Antineoplastic Agents

Antineoplastic Agents

Antineoplastic medications: drugs used to treat cancer, also called

Cancer drugs , Cytotoxic agents Anticancer drugs.

Cancer

• Along with heart disease, cancer is the largest cause of death in the developed world

• Cancer affects 1 in 3 people and is responsible for 25% of all deaths

Cancer is an unregulated proliferation of cells due to loss of normal controls, resulting in

1.unregulated growth, 2. lack of differentiation, 3.local tissue invasion, 4.and, often, metastasis.

• Cancer can develop in any tissue or organ at any age. There is often an immune response to tumor.

• Many cancers are curable if detected at an early stage, and long-term remission is often possible in later stages

Etiology of Cancer

• Genetics

• Viruses

• Occupational and Environmental Carcinogens

• Radiation

Causes of Cancer:

1. 30 % is due to smoking: lung, mouth, pharynx, larynx, esophagus, urinary bladder, pancreas, and kidney cancers.

2. Lifestyle – diet, alcohol consumption, reproductive behavior, sexual behavior, exposure to sunlight, etc.

3. At least 15% are related to viruses, e.g. cervical cancer caused by human papillomavirus.

Types of Tumors:

-Benign: non cancerous and not an immediate threat to life, even though treatment eventually may be required for health.

-Malignant: tending to worsen and cause death, invasive and metastasis

Characteristics of cancer cells:

• Persistent uncontrolled cell proliferation

• lack of differentiation• Invasive growth• Metastases (a tumor may shed cells into the circulation.

Although most circulating tumor cells die as a result of intravascular trauma, a tiny number adhere to the vascular endothelium and penetrate into surrounding tissues, generating independent tumors (metastases) at distant sites.)

Cell cycle Scientists have determined that cell

cycle can be divided into:. Gap 0 (G0): There are times when a cell

will leave the cycle and quit dividing. This may be a temporary resting period or more permanent. An example of the latter is a cell that has reached an end stage of development and will no longer divide (e.g. neuron).

Gap 1 (G1): Cells increase in size in Gap 1, produce enzymes needed for DNA synthesis

S Phase: To produce two similar daughter cells, the complete DNA instructions in the cell must be duplicated. DNA replication occurs during this S (synthesis) phase.

Gap 2 (G2): It is the gap between DNA synthesis and mitosis, the cell will continue to grow and produce new proteins & RNA.

Mitosis or M Phase: Cell growth and protein production stop at this stage in the cell cycle. All of the cell's energy is focused on the complex and orderly division into two similar daughter cells.

• The term cell cycle refers to the sequence of events that take place within a cell as it tools up for division.

• The phases of the cell cycle are:G1-preparation for DNA synthesisS-DNA synthesisG2-preparation for division mitosis-division into two daughter cells.

Simplified diagram of the effect of growth factors on a cell in G0

• 4. The overall effect of growth factor action is the generation of the cell cycle transducers. A cell such as the one depicted will then embark on G1 phase of the cell cycle. Most growth factor receptors have integral tyrosine kinase (These receptors dimerise (form pairs), then phosphorylate each other's tyrosine residues. The early cytosolic transducers include proteins that bind to the phosphorylated tyrosine residues. Optimum effect requires cooperation with integrin action. Integrins (which have α and β subunits) connect the extracellular matrix with intracellular signalling pathways and also with the cell's cytoskeleton (not shown here). G-protein-coupled receptors can also stimulate cell proliferation, because their intracellular pathways can connect with the Ras/kinase cascade (not shown). AP, adapter protein; FA kinase, focal adhesion kinase; Rb, retinoblastoma

The cell cycle

• Growth factor action stimulates a quiescent cell-said to be in G0 (G nought)-to divide, i.e. to start on G1 phase.

• In G0 phase, a hypophosphorylated protein, coded for by the Rb gene, holds the cycle in check by inhibiting expression of critical factors necessary for DNA replication.

• Progress through the cycle is controlled by specific kinases (cyclin-dependent kinases, cdks) that are activated by binding to proteins termed cyclins.

• Four main cyclin/cdk complexes involving cyclins D, E, A and B drive the cycle; the first complex, cyclin D/cdk, releases the Rb protein-mediated inhibition.

• Various families of proteins act as cdk inhibitors. Important is protein p21, which is expressed when DNA damage causes transcription of gene p53. The p21 protein stops the cycle at check point 1.

Angiogenesis• is the formation of new capillaries from

existing blood vessels, an important stimulus being vascular endothelial growth factor (VEGF). The sequence of events is as follows.

• The basement membrane is degraded locally by proteases.

• Endothelial cells migrate out, forming a sprout.

• Endothelial cells following the leading cells proliferate under the influence of VEGF.

• Matrix is laid down around the new capillary

Apoptosis

• is programmed cell death, essential in embryogenesis and tissue homeostasis; it is brought about principally by a cascade of proteases-the caspases. Two sets of initiator caspases converge on a set of effector caspases.

• There are two main pathways to activation of the effector caspases: the death receptor pathway and the mitochondrial pathway. – The death receptor pathway involves stimulation

of members of the tumour necrosis factor receptor family; and the main initiator caspase is caspase 8.

– The mitochondrial pathway is activated by internal factors such as DNA damage, which results in transcription of gene p53. The p53 protein activates a subpathway that results in release from the mitochondrion of cytochrome c. This in turn complexes with protein Apaf-1, and together they activate initiator caspase 9.

• In undamaged cells, survival factors (cytokines, hormones, cell-to-cell contact factors) continuously activate antiapoptotic mechanisms. Withdrawal of survival factor stimulation causes cell death through the mitochondrial pathway.

• The effector caspases (e.g. caspase 3) start a pathway that results in cleavage of cell constituents, DNA, cytoskeletal components, enzymes, etc. This reduces the cell to a cluster of membrane-bound entities that are eventually phagocytosed by macrophages

Genetics Etiology of Cancer

Etiology of Cancer

• Genetic mutations are largely responsible for the generation of malignant cells. Two major categories of mutated genes are oncogenes and tumor suppressor genes.

1-Oncogenes are abnormal forms of normal genes (proto-oncogenes) that regulate cell growth. Mutation of these genes may result in direct and continuous stimulation of the molecular biologic pathways that control cellular growth and division.

For example, the ras gene encodes the Ras protein, which regulates cell division. Mutations may result in the inappropriate activation of the Ras protein, leading to uncontrolled cell growth and division.

2-Tumor suppressor genes are inherent genes that play a role in cell division and DNA repair and are critical for detecting inappropriate growth signals in cells. If these genes, as a result of inherited or acquired mutations, become unable to function, genetic mutations in other genes can proceed unchecked, leading to neoplastic transformation.

• Another important regulatory protein, p53, prevents replication of damaged DNA in normal cells and promotes cell death (apoptosis) in cells with abnormal DNA. Inactive or altered p53 allows cells with abnormal DNA to survive and divide. The p53 gene is defective in many human cancers.

Telomeres

• Telomeres are nucleoprotein complexes that cap the ends of chromosomes and maintain their integrity. Telomere shortening occur with aging .Telomerase is an enzyme that provides for telomere synthesis and maintenance, thus telomerase may potentially allow for cellular immortality. Telomerase activity may promote tumors through multiple, complex mechanisms, especially by subverting the normal DNA synthetic checkpoints.

• Viruses contribute to the pathogenesis of human malignancies through the integration of viral genetic elements into the host DNA. These new genes are expressed by the host; they may affect cell growth or division, or disrupt normal host genes required for control of cell growth and division. Alternatively, viral infection may result in immune dysfunction, leading to decreased immune surveillance for early tumors.

E.G. :Epstein-Barr, nasopharyngeal carcinoma -Hepatitis B virus, hepatocellular carcinoma -HIV Kaposi's sarcoma.

• Immune system dysfunction as a result of genetic mutation, acquired disease, aging, or immunosuppressants interferes with normal immune surveillance of early tumors and results in higher rates of cancer. Known cancer-associated immune disorders include : immune deficiency secondary to immunosuppressants or HIV infection ( Kaposi's sarcoma)& rheumatologic conditions, such as Rheumatoid Arrhythrities (B-type lymphoma).

• Carcinogenesis can result from ionizing radiation and may develop from 2 different mechanisms;

1. Direct ionization – damages DNA and other molecules can cause direct somatic mutations

2. Secondary effectors such as oxygen radicals can be formed by interaction with ionizing radiation. Oxygen free radicals can damage and kill cells and also induce mutations

Pathogenesis of Neoplasia :

• Cancer development can begin with a brief exposure (hours or days) to a chemical into an activated form and the chemical need not be present ever again.

• However, DNA is altered via mutagens including chemical carcinogens, viruses, and radiation. This mutations is inherted by at least one cell division (intiation).

• This mutation mainly lead to activation of proto-oncogene into oncogenes (leading to uncontrolled cell proliferation) and/or inactivation of tumor suppressor genes (leading to resistance to apoptosis.)

• Upon exposure to other epigenetic factors (hormones, co- carcinogens, immunosuppressant…which themselves are non carcinogenic) tumor growth is promoted (promotion)

• Initiation - point at which an irreversible

alteration, usually genetic, is introduced into a target cell.

Initiation:

(1) is essentially irreversible

(2) caused only by carcinogenic compounds

(3) occurs rapidly after carcinogen exposure

(4) alone does not result in tumor formation

• Promotion is the process whereby an initiated tissue or organ develop focal proliferations and it requires the presence of continuous stimulation.

Promotion(1) reversible(2) acts only after exposure to an

initiating agent(3) requires repeated administration of apromoter(4) is not carcinogenic in itself

Etiology and Pathogenesis of NeoplasiaInitiation and Promotion

How long does it take to produce a clinically detectable neoplasm ?

1. It can be readily calculated tat it takes at least 30 population doublings toproduce 10 9 cells (about 1 gram in weight) from a single, initial transformed cell. Itthen takes only about 10 population doublings to produce a neoplasm of 10 12 cells(weight about 1 Kg, which is the maximal size compatible with life).

2. By the time a solid neoplasm is clinically detected, it has already completeda major portion of its life cycle (The latent period before which a neoplasm becomes

clinically detectable is quite unpredictably long, usually years).

3. The rate of growth of a neoplasm is determined by the proportion of cellsin the growth fraction and the degree of imbalance between cell proliferation and cellloss. In the submicroscopic phases of neoplastic growth most cells are in theproliferative pool (growth fraction). By the time a neoplasm is clinically detectablemost cells in a neoplasm are not in the growth fraction.

4. The growth fraction of neoplastic cells has a profound effect on theirsusceptibility to cancer chemotherapy.

There are three basic treatment possibilities for cancer: surgery, radiotherapy, and chemotherapy.Some cancers where chemotherapy works very well: • Childhood leukemia• Retinoblastoma• Osteosarcoma• Testicular cancer• Hodgkin’s Disease• Some lymphomas• Some early breast cancers

Cancers that are very difficult to treat with chemotherapeutics (need surgery or radiotherapy first):

• Colon• Lung• Late stage breast cancer• Pancreatic cancer

Problems associated with chemotherapy1-Resistance to chemotherapy

Resistance to chemotherapy may develop by several mechanisms:

• Decrease in the amount of drug uptake by cancer cellsex Methotrexate• Increase in the amount of drug removed by cancer cells.

(Transporters=P-glycoprotein).ex. Vinblastine ,doxorubicin, bleomycin ,etapsoid….• Decrease or alteration in target molecule sensitivity – this

is caused by mutation in the molecule targeted by the drugex. Methotrexate,Mercaptopurine,doxorubicin• Increase in DNA repair ability of the cell via an increased

expression of DNA repairing enzymes.ex. Alkylating agent

2-Toxicity and side Effects of Antineoplastic Agents:

Normal cells in the body that tend to be injured the most due to chemotherapy are those which have a high growth fraction. Those are bone marrow, GI Tract ,hair follicles, reproductive organs .Leading to the followings:

• Alopecia- hair loss• Myelosuppression-bone marrow loss• Emetic potential: disruptive to cells in stomach

which causes: Nausea/vomiting• Low WBC count- low immunity

Treatment of Chemotherapy Toxicity

Injury to: Results in: Time Course: Treatment of this side effect:

Other:

Bone marrow: Decreased

Neutrophils

Infection Begins 10-14 days after tmt initiation. Takes 3-4

wks for recovery.

Give colony stimulating factors

(CSFs)

.

Bone marrow: Decreased Platelets

Bleeding, especially

from nose and gums

Platelet infusion

Bone marrow: Decreased

Erythrocytes

Anemia 120 days after therapy is imitated. By this time

therapy has usually stopped, so this is a rare

effect.

erythropoetin

GI tract (1Stomatitis (2 pain and

infection3)Nausea + vomiting

Begins a few days after tmt initiation and lasts until two weeks after termination of tmt. a

Treat stomatitis with anesthetics and antifungal.

Treat nausea with anti-emetics like

ondansetron

You can also use glucocorticoids&

lorazepam to reduce the

inflammation.

Hair follicles Alopecia Begins 7 –10 days after initiation of tmt and continues until 1 – 2

months post tmt.

reversable

Reproductive tract

Irreversible sterility in

males, teratogenic

Treatment-induced tumor

Many anticancer drugs are mutagens and can cause the rise of neoplasm ten or more years after the original cancer was cured.

Cell cycle Scientists have determined that cell

cycle can be divided into:. Gap 0 (G0): There are times when a cell

will leave the cycle and quit dividing. This may be a temporary resting period or more permanent. An example of the latter is a cell that has reached an end stage of development and will no longer divide (e.g. neuron).

Gap 1 (G1): Cells increase in size in Gap 1, produce enzymes needed for DNA synthesis

S Phase: To produce two similar daughter cells, the complete DNA instructions in the cell must be duplicated. DNA replication occurs during this S (synthesis) phase.

Gap 2 (G2): It is the gap between DNA synthesis and mitosis, the cell will continue to grow and produce new proteins & RNA.

Mitosis or M Phase: Cell growth and protein production stop at this stage in the cell cycle. All of the cell's energy is focused on the complex and orderly division into two similar daughter cells.

Cancer chemotherapeutic agents

They are classified into:• Cell-cycle non specific agents(CCNS): are cytotoxic in any

phase of the cycle even on G0 phase and so are more effective against large slowly growing tumors.

E.G.Bleomycin.

• Cell-cycle specific (CCS): are cytotoxic on all phases but not on cells out of the cycle(at G0 ) and so are more effective against rapidly growing tumors. Work better in combination than alone

E.G. Mitomycin, doxorubicin,….etc.

• Phase specific : act on specific phase of the cycle E.G.Vinca alkaloids act more in M-phase ,antimetabolites (mainly act on S-

phase.)

Anticancer DrugsThere are three Major Groups of Anticancer Drugs:1) Cytotoxic Drugs (largest group)• -Alkylating agents • -Antimetabolites• -Antitumor antibiotics• -Plant alkaloids• -Miscellaneous cytotoxic drugs2) Hormones and hormone antagonists These are among the best-tolerated chemotherapeutics

because they target specific receptors, and thus only specific cell types e.g. Tamoxifen

3) Immunomodulators• -Immunostimulants, including interferons and interleukins• -Immunosuppressant

2- Hormones and hormone antagonists

Corticosteroids

Corticosteroids have broad use in cancer treatment. Some are used to treat adult leukemias, adult lymphomas, and acute childhood leukemia.

Immunosuppressive mechanism• Glucocorticoids suppress the cell-mediated

immunity. They act by inhibiting genes that code for the cytokines interlukin and TNF-γ, the most important of which is the IL-2. The inhibition of cytokine production reduces the T cell proliferation.

• Glucocorticoids also suppress the expansion and antibody synthesis.

Side effectsHyperglycemia due to increased gluconeogenesis, insulin resistance caution in those with diabetes mellitus reduced bone density (osteoporosis, higher fracture risk, slower fracture repair)

weight gain due to increased visceral and truncal fat deposition (central obesity) and appetite stimulation

• adrenal insufficiency (if used for long time and stopped suddenly without a taper)

• muscle breakdown (proteolysis), weakness; reduced muscle mass and repair

• growth failure, pubertal delay • Increased urea formation; negative nitrogen balance

The most common corticosteroids used in cancer treatment are:

• · dexamethasone (Decadron)brain tumor• · hydrocortisone• · methylprednisolone (Medrol)

Estrogens & ProgestonsMainly used in androgen dependent

prostatic tumors

Gonadotropin−releasing hormone analogues

Goserelin Acetate· Goserelin acetate is a synthetic hormone that acts

similarly to the naturally occurring gonadotropin−releasing hormone (GnRH). In men, this results in decreased blood levels of the male hormone testosterone. In women, it decreases blood levels of the female hormone estrogen.

• It is used for treatment of breast and prostatic cancer

Side effects• · sweating ,hot flashes, impotence

(erectile dysfunction),sterility & gyncomestia

• · depression or other mood changes• · Other common side effects in women

include: light, irregular, vaginal bleeding & no menstrual period

Tamoxifen• Tamoxifen selectively inhibits the effects of estrogen on

breast tissue, while selectively mimicking the effects of estrogen on bone (by increasing bone mineral density) and uterine tissues. These qualities make tamoxifen an excellent therapeutic agent against breast cancer. it is known to compete with estrogen by binding to estrogen receptors on the membrane of target cells, thus limiting the effects of estrogen on breast tissue.

• Tamoxifen may also has other anti−tumor activities :affecting oncogene expression& promotion of apoptosis (cancer cell death)

Hormone antagonists

Adverse Effects• CNS: Depression, light headedness,

dizziness, headache, decreased visual acuity &retinopathy

• GI: Nausea, vomiting• Hematological: Hypercalcemia• GU: Vaginal bleeding, vaginal

discharge & menstrual irregularities• Dermatologic: Hot flashes, skin rash

Immunomodulators

Immune system and cancer • The immune system serves as one of the

primary defenses against cancer. When normal tissue becomes a tumor or cancerous tissue, new antigens develop on their surface. These antigens send a signal to immune cells such as the T lymphocytes and macrophages, which in turn directly kill the tumor cells or release substances like cytokines that may bring about tumor cell death.

Immunomodulators

Immunosuppressant Immunostimulants

Immunosuppressant• 1 Glucocorticoids • 2 Cytotoxic

– a- Alkylating agents – b- Antimetabolites

• 1 Methotrexate • 2.Azathioprine and Mercaptopurine

• 3. Drugs acting on immunophilins – 1 Cyclosporin – 2. Sirolimus

Drugs acting on immunophilins

Cyclosporin is a calcineurin inhibitor. is one of the most widely used

immunosuppressive drugs. It is a fungal peptide, composed of 11 amino acids.

• Cyclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophilin inhibits calcineurin, which under normal circumstances induces the transcription of interleukin-2. The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.

.

• Cyclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer immunosuppressants, as it is nephrotoxic

Sirolimus

• Sirolimus is a macrolide lactone, produced by the Streptomyce hygroscopicus It is used to prevent rejection reactions. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side effects.

• Contrary to cyclosporine that affect the first phase of the T lymphocyte activation, sirolimus affects the second one, namely the signal transduction and their clonal proliferation. Therefore, sirolimus acts synergistically with cyclosporine and, in combination with other immunosuppressants, has few side effects. Indirectly it inhibits several T lympohocyte kinases and phosphatases, preventing the transmission of signal into their activity and the transition of the cell cycle from G1 to S phase. Similarly, it prevents the B cell differentiation to the plasma cells, which lowers the quantity of IgM, IgG and IgA antibodies produced. It acts immunoregulatory

Immunostimulants Biologic therapy, also called

immunostimulants, is a treatment that uses drugs to improve the way your body’s immune system fights disease. Your immune system is your body’s natural defense against disease. A healthy and strong immune system can detect the difference between healthy cells and cancer cells. Biologic therapy attempts to stimulate, or enhance the immune system so that it can fight the cancer

1-Monoclonal Antibodies

Monoclonal antibodies are proteins produced in the laboratory from a single clone of a B−cell, the type of cells of the immune system that make antibodies. When used as a treatment for cancer, there are three general strategies with monoclonal antibodies:

• One uses the ability of the antibodies to bind to the cancer cells having the tumor antigens on their surface. The immune system will see the cancer cells marked with bound antibodies as foreign and destroy them.

•

• A second strategy is to use the antibodies to block the binding of cytokines or other proteins that are needed by the cancerous cells to maintain their uncontrolled growth. Monoclonal antibodies designed to work like this bind to the cytokine receptors that are on the tumor cell surface.

• A final strategy involves special antibodies that are linked (conjugated) to a substance that is deadly to the cancer cells. E.G. radioactive isotopes, have been successfully conjugated to antibodies. The antibodies are then used to specifically destroy he tumor cells with the radioactivity or toxic substance.

Trastuzumab

• Trastuzumab is a humanized monoclonal antibody produced by recombinant DNA technology that binds specifically to the human epidermal growth factor receptor 2 protein (also known as HER2) that is found on the cell surface of some cancer tumors, most notably breast cancer(25−30% of breast malignancies) and also targets it for destruction by the natural killer cells of immune system.

2-Biological response modifiers

Researchers have been working on stimulating the immune cells during cancer with substances broadly classified as biological response modifiers. Cytokines are one such substance. These are proteins that are predominantly released by immune cells upon activation or stimulation.

Aldesleukin

• Aldesleukin is interleukin, that is used to treat metastasis renal cell carcinoma (a form of kidney cancer) and metastasis melanoma. Aldesleukin is also known as interleukin−2, IL−2

• When renal cell carcinoma and metastasis melanoma (cancer of the skin that arises in the pigmented cells of the skin or eyes) do not respond to other therapies, they are candidates for treatment with aldesleukin.

• Aldesleukin is a biological response modifier (BRM). It promotes the development of T cells, or the cells in the lymphatic system that can fight cancer cells.

Side effect• Flu-like symptoms (chills, fever, fatigue) • Loss of appetite • Skin problems such as a rash, itchiness,

scaling • Cardiac arrhythmias • Gastrointestinal disturbance, such as nausea

and vomiting • Neurological effects, such as depression and

poor concentration

Interferons

• Interferons are small, natural cytokines that are produced by leucocytes ,T−lymphocytes, and fibroblasts in response to infection and other biological stimuli.

• The goal of interferon use is to activate tumor−specific cytotoxic T−lymphocytes. Thus, tumor cells would be destroyed based on immunotherapy.

• Interferons attach to special receptors on the surface of cell membranes. Then produce variety of functions including enhancing or inhibiting enzymes, decreasing cell proliferation, or enhancing the activity of macrophages and T−lymphocytes. There are several different classes of interferons, cancer therapy primarily focuses on alpha interferons.

• Alpha interferons are used to treat cancers such as hairy cell leukemia, malignant melanoma, and Kaposi's sarcoma (an AIDS−related cancer) as well as many other cancers

Side effects• muscle aches, unusual metallic taste in the

mouth, fever and chills, and general flu−like symptoms such as headache, loss of appetite (anorexia), nausea and vomiting, and fatigue. To reduce the flu−like symptoms physicians may suggest that the patient take acetaminophen before each dosage.

• confusion, trouble thinking and focusing, mental depression, nervousness, or numbness or tingling of fingers,

Levamisole

• Levamisole act to restore depressed immune function. It increases the response of T cells, or cells belonging to the lymphatic system that can fight cancer cells. It also seems to increase the activity of cells that attack and destroy invading cancer cells, including both monocytes and macrophages.

Side Effects• Allergic reaction. • Decreased bone marrow function, resulting in

fatigue or signs of infection • Problems related to the nervous system, such as

confusion, loss of consciousness, or speech disturbances

3-Angiogenesis inhibitors

• Angiogenesis is the normal process by which the human body forms new blood vessels. Angiogenesis is important in the development of cancer because tumors require blood vessels to grow and spread to nearby tissue. Once a tumor reaches a certain size it needs to develop a blood supply in order to grow. Cancer cells will secrete certain chemicals to promote angiogenesis. Angiogenesis inhibitors are drugs that can stop this process. These anti-angiogenesis agents are being investigated as potential cancer therapies.

Thalidomide

• Thalidomide interferes with the growth of rapidly dividing cells.It interferes with the formation of blood vessels. It is called an antiangiogenic drug

• It is used to treat several types of cancers, including kidney, ovarian, and breast cancer.

Side effects :• Orthostatic hypotension• Thalidomide may cause peripheral neuropathy (numbness,

tingling, pain, or burning sensations in the feet or hands). • Thalidomide may cause severe birth defects or fetal death if

taken by pregnant women (phocomelia). • Rash • Lack of bowel movements