous system. For example, an  astrocytic tumor  begins in star-shaped brain cells called  astrocytes , which help keep  nerve cells  healthy. Brain tumors can be benign (not cancer) or malignant (cancer).

Are there other types of tumors?

Germ Cell Tumors

Germ cell tumors are a type of tumor that begins in the cells that give rise to sperm or eggs. These tumors can occur almost anywhere in the body and can be either benign or malignant.

Neuroendocrine Tumors

Neuroendocrine tumors form from cells that release hormones into the blood in response to a signal from the nervous system. These tumors, which may make higher-than-normal amounts of hormones, can cause many different symptoms. Neuroendocrine tumors may be benign or malignant.

Carcinoid Tumors

Carcinoid tumors are a type of neuroendocrine tumor. They are slow-growing tumors that are usually found in the gastrointestinal system (most often in the rectum and small intestine). Carcinoid tumors may spread to the liver or other sites in the body, and they may secrete substances such as serotonin or prostaglandins, causing  carcinoid syndrome .

ANTICANCER DRUGS Anticancer drugs are agents that demonstrate activity against malignant disease. They include hormones, natural products, antibodies, metabolites, alkylating agents as well as a variety of other chemicals that do not fall within these discrete classes but are capable of preventing the replication of cancer cells. Hormones are used primarily in the treatment of cancers of the breast and sex organs. These tissues require hormones such as estrogens, androgens or progestins for growth and development. By countering these hormones with an antagonizing hormone, the growth of that tissue is inhibited, as is the cancer growing in the area. For example, estrogens are required for female breast development and growth. Tamoxifen competes with endogenous estrogens for receptor sites in breast tissue where the estrogens normally exert their actions. The result is a decrease in the growth of breast tissue and of breast cancer tissue. Adrenocorticosteroids are also used for treating some types of cancer. These hormones are an example of a site-specific antineoplastic drug, but they work only on certain types of cancer.

Understanding of the basic biology of cancer cells has led to drugs with entirely new targets. One agent, interleukin-2 , regulates the proliferation of tumor-killing lymphocytes. Interleukin-2 is used in the treatment of malignant melanoma and renal (kidney) carcinoma. Trans-retinoic acid can promote remission in patients with acute promyelocytic leukemia by inducing normal differentiation of the cancerous cells. A related compound, 13-cis-retinoic acid, prevents the development of secondary tumors in some individuals. A particularly exciting application of cancer biochemistry stems from the understanding of DNA translocation in chronic myelocytic leukemia. This translocation codes for a tyrosine kinase, an enzyme that phosphorylates other proteins and is essential for cell survival. Inhibition of the kinase by imatininib has been shown to be highly effective in treating patients who are resistant to standard therapies. Hydroxyuren inhibits the enzyme ribonucleotide reductase, an important element in DNA synthesis. It is used to reduce the high granulocyte count found in chronic myelocytic leukemia. Mitotane, a derivative of the insecticide DDT, causes necrosis of adrenal glands .

A number of agents synthesized from plants are used in the treatment of cancer. Paclitaxel was first isolated from the bark of the western yew tree. It stops cell division by an action on the microtubules and has been tested for activity against ovarian and breast cancers. The camptothecins are a class of antineoplastic agents that target DNA replication. The first compound in this class was isolated from the Chinese camptotheca tree. Irinotecan and topotecan are used in the treatment of  colorectal, ovarian, and small-cell  lung cancer. Vinblastin and vincristine, derived from the periwinkle plant, along with etoposide, act primarily to stop spindle formation within the dividing cell during DNA replication and cell division. These drugs are important agents in the treatment of leukemias, lymphomas, and testicular cancerEtoposide, a semisynthetic derivative of a toxin found in roots of the American mayapple, affects an enzyme and causes breakage of DNA strands.

IMMUNOCHEMISTRY

Immunochemistry is a branch of  chemistry  that involves the study of the molecular mechanisms underlying the function of the  immune system , especially the nature of antibodies, antigens and their interactions.

Various methods in immunochemistry have been developed and refined, and been used in scientific study, from  virology  to  molecular evolution .

One of the earliest examples of immunochemistry is the  Wasserman test  to detect  syphilis Svante Arrhenius , whose contribution to the understanding of ionic crystals (Lecture 4), was also one of the pioneers in this field. He published Immunochemistry in 1907 which described the application of the methods of physical chemistry to the study of the theory of  toxins  and  antitoxins .

An antibody (Ab), also known as an immunoglobulin (Ig),is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses

The antibody recognizes a unique molecule of the pathogen, called an antigen, via the fragment antigen-binding (Fab) variable region. Each tip of the "Y" of an antibody contains a paratope (analogous to a lock) that is specific for one particular epitope (analogous to a key) on an antigen, allowing these two structures to bind together with precision. See figure below. https://upload.wikimedia.org/wikipedia/commons/thumb/2/2d/Antibody.svg/260px-Antibody.svg.png

Each antibody binds to a specific antigen; an interaction similar to a lock and key. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize its target directly (for example, by inhibiting a part of a microbe that is essential for its invasion and survival). Depending on the antigen, the binding may impede the biological process causing the disease or may activate macrophages to destroy the foreign substance. The ability of an antibody to communicate with the other components of the immune system is mediated via its Fc region (located at the base of the "Y"), which contains a conserved glycosylation site involved in these interactions. The production of antibodies is the main function of the humoral immune system.

CHEMOTHERAPY

Chemotherapy is a type of cancer treatment that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent (which almost always involves combinations of drugs), or it may aim to prolong life or to reduce symptoms (palliative chemotherapy).

The term chemotherapy has come to connote non-specific usage of agents to inhibit cell division (mitosis).

Chemotherapy kills cells that are in the process of splitting into 2 new cells.

Body tissues are made of billions of individual cells. Once we are fully grown, most of the body's cells don't divide and multiply much. They only divide if they need to repair damage.

When cells divide, they split into 2 identical new cells. So where there was 1 cell, there are now 2. Then these divide to make 4, then 8 and so on.

In cancer, the cells keep on dividing until there is a mass of cells. This mass of cells becomes a lump, called a tumor.

Because cancer cells divide much more often than most normal cells, chemotherapy is much more likely to kill them.

Some drugs kill dividing cells by damaging the part of the cell's control center that makes it divide. Other drugs interrupt the chemical processes involved in cell division.

Chemotherapy damages cells as they divide.

In the center of each living cell is a dark blob, called the nucleus. The nucleus is the control center of the cell. It contains chromosomes, which are made up of genes.

These genes have to be copied exactly each time a cell divides into 2 to make new cells.

Diagram showing how new genes are made for new cells

Chemotherapy damages the genes inside the nucleus of cells.

The term, chemotherapy, excludes more selective agents that block extracellular signals (signal transduction). The development of therapies with specific molecular or genetic targets, which inhibit growth-promoting signals from classic endocrine hormones (primarily estrogens for breast cancer and androgens for prostate cancer) are now called hormonal therapies. By contrast, other inhibitions of growth-signals like those associated with receptor tyrosine kinases  (kinases are enzymes that catalyzes the transfer of a phosphate group from ATP to a specified molecule ) are referred to as targeted therapy.