ANTINEOPLASTIC AGENTS

Edited by:Israa Eltayib

Antineoplastic AgentsAntineoplastic medications:

drugs used to treat cancer, also called cancer

drugs ,cytotoxic agents and anticancer drugs.

Problems associated with chemotherapy

1-Resistance to chemotherapy• Resistance to chemotherapy may develop by several

mechanisms: 1. Decrease in the amount of drug uptake by cancer cells

e.g, Methotrexate2. Increase in the amount of drug removed by cancer

cells. (Transporters=P-glycoprotein). e.g, Vinblastine ,doxorubicin, bleomycin ,etapsoid….

3. Decrease or alteration in target molecule sensitivity – this is caused by mutation in the molecule targeted by the drug e.g, Methotrexate, Mercaptopurine, doxorubicin

4. Increase in DNA repair ability of the cell via an increased expression of DNA repairing enzymes. e.g, Alkylating agent

2-Toxicity and side Effects of Antineoplastic Agents:

• Normal cells in the body that tend to be injured by the chemotherapy are those which have a high growth fraction.

• They 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 ToxicityInjury 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.

*( Erythropoietin is an Erythropoietin is an essential hormone for red essential hormone for red

cell productioncell production........Erythropoetin

GI tract (1Stomatitis –inflammation of mucous lining of

mouth ((2 pain and infection

3)Nausea + vomiting

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

termination of tmt .

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.

reversablereversable

Reproductive tract Irreversible sterility in males, teratogenic

3-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 cycleScientists 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 .

CYTOTOXIC DRUGS

I-Alkylating Agents (CCNS-cellcycle Non-specific)

Mechanism of Alkylating Agents• These drugs work by alkylation with nucleophilic substitution . They

alkylate a variety of cellular constituents, such as cell membranes, proteins, and most importantly DNA. More specifically, the nitrogenous bases of DNA are alkylated.

• (*nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile(Common nucleophiles are hydroxide ions, cyanide ions, water and ammonia.) selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms to replace a so-called leaving group; the positive or partially positive atom is referred to as an electrophile. The whole molecular entity of which the electrophile and the leaving group are part is usually called the substrate.)*

•

The drugs start off as pro-drugs that become activated when a chlorine atom is extracted. A carbonium ion is thus formed. This “carbonium ion” is very electrophilic and will then attack any free pair of electrons (i.e. on the N7 of guanine). This electrophilic attack results in a bond being formed between the drug and the guanine of DNA. As a result of this “alkylation”, there are a few consequences:

1) Miscoding (In transcription)2) Cross linking- this only occurs if the drug is

bifunctional (*bifunctional, meaning they have two active sites. Create a carbonium ion that reacts with guanine nucleophile. Causes interstrand crosslinking, which halts replication*).

Alkylating Agents(CCNS)

Subgroups of Alkylating Agents1) Nitrogen mustards2) Nitrosoureas3) Alkyl sulfonates4) 4-Platinum Coordination Compounds

1-Nitrogen MustardsE.G.: Mechlorethamine, cyclophosphamid, melphalan & chlorambucila-Mechlorethamine- first alkylating agent employed clinically - bifunctional, thus can crosslink DNA- extremely unstable and is inactivated within a few minutes following administration. Thus it is given IV. Clinical Uses-Hodgkin’s Disease (*Hodgkin disease (Hodgkin lymphoma) is a type of lymphoma, a cancer that starts in cells called lymphocytes, which are part of the body's immune system.*)

-Non-Hodgkin’s LymphomaToxicity/ Side Effects- Dose limiting toxicity is bone marrow depression- Nausea/ Vomiting - Alopecia- Diarrhea - Sterility (*inability to effect sexual reproduction *)

b-Cyclophsphamid -It acts as cytotoxic and immunosuppressor agent.- Prodrug which must be activated by the cytochrome p450 system, which turns it into a nitrogen mustard. - bifunctional agent-most widely used alkylating agent

Clinical Uses- Hodgkin’s Disease- Non-Hodgkin’s lymphoma- Solid tumors of head, neck, ovaries, and breast- frequently used in combination with methotrexate (anti-metabolite) or doxorubicin (anti-tumor antibiotic), or fluorouracil as adjuvant therapy post breast cancer surgery- Organ transplant recipients (due to immunosuppressive actions)

Toxicity/ Side Effects- bone marrow depression- severe nausea and vomiting- acute hemorrhagic cystitis and renal damage?? (can be minimized via high fluid intake/infusion and the use of………?)- sterility- hypersensitivity reactions

Treatment of cyclophsphamid toxicity

2-Nitrosoureas- bifunctional- active against broad spectrum of neoplastic

disease- inhibits synthesis of both DNA and RNA, as well

as proteins- These drugs are highly lipophilic, so they can

easily cross blood-brain-barrier, and are great for CNS tumors.

- Big problem in this class is that they are highly mutagenic and highly carcinogenic.

- Major toxicity is DELAYED bone marrow depression & Pulmonary fibrosis.

Clinical uses- primary and metastasis tumors of the brain- Hodgkin’s Disease- Non-Hodgkin’s lymphoma (*The non-Hodgkin lymphomas (NHLs) are diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas.*)- Adenocarcinoma of stomach, colon, and rectal cancer- Hepatocarcinoma

E.G.:a-Carmustine b-Lomustine

3-Alkyl SulfonatesBusulfanClinical usesGreat effect on for Chronic granulocytic Leukemia

Toxicity/ Side Effects- Dose limiting toxicity is bone marrow depression.- Pulmonary infiltrates and pulmonary fibrosis- Tonic-clonic seizures in epileptics- Nausea and vomiting- Alopecia- Sterility (*inability to effect sexual reproduction *)- Skin hyper pigmentation- Cataracts- Hepatitis

4-Platinum Coordination CompoundsE.G.:Cisplatin• forms crosslinks within DNA strands. Cis-platin is not really an

“alkylating” agent, but since it operates via the same mechanism as the alkylating agents, it is placed within that group.

Clinical Uses- Very powerful against TESTICULAR CANCER- Also good for carcinomas of ovary, bladder, head, and neckToxicity/ Side Effects- Renal tubular damage (minimized via massive hydration, coupled

with anti-emetics)- Ototoxicity and peripheral neuropathy- VERY SEVERE vomiting( Ondanosetron…?)

Carboplatin: is a derivative of cisplatin with less nephero- ,neuro- & ototoxicity.

(L.E)

Lecture No: 02 II-Antimetabolites (CCS)

An antimetabolite is a chemical with a similar structure to a metabolite required for normal biochemical reactions, yet different enough to interfere with the normal functions of cells, including cell division.All antimetabolites are used in cancer treatment, as they interfere with DNA production and therefore cell division and the growth of tumors (mainly in S-phase specific).They are classified into: 1- Folic acid analogues 2- Purine analogues 3- Pyrimidine analogues

II-Antimetabolites (CCS)

Purin and pyrimidine antagonists are phosphorelated inside the body into nucleotid form in order to be cytotoxicUsesleukemia. non-Hodgkin's lymphomainflammatory bowel disease such as Crohn's Disease and ulcerative colitisIt is widely used as immunosuppressant in transplantations to control rejection reactions.

1-Folic acid analogues Methotrexate:• A folic acid analogue, prevents the formation of tetrahydrofolate,

essential for purine and pyrimidine synthesis, by inhibiting dihydrofolate reductase. This leads to inhibition of production of DNA, RNA and proteins (as tetrahydrofolate is also involved in the synthesis of amino acids as serine and methionine).

• It is actively taken up into the cells by the same transport system for folate (resistance…..?)

• The most common toxicity is nepherotoxicity (precipitation of the drug in renal tubule.)

Cont: Folic acid analogues1-Methotrexate compete with folic acid for DHFR and inhibits it . Therefore, it inhibits the synthesis of DNA, RNA and proteins.2-Also,DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolat which is needed for the de novo synthesis of the deoxynucleoside thymidine phosphate DTMP ( required for DNA synthesis)

2-Purine analoguesMercaptopurine (6−mercaptopurine, or 6−MP) :• It is immunosuppressive cytotoxic substance. It is widely

used in transplantations to control rejection reactions. • It is acts as a purine analogue and once enter the cell, it is

converted to 6-MP-ribosephophate and can be incorporated into RNA&DNA resulting in non functioning RNA & DNA & finally inducing cell cycle arrest and apoptosis.

-It also inhibits purine ring biosynthesisAdverse reactions• Diarrhea, nausea, vomiting, loss of appetite, • Allergic reaction include rash, itching, swelling, dizziness,

trouble breathing.• Mercaptopurine cause myelosuppression. Those taking

mercaptopurine should get permission from a doctor in order to receive immunizations and vaccinations.

Azathioprine: It is one of the main immunosuppressive

cytotoxic substance. It is widely used in transplantations to control rejection reactions. It is nonenzymatically cleaved to 6 - M P that acts as a purine analogue and inhibits DNA synthesis

3-Pyrimidine analogues5-flurouracil (5-FU)• It act as a uracil analogue, it is transformed inside the cell

into 5-FU deoxynucleotide which compete with deoxyuridine monophosphate DUMP for thymidylate synthase leading to inhibition of deoxythymidine monophosphate DTMP synthesis so inhibition of DNA synthesis (Not RNA or protein)

• Also it is incorporated into DNA , non functioning DNA .• finally inducing cell cycle arrest and apoptosis by

inhibiting the cell's ability to synthesize DNA. • It is an S-phase specific drug • 5−FU may be used in combination with other

chemotherapy agents to treat cancers of the breast, stomach, colon, rectum, and pancreas.

Side effect1- Most unwanted effect is GIT epithelial damage, diarrhea and mouth ulcers. 2-the most dangerous side effect is bone marrow suppression

Cytarabine It is analogue to 2-deoxycytidine and in the body it is converted into cytosine triphosphate and inhibit DNA polymerase thus inhibiting DNA synthesis.

5-flurouracil (5-FU)

Cytarabine

III-Antitumor antibiotics (CCNS): 1-Dactinomycinis isolated from soil bacteria of the genus Streptomyces.It was the first antibiotic shown to have anti-cancer activity and used in treatment of a variety of cancers.It inhibits transcription by binding to DNA at the transcription initiation complex and preventing elongation by RNA polymerase. As it can bind DNA duplexes, it can also interfere with DNA replication

2-Doxorubicin (adriamycin)Mechanism of action•Doxorubicin is anthracyclin antibiotic interferes with the cells' production of DNA and RNA by inserting itself between adjacent base pair causing local uncoiling thus blocking DNA and RNA synthesis.•Also its antitumor effect is related to its inhibition of topoisomerase II enzyme (responsible for DNA repair).•CYP 450 catalyzes the conversion of Doxorubicin into semiquinone free radicals which produce superoxide ion & H2O2 that mediate single strand scission in DNA

Uses• Multiple cancers including breast, bone, ovarian & leukemia.• Acute lymphocytic leukemia (ALL). • Non−Hodgkin's lymphoma• Side effects• A major problem with the use of doxorubicin is that it cause

irreversible heart problems specially heart failure …….(why?)• Hypersensitivity, myelosuppression• Nausea, vomiting & diarrhea• Urine and tears may take on a red color.

3-Mitomycin•Mitomycin−C is an antitumor antibiotic. Mechanisimically however, it belongs to DNA alkylating agents.•Upon bioactivation inside the cell ,it preferentially alkylates O6 of guanine base in DNA leading to cross linking of DNA.•It also degrade DNA through formation of free radicals. •Side effects

– mitomycin−C may cause bone marrow suppression. – Lung fibrosis may occur. If these lung problems do

occur, corticosteroids may provide effective therapy. Stopping mitomycin−C therapy may also be recommended.

4-Bleomycin•It is cytotoxic in any phase of the cycle even on G0 phase •Bleomycin degrade preformed DNA causing chain fragmentation and release of free bases through the formation of free radicals (superoxide and hydroxyl radicals).

Uses•Bleomycin is used in the treatment of a number of different cancers, including cancer of the head and neck, skin, esophagus, lung, testis, and genitourinary tract. •In addition, it is used in the treatment of Hodgkin's disease and non−Hodgkin's lymphomas.

Side effects•Pulmonary fibrosis •Raynaud's phenomenon (which affects the fingers and toes, may involve pain, pale color, and abnormal sensation as burning) •In addition, headache, and nausea and vomiting may occur.

5-Procarbazine•Procarbazine is an anticancer agent inhibits DNA and RNA synthesis in cells•interfering with mitosis.Uses•Procarbazine is used in the treatment of various cancers, although the best established usage is with Hodgkin's disease.• Other cancers in which procarbazine is sometimes used include lymphomas, brain tumors, skin cancer, lung cancer, and multiple myeloma.Side effects•it decreases the white blood cells and the platelet cells. •The most severe side effect is nausea and vomiting.•There may be neurological side effects such as confusion, sleepiness, depression, nightmares, agitation, and nervousness (it is weak MAOI………hypertension???)

Lecture No:03IV-Plant alkaloids (Phase specific)

1-The vinca alkaloids Vincristine & vinblastine (M-phase)Mechanism of action Tubulin is a structural protein which polymerises to form microtubules.

The cell cytoskeleton and mitotic spindle, amongst other things, are made of microtubules. Vincristine binds to tubulin inhibiting polymerization of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. The vinca alkaloids therefore affect all rapidly dividing cell types including cancer cells, but also intestinal epithelium and bone marrow.

Side effects The main side-effects of vincristine are peripheral neuropathy.

Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100. %. vinblastin is less neurotoxic

Uses• Non Hodgkin's& Hodgkin's disease, malignant lymphomas and

leukemia.

2-TaxanesPaclitaxel & docetaxel it is used for treatment of lung, ovarian and breast cancer. Mechanism of action paclitaxel hyper-stabilizes microtubule structure (freez them). Paclitaxel binds to the β subunit of tubulin ,the resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules is necessary for their function.Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.Side effectsBone marrow suppression and neurotoxicity

3-Etoposide• Chemically it is deriven from podophyllotoxin, a toxin

found in the mandrake root.

• An inhibitor of the enzyme topoisomerase II. cause breaks in the DNA inside the cancer cells and prevent them from further dividing and multiplying. Then the cells die.

Side effect• Vomiting & alopecia • Bone marrow suppressionuses • It has been useful for treatment of testicular cancer and

small cell lung cancer.

V-Miscellaneous cytotoxic drugs1-Crisantaspase• It is a preparation of asparaginase which kills

cancer cells by breaking down certain protein (L−asparagine) that is necessary for survival and growth . certain tumors are incapable of forming such protein e.g. acute lymphoblastic leukemia ALL.

• Fortunately, normal cells are not dependent on L−asparagine for survival.

• Asparaginase is mainly given in combination with vincristine and steroids (either prednisone or dexamethasone).

2-Mitotan• effective in the treatment of adrenocortical

carcinoma.• As a chemical, mitotane resembles the

insecticides DDD and DDT, although mitotane does not harm people as these do. Scientists do not understand why, but the drug causes damage to the adrenocortex in such a way as to be helpful for some patients with adrenocortical tumors. In addition, mitotane restricts the ability of the gland to produce steroids.

2 -Hormones and hormone antagonists

1-Corticosteroids Corticosteroids have broad use in cancer treatment. Some are used to treat adult leukemias, adult lymphomas, and acute childhood leukemia. Immunosuppressive mechanismGlucocorticoids 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 tapering )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)· hydrocortisone · methylprednisolone (Medrol)

2-Estrogens & ProgestonsMainly used in androgen dependent prostatic tumors3-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 cancerSide 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

Hormone antagonistsTamoxifen• 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)

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

Lecture No:043-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

a-Immunosuppressant1 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 immunophilinsCyclosporin 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.

b-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.

AldesleukinAldesleukin 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 effectFlu-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

InterferonsInterferons 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 cancersSide effectsmuscle 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,

LevamisoleLevamisole 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 EffectsAllergic 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 hypotensionThalidomide 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

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