Antineoplastic AgentsAntineoplastic AgentsAntineoplastic medications: drugs used to treat cancer, also called cancer Antineoplastic medications: drugs used to treat cancer, also called cancer

drugs ,cytotoxic agents and anticancer drugs.drugs ,cytotoxic agents and anticancer drugs.

CancerCancerAlong with heart disease, cancer is the largest cause of death in the developed worldAlong with heart disease, cancer is the largest cause of death in the developed worldCancer affects 1 in 3 people and is responsible for 25% of all deathsCancer affects 1 in 3 people and is responsible for 25% of all deathsCancer is an unregulated proliferation of cells due to loss of normal controls, Cancer is an unregulated proliferation of cells due to loss of normal controls, resulting in unregulated growth, lack of differentiation, local tissue invasion, and, resulting in unregulated growth, lack of differentiation, local tissue invasion, and, often, metastasis.often, metastasis. Cancer can develop in any tissue or organ at any age. There is often an immune Cancer can develop in any tissue or organ at any age. There is often an immune response to tumor.response to tumor.Many cancers are curable if detected at an early stage, and long-term remission is Many cancers are curable if detected at an early stage, and long-term remission is often possible in later stages. often possible in later stages.

Causes of CancerCauses of Cancer::1. 30 % is due to smoking: lung, mouth, pharynx, larynx, esophagus, urinary bladder, 1. 30 % is due to smoking: lung, mouth, pharynx, larynx, esophagus, urinary bladder,

pancreas, and kidney cancers.pancreas, and kidney cancers.2. Lifestyle – diet, alcohol consumption, reproductive behavior, sexual behavior, 2. Lifestyle – diet, alcohol consumption, reproductive behavior, sexual behavior,

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

papillomavirus.papillomavirus.

Types of TumorsTypes of Tumors:: -Benign: non cancerous and not an immediate threat to life, even though -Benign: non cancerous and not an immediate threat to life, even though

treatment eventually may be required for health.treatment eventually may be required for health.

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

Characteristics of cancer cells:Characteristics of cancer cells:Persistent cell proliferationPersistent cell proliferationInvasive growthInvasive growthMetastases Metastases (a tumor may shed cells into the circulation. Although most circulating tumor cells die as a result (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, of intravascular trauma, a tiny number adhere to the vascular endothelium and penetrate into surrounding tissues, generating independent tumors (metastases) at distant sites.) generating independent tumors (metastases) at distant sites.)

Etiology of CancerEtiology of Cancer Genetics Genetics VirusesViruses Occupational and Environmental CarcinogensOccupational and Environmental CarcinogensRadiationRadiation

Cont.: Etiology of CancerCont.: Etiology of Cancer

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

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

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

2-2-Tumor suppressor genes are inherent genes that play a role in cell Tumor suppressor genes are inherent genes that play a role in cell division and division and DNA repairDNA repair and are critical for detecting inappropriate and are critical for detecting inappropriate growth signals in cellsgrowth signals in cells. . If these genes, as a result of inherited or If these genes, as a result of inherited or acquired mutations, become unable to function, genetic mutations in acquired mutations, become unable to function, genetic mutations in other genes can proceed other genes can proceed unchecked,unchecked, leading to neoplastic leading to neoplastic transformationtransformation..Another important regulatory protein, p53, prevents replication of Another important regulatory protein, p53, prevents replication of damaged DNA in normal cells and promotes cell death damaged DNA in normal cells and promotes cell death ((apoptosisapoptosis) ) in in cells with abnormal DNAcells with abnormal DNA. . Inactive or altered p53 allows cells with Inactive or altered p53 allows cells with abnormal DNA to survive and divideabnormal DNA to survive and divide. . The The p53p53 gene is defective in gene is defective in many human cancers.many human cancers.Telomeres are nucleoprotein complexes that cap the ends of Telomeres are nucleoprotein complexes that cap the ends of chromosomes and maintain their integritychromosomes and maintain their integrity. . Telomere shortening occur Telomere shortening occur with aging .Telomerase is an enzyme that provides for telomere with aging .Telomerase is an enzyme that provides for telomere synthesis and maintenance, thus telomerase may potentially allow for synthesis and maintenance, thus telomerase may potentially allow for cellular immortalitycellular immortality. . Telomerase activity may promote tumors Telomerase activity may promote tumors through multiple, complex mechanisms, especially by subverting the through multiple, complex mechanisms, especially by subverting the normal DNA synthetic checkpointsnormal DNA synthetic checkpoints..

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

E.G. :Epstein-Barr, nasopharyngeal carcinoma -Hepatitis B virus, hepatocellular E.G. :Epstein-Barr, nasopharyngeal carcinoma -Hepatitis B virus, hepatocellular carcinoma -HIV Kaposi's sarcoma.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, However, DNA is altered via mutagens including chemical carcinogens, viruses, and radiation. This mutations is inherted by at least one cell division (intiation). and radiation. This mutations is inherted by at least one cell division (intiation).

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

Upon exposure to other epigenetic factors (hormones, co- carcinogens, Upon exposure to other epigenetic factors (hormones, co- carcinogens, immunosuppressant…which themselves are non carcinogenic) tumor growth is immunosuppressant…which themselves are non carcinogenic) tumor growth is promoted (promotion)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 There are three basic treatment possibilities for cancer: surgery, radiotherapy, and cancer: surgery, radiotherapy, and chemotherapy.chemotherapy.Some cancers where chemotherapy works very wellSome cancers where chemotherapy works very well: :

Childhood leukemiaChildhood leukemiaRetinoblastomaRetinoblastomaOsteosarcomaOsteosarcomaTesticular cancerTesticular cancerHodgkin’s DiseaseHodgkin’s DiseaseSome lymphomasSome lymphomasSome early breast cancersSome early breast cancers

Cancers that are very difficult to treat with chemotherapeutics (need Cancers that are very difficult to treat with chemotherapeutics (need surgery or radiotherapy first)surgery or radiotherapy first)::ColonColonLungLungLate stage breast cancerLate stage breast cancerPancreatic cancerPancreatic cancer

((WHY???).WHY???).

Problems associated with chemotherapyProblems associated with chemotherapy1-Resistance to chemotherapy1-Resistance to chemotherapy

Resistance to chemotherapy may develop by several Resistance to chemotherapy may develop by several mechanisms:mechanisms: Decrease in the amount of drug uptake by cancer cellsDecrease in the amount of drug uptake by cancer cells

E.G. MethotrexateE.G. MethotrexateIncrease in the amount of drug removed by cancer cells. Increase in the amount of drug removed by cancer cells. (Transporters=P-glycoprotein).(Transporters=P-glycoprotein).

E.G. Vinblastine ,doxorubicin, bleomycin ,etapsoid….E.G. Vinblastine ,doxorubicin, bleomycin ,etapsoid….Decrease or alteration in target molecule sensitivity – this is Decrease or alteration in target molecule sensitivity – this is caused by mutation in the molecule targeted by the drugcaused by mutation in the molecule targeted by the drug

E.G. Methotrexate,Mercaptopurine,doxorubicinE.G. Methotrexate,Mercaptopurine,doxorubicinIncrease in DNA repair ability of the cell via an increased Increase in DNA repair ability of the cell via an increased expression of DNA repairing enzymes.expression of DNA repairing enzymes.

E.G. Alkylating agent E.G. Alkylating agent

2-Toxicity and side Effects of Antineoplastic Agents2-Toxicity and side Effects of Antineoplastic Agents::

Normal cells in the body that tend to be Normal cells in the body that tend to be injured the most due to chemotherapy are injured the most due to chemotherapy are those which have a high growth fraction. those which have a high growth fraction. Those are bThose are bone marrow, GI Tract ,hair one marrow, GI Tract ,hair follicles, reproductive organs .Leading to the follicles, reproductive organs .Leading to the followings:followings:Alopecia- hair lossAlopecia- hair lossMyelosuppression-bone marrow lossMyelosuppression-bone marrow lossEmetic potential: disruptive to cells in stomach which Emetic potential: disruptive to cells in stomach which causes: Nausea/vomitingcauses: Nausea/vomitingLow WBC count- low immunityLow WBC count- low immunity

Treatment of Chemotherapy ToxicityTreatment of Chemotherapy Toxicity

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

Other:

Bone marrow: Decreased

Neutrophils

InfectionBegins 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

Anemia120 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 .

Treat stomatitis with anesthetics and

antifungal. Treat nausea with anti-

emetics like ondansetron

You can also use glucocorticoids&

lorazepam to reduce the inflammation.

Hair folliclesAlopeciaBegins 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 tumor3-Treatment-induced tumor

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

Cell cycleCell cycle Scientists have determined that cell Scientists have determined that cell

cycle can be divided into:.cycle can be divided into:. Gap 0 (G0Gap 0 (G0): There are times when a cell ): There are times when a cell

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

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

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

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

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

Cancer chemotherapeutic Cancer chemotherapeutic agentsagents

They are classified into:They are classified into:Cell-cycle non specific agents(CCNS):Cell-cycle non specific agents(CCNS): are cytotoxic in any phase are cytotoxic in any phase of the cycle even on Gof the cycle even on G00 phase and so are more effective against phase and so are more effective against large slowly growing tumorslarge slowly growing tumors..

E.G.Bleomycin.E.G.Bleomycin.

Cell-cycle specific (CCS):Cell-cycle specific (CCS): are cytotoxic on all phases but not on are cytotoxic on all phases but not on cells out of the cycle(at Gcells out of the cycle(at G00 ) and so are more effective against ) and so are more effective against rapidly growing tumors. Work better in combination than alonerapidly growing tumors. Work better in combination than alone

E.G. Mitomycin, doxorubicin,….etc.E.G. Mitomycin, doxorubicin,….etc.

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

phase.)phase.)

Anticancer DrugsAnticancer DrugsThere are three Major Groups of Anticancer Drugs:There are three Major Groups of Anticancer Drugs:1) Cytotoxic Drugs (largest group)1) Cytotoxic Drugs (largest group)

-Alkylating agents -Alkylating agents -Antimetabolites-Antimetabolites

-Antitumor antibiotics-Antitumor antibiotics -Plant alkaloids-Plant alkaloids -Miscellaneous cytotoxic drugs-Miscellaneous cytotoxic drugs

2) Hormones and hormone antagonists2) Hormones and hormone antagonists These are among the best-tolerated chemotherapeutics because These are among the best-tolerated chemotherapeutics because

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

3) Immunomodulators3) Immunomodulators-Immunostimulants, including interferons and interleukins-Immunostimulants, including interferons and interleukins-Immunosuppressant-Immunosuppressant

1-1-Cytotoxic DrugsCytotoxic Drugs

I-Alkylating Agents (CCNSI-Alkylating Agents (CCNS))Mechanism of Alkylating AgentsMechanism of Alkylating Agents

These drugs work by alkylation with nucleophilic substitution . They alkylate a These drugs work by alkylation with nucleophilic substitution . They alkylate a variety of cellular constituents, such as cell membranes, proteins, and most variety of cellular constituents, such as cell membranes, proteins, and most importantly importantly DNADNA. More specifically, the nitrogenous bases of DNA are what get . More specifically, the nitrogenous bases of DNA are what get alkylated. alkylated.

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

1) 1) Miscoding (In transcription)Miscoding (In transcription)

2) 2) Cross linkingCross linking- this only occurs if the drug is bifunctional - this only occurs if the drug is bifunctional

The net result is cancer cell undergo apoptosisThe net result is cancer cell undergo apoptosis ..

Alkylating Agents(CCNS)Alkylating Agents(CCNS)

Subgroups of Alkylating AgentsSubgroups of Alkylating Agents1) Nitrogen mustards1) Nitrogen mustards2) Nitrosoureas2) Nitrosoureas3) Alkyl sulfonates3) Alkyl sulfonates4) 4-Platinum Coordination Compounds 4) 4-Platinum Coordination Compounds

1-Nitrogen Mustards1-Nitrogen MustardsE.G.: Mechlorethamine, cyclophosphamid, melphalan & chlorambucilE.G.: Mechlorethamine, cyclophosphamid, melphalan & chlorambucila-Mechlorethaminea-Mechlorethamine- first alkylating agent employed clinically - first alkylating agent employed clinically - bifunctional, thus can crosslink DNA- bifunctional, thus can crosslink DNA- extremely unstable and is inactivated within a few minutes following administration.- extremely unstable and is inactivated within a few minutes following administration. Thus it is given IV. Thus it is given IV.

Clinical UsesClinical Uses-Hodgkin’s Disease-Hodgkin’s Disease-Non-Hodgkin’s Lymphoma-Non-Hodgkin’s Lymphoma

Toxicity/ Side EffectsToxicity/ Side Effects- Dose limiting toxicity is bone marrow depression- Dose limiting toxicity is bone marrow depression- Nausea/ Vomiting- Nausea/ Vomiting - Alopecia- Alopecia- Diarrhea- Diarrhea - Sterility - Sterility

b-Cyclophsphamidb-Cyclophsphamid -It acts as cytotoxic and -It acts as cytotoxic and immunosuppressor agentimmunosuppressor agent..- Prodrug which must be activated by the cytochrome p450 system, which turns it into a nitrogen - Prodrug which must be activated by the cytochrome p450 system, which turns it into a nitrogen

mustard. mustard. - bifunctional agent- bifunctional agent-most widely used alkylating agent-most widely used alkylating agent

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

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

Treatment of Treatment of cyclophsphamid toxicitycyclophsphamid toxicity

2-Nitrosoureas2-Nitrosoureas- bifunctional- bifunctional- active against broad spectrum of neoplastic disease- active against broad spectrum of neoplastic disease- inhibits synthesis of both DNA and RNA, as well as proteins- 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 - These drugs are highly lipophilic, so they can easily cross blood-brain-barrier, and are great for CNS tumors.great for CNS tumors.- Big problem in this class is that they are highly mutagenic and highly carcinogenic.- Big problem in this class is that they are highly mutagenic and highly carcinogenic.- Major toxicity is - Major toxicity is DELAYED bone marrow depressionDELAYED bone marrow depression & & PulmonaryPulmonary fibrosisfibrosis..

Clinical usesClinical uses- - primary and metastasis tumors of the brainprimary and metastasis tumors of the brain- Hodgkin’s Disease- Hodgkin’s Disease- Non-Hodgkin’s lymphoma- Non-Hodgkin’s lymphoma- Adenocarcinoma of stomach, colon, and rectal cancer- Adenocarcinoma of stomach, colon, and rectal cancer- Hepatocarcinoma- Hepatocarcinoma

E.G.:E.G.:a-Carmustine a-Carmustine bb-Lomustine -Lomustine

3-Alkyl Sulfonates3-Alkyl SulfonatesBusulfanBusulfanClinical usesClinical usesGreat effect on for Chronic granulocytic Leukemia Great effect on for Chronic granulocytic Leukemia

Toxicity/ Side EffectsToxicity/ Side Effects- Dose limiting toxicity is bone marrow depression.- Dose limiting toxicity is bone marrow depression.- Pulmonary infiltrates and pulmonary fibrosis- Pulmonary infiltrates and pulmonary fibrosis- - Tonic-clonic seizures in epilepticsTonic-clonic seizures in epileptics- Nausea and vomiting- Nausea and vomiting- Alopecia- Alopecia- Sterility- Sterility- Skin hyper pigmentation- Skin hyper pigmentation- Cataracts- Cataracts- Hepatitis- Hepatitis

4-Platinum Coordination Compounds4-Platinum Coordination CompoundsE.G.:E.G.:CisplatinCisplatin

forms crosslinks forms crosslinks withinwithin DNA strands. DNA strands. Cis-platin is not really an “alkylating” Cis-platin is not really an “alkylating” agent, but since it operates via the same mechanism as the alkylating agents, it is agent, but since it operates via the same mechanism as the alkylating agents, it is placed within that group. placed within that group.

Clinical UsesClinical Uses- Very powerful against TESTICULAR CANCER- Very powerful against TESTICULAR CANCER- Also good for carcinomas of ovary, bladder, head, and neck- Also good for carcinomas of ovary, bladder, head, and neck

Toxicity/ Side EffectsToxicity/ Side Effects- Renal tubular damage (minimized via massive hydration coupled with anti-emetics)- Renal tubular damage (minimized via massive hydration coupled with anti-emetics)- Ototoxicity and peripheral neuropathy- Ototoxicity and peripheral neuropathy- VERY SEVER vomiting( Ondanosetron…?)- VERY SEVER vomiting( Ondanosetron…?)

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

II-Antimetabolites (CCS)II-Antimetabolites (CCS)An antimetabolite is a chemical with a similar structure to a metabolite required for normal 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 biochemical reactions, yet different enough to interfere with the normal functions of cells, including cell division.cell division.All antimetabolites are used in cancer treatment, as they interfere with DNA production and 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).therefore cell division and the growth of tumors (mainly in S-phase specific).

They are classified into:They are classified into: 1- Folic acid analogues1- Folic acid analogues 2- Purine analogues2- Purine analogues 3- Pyrimidine analogues 3- Pyrimidine analogues

Purin and pyrimidine antagonists are phosphorelated inside the body into nucleotid form in order to Purin and pyrimidine antagonists are phosphorelated inside the body into nucleotid form in order to be cytotoxicbe cytotoxic

UsesUsesleukemia. leukemia. non-Hodgkin's lymphomanon-Hodgkin's lymphomainflammatory bowel disease such as Crohn's Disease and ulcerative colitisinflammatory bowel disease such as Crohn's Disease and ulcerative colitisIt is widely used as It is widely used as immunosuppressantimmunosuppressant in transplantations to control rejection reactions. in transplantations to control rejection reactions.

Methotrexate:Methotrexate: -A folic acid analogue, prevents the formation of tetrahydrofolate, -A folic acid analogue, prevents the formation of tetrahydrofolate,

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

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

The most common toxicity is nepherotoxicity (pptThe most common toxicity is nepherotoxicity (pptnn of the drug in of the drug in renal tubule.)renal tubule.)

1-1-Folic acidFolic acid analoguesanalogues

Cont: Cont: Folic acid analoguesFolic acid analogues1-1-Methotrexate compete with folic acid for DHFR and inhibits it . Therefore, it inhibits the Methotrexate compete with folic acid for DHFR and inhibits it . Therefore, it inhibits the synthesis of DNA, RNA and proteins.synthesis of DNA, RNA and proteins.2-Also,DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolat which is 2-Also,DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolat which is needed for the needed for the de novode novo synthesis of the deoxynucleoside thymidine phosphate DTMP synthesis of the deoxynucleoside thymidine phosphate DTMP ( required for DNA synthesis)( required for DNA synthesis)

2-Purine analogues2-Purine analoguesMercaptopurine (6−mercaptopurine, or 6−MPMercaptopurine (6−mercaptopurine, or 6−MP) :) : --It is It is immunosuppressiveimmunosuppressive cytotoxic substance. It is widely used in transplantations cytotoxic substance. It is widely used in transplantations

to control rejection reactions. to control rejection reactions. -It is acts as a purine analogue and once enter the cell, it is converted to 6-MP--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 ribosephophate and can be incorporated into RNA&DNA resulting in non functioning functioning RNA & DNARNA & DNA &finally inducing cell cycle arrest and apoptosis. &finally inducing cell cycle arrest and apoptosis.

-It also inhibits purring ring biosynthesis-It also inhibits purring ring biosynthesis

Adverse reactionsAdverse reactionsDiarrhea, nausea, vomiting, loss of appetite, Diarrhea, nausea, vomiting, loss of appetite, Allergic reaction include rash, itching, swelling, dizziness, trouble breathing.Allergic reaction include rash, itching, swelling, dizziness, trouble breathing.Mercaptopurine cause myelosuppression. Those taking mercaptopurine should get Mercaptopurine cause myelosuppression. Those taking mercaptopurine should get permission from a doctor in order to receive immunizations and vaccinations.permission from a doctor in order to receive immunizations and vaccinations.

Azathioprine:Azathioprine: It is one of the mainIt is one of the main immunosuppressiveimmunosuppressive cytotoxic substance. It is widely used in cytotoxic substance. It is widely used in

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

3-3-Pyrimidine analoguesPyrimidine analogues 5-flurouracil (5-FU)5-flurouracil (5-FU)

It act as a uracil analogue, it is transformed inside the cell into 5-FU deoxynucleotide which It act as a uracil analogue, it is transformed inside the cell into 5-FU deoxynucleotide which compete with deoxyuridine monophosphate DUMP for compete with deoxyuridine monophosphate DUMP for thymidylate synthasethymidylate synthase leading to inhibition leading to inhibition of deoxythymidine monophosphate DTMP synthesis inhibition of DNA synthesis of deoxythymidine monophosphate DTMP synthesis inhibition of DNA synthesis ((Not Not RNA RNA or protienor protien))Also it is incorporated into DNA non functioning DNA .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. finally inducing cell cycle arrest and apoptosis by inhibiting the cell's ability to synthesize DNA. It is an S-phase specific drug It is an S-phase specific drug 5−FU may be used in combination with other chemotherapy agents to treat cancers of the breast, 5−FU may be used in combination with other chemotherapy agents to treat cancers of the breast, stomach,colon, rectum, and pancreas.stomach,colon, rectum, and pancreas.

Side effectSide effect1- Most unwanted effect is GIT epithelial damage, diarrhea and mouth ulcers. 1- Most unwanted effect is GIT epithelial damage, diarrhea and mouth ulcers. 2-the most dangerous side effect is bone marrow suppression2-the most dangerous side effect is bone marrow suppression

CytarabineCytarabine It is analogue to 2-deoxycytidine and in the body it is converted into cytosine triphosphate and It is analogue to 2-deoxycytidine and in the body it is converted into cytosine triphosphate and

inhibit DNA polymerase thus inhibiting DNA synthesis.inhibit DNA polymerase thus inhibiting DNA synthesis.

5-flurouracil 5-flurouracil (5-FU)(5-FU)

CytarabineCytarabine

III-Antitumor antibiotics (CCNS) :III-Antitumor antibiotics (CCNS) :1-Dactinomycin1-Dactinomycin

is isolated from soil bacteria of the genus is isolated from soil bacteria of the genus StreptomycesStreptomyces..It was the first antibiotic shown to have anti-cancer activity and used in treatment It was the first antibiotic shown to have anti-cancer activity and used in treatment of a variety of cancers.of a variety of cancers.It inhibits transcription by binding to DNA at the transcription initiation complex It inhibits transcription by binding to DNA at the transcription initiation complex and preventing elongation by RNA polymerase.and preventing elongation by RNA polymerase. As it can bind DNA duplexes, it can also interfere with DNA replicationAs it can bind DNA duplexes, it can also interfere with DNA replication

2-Doxorubicin (adriamycin)2-Doxorubicin (adriamycin)Mechanism of actionMechanism of action

Doxorubicin is anthracyclin antibiotic interferes with the cells' production of DNA Doxorubicin is anthracyclin antibiotic interferes with the cells' production of DNA and RNA by inserting itself between adjacent base pair causing local uncoiling and RNA by inserting itself between adjacent base pair causing local uncoiling thus blocking DNA and RNA synthesis.thus blocking DNA and RNA synthesis.

Also its antitumor effect is related to its inhibition of topoisomerase II enzyme Also its antitumor effect is related to its inhibition of topoisomerase II enzyme (responsipole for DNA repair).(responsipole for DNA repair).

CYTP 450 catalyzes the conversion of Dox. into semiquinone free radicals which CYTP 450 catalyzes the conversion of Dox. into semiquinone free radicals which produce superoxide ion & H2O2 that mediate single strand scission in DNAproduce superoxide ion & H2O2 that mediate single strand scission in DNA

UsesUsesMultiple cancers includingMultiple cancers including breast, bone, ovarian & leukemia.breast, bone, ovarian & leukemia.Acute lymphocytic leukemia (ALL). Acute lymphocytic leukemia (ALL). Non−Hodgkin's lymphomaNon−Hodgkin's lymphoma

Side effectsSide effectsA major problem with the use of doxorubicin is that it cause irreversible heart problems A major problem with the use of doxorubicin is that it cause irreversible heart problems specially heart failure …….(why?)specially heart failure …….(why?)Hypersensitivity, myelosuppressionHypersensitivity, myelosuppressionNausea, vomiting & diarrheaNausea, vomiting & diarrheaUrine and tears may take on a red color.Urine and tears may take on a red color.

3-Mitomycin−C3-Mitomycin−CMitomycin−C is an antitumor antibiotic. Mechanistically however, it belongs to DNA alkylating Mitomycin−C is an antitumor antibiotic. Mechanistically however, it belongs to DNA alkylating agents.agents.Upon bioactivation inside the cell ,it preferentially alkylates O6 of guanine base in DNA Upon bioactivation inside the cell ,it preferentially alkylates O6 of guanine base in DNA leading to cross linking of DNA.leading to cross linking of DNA.It also degrade DNA through formation of free radicals. It also degrade DNA through formation of free radicals.

Side effectsSide effects -mitomycin−C may cause bone marrow suppression. -mitomycin−C may cause bone marrow suppression. --Lung fibrosis may occurLung fibrosis may occur. If these lung problems do occur, corticosteroids may provide . If these lung problems do occur, corticosteroids may provide

effective therapy. Stopping mitomycin−C therapy may also be recommendedeffective therapy. Stopping mitomycin−C therapy may also be recommended..

4-Bleomycin4-BleomycinIt is cytotoxic in any phase of the cycle even on G0 phase It is cytotoxic in any phase of the cycle even on G0 phase Bleomycin degrade performed DNA causing chain fragmentation and Bleomycin degrade performed DNA causing chain fragmentation and release of free bases through the formation of free radicals (superoxide release of free bases through the formation of free radicals (superoxide and hydroxyl radicals).and hydroxyl radicals).

UsesUses -Bleomycin is used in the treatment of a number of different cancers, -Bleomycin is used in the treatment of a number of different cancers,

including cancer of the head and neck, skin, esophagus, lung, testis, and including cancer of the head and neck, skin, esophagus, lung, testis, and genitourinary tract. genitourinary tract.

-In addition, it is used in the treatment of Hodgkin's disease and -In addition, it is used in the treatment of Hodgkin's disease and non−Hodgkin's lymphomas. non−Hodgkin's lymphomas.

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

5-Procarbazine5-ProcarbazineProcarbazine is an anticancer agent inhibits DNA and RNA synthesis Procarbazine is an anticancer agent inhibits DNA and RNA synthesis in cellsin cellsinterfering with mitosis.interfering with mitosis.

UsesUsesProcarbazine is used in the treatment of various cancers, although the Procarbazine is used in the treatment of various cancers, although the best established usage is with Hodgkin's diseasebest established usage is with Hodgkin's disease.. Other cancers in which procarbazine is sometimes used include Other cancers in which procarbazine is sometimes used include lymphomas, brain tumors, skin cancer, lung cancer, and multiple lymphomas, brain tumors, skin cancer, lung cancer, and multiple myeloma.myeloma.

Side effectsSide effects it decreases the white blood cells and the platelet cells. it decreases the white blood cells and the platelet cells. The most severe side effect is nausea and vomiting.The most severe side effect is nausea and vomiting.There may be neurological side effects such as confusion, sleepiness, There may be neurological side effects such as confusion, sleepiness, depression, nightmares, agitation, and nervousness (it is weak depression, nightmares, agitation, and nervousness (it is weak MAOI………hypertension???)MAOI………hypertension???)

IV-Plant IV-Plant alkaloids (Phase specificalkaloids (Phase specific))

1-The vinca alkaloids1-The vinca alkaloids Vincristine & vinblastine (M-phase)Vincristine & vinblastine (M-phase)Mechanism of actionMechanism of action TubulinTubulin is a structural protein which polymerises to form microtubules. The is a structural protein which polymerises to form microtubules. The

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

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

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

UsesUses Non Hodgkin'sNon Hodgkin's& Hodgkin's disease& Hodgkin's disease, malignant lymphomas and leukemia., malignant lymphomas and leukemia.

2-Taxanes2-TaxanesPaclitaxel & docetaxelPaclitaxel & docetaxel it is used for treatment of it is used for treatment of lunglung, ovarian and , ovarian and breast breast cancer.cancer.

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

Side effectsSide effectsBone marrow suppression and neurotoxicityBone marrow suppression and neurotoxicity

3-Etoposide3-EtoposideChemically it is deriven from podophyllotoxin, a toxin found Chemically it is deriven from podophyllotoxin, a toxin found in the mandrake root.in the mandrake root.

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

Side effectSide effectVomiting & alopeciaVomiting & alopecia Bone marrow suppressionBone marrow suppression

usesuses It has been useful for treatment of testicular cancer and It has been useful for treatment of testicular cancer and small cell lung cancer. small cell lung cancer.

VV--Miscellaneous cytotoxic drugsMiscellaneous cytotoxic drugs1-Crisantaspase1-Crisantaspase

It is a preparation of asparaginase which kills cancer cells by breaking It is a preparation of asparaginase which kills cancer cells by breaking down certain protein (L−asparagine) that is necessary for survival and down certain protein (L−asparagine) that is necessary for survival and growth of certain tumors incapable of forming such protein e.g. acute growth of certain tumors incapable of forming such protein e.g. acute lymphoblastic leukemia ALL.lymphoblastic leukemia ALL.Fortunately, normal cells are not dependent on L−asparagine for survival.Fortunately, normal cells are not dependent on L−asparagine for survival.Asparaginase is mainly given in combination with vincristine and steroids Asparaginase is mainly given in combination with vincristine and steroids (either prednisone or dexamethasone).(either prednisone or dexamethasone).

2-Mitotan2-Mitotaneffective in the treatment of adrenocortical carcinoma.effective in the treatment of adrenocortical carcinoma.

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

2- 2- Hormones and hormone Hormones and hormone antagonistsantagonists

1-Corticosteroids 1-Corticosteroids Corticosteroids have broad use in cancer treatment. Some are used to treat adult leukemias, adult Corticosteroids have broad use in cancer treatment. Some are used to treat adult leukemias, adult

lymphomas, and acute childhood leukemia.lymphomas, and acute childhood leukemia. Immunosuppressive mechanismImmunosuppressive mechanism

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

Side effectsSide effectsHyperglycemia due to increased gluconeogenesis, insulin resistance caution in those with diabetes Hyperglycemia due to increased gluconeogenesis, insulin resistance caution in those with diabetes mellitus mellitus reduced bone density (osteoporosis, higher fracture risk, slower fracture repair) 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 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) adrenal insufficiency (if used for long time and stopped suddenly without a taper) muscle breakdown (proteolysis), weakness; reduced muscle mass and repair muscle breakdown (proteolysis), weakness; reduced muscle mass and repair growth failure, pubertal delay growth failure, pubertal delay Increased urea formation; negative nitrogen balance Increased urea formation; negative nitrogen balance

The most common corticosteroids used in cancer treatment are:The most common corticosteroids used in cancer treatment are:· dexamethasone (Decadron)· dexamethasone (Decadron)· hydrocortisone· hydrocortisone· methylprednisolone (Medrol)· methylprednisolone (Medrol)

2-Estrogens & Progestons2-Estrogens & ProgestonsMainly used in androgen dependent prostatic tumorsMainly used in androgen dependent prostatic tumors

3-Gonadotropin−releasing hormone analogues3-Gonadotropin−releasing hormone analogues

Goserelin AcetateGoserelin Acetate·· Goserelin acetate is a synthetic hormone that acts similarly to the naturally Goserelin acetate is a synthetic hormone that acts similarly to the naturally

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

It is used for treatment of breast and prostatic cancerIt is used for treatment of breast and prostatic cancer

Side effectsSide effects· sweating ,hot flashes, impotence (erectile dysfunction),sterility & gyncomestia· sweating ,hot flashes, impotence (erectile dysfunction),sterility & gyncomestia· depression or other mood changes· depression or other mood changes· Other common side effects in women include: light, irregular, vaginal bleeding & · Other common side effects in women include: light, irregular, vaginal bleeding & no menstrual periodno menstrual period

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

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

Adverse EffectsAdverse Effects

CNS: Depression, light headedness, dizziness, headache, decreased visual CNS: Depression, light headedness, dizziness, headache, decreased visual acuity &retinopathy acuity &retinopathy GI: GI: Nausea, vomitingNausea, vomitingHematological: HypercalcemiaHematological: HypercalcemiaGU: GU: Vaginal bleeding, vaginal discharge & menstrual irregularitiesVaginal bleeding, vaginal discharge & menstrual irregularitiesDermatologic: Dermatologic: Hot flashes, skin rashHot flashes, skin rash

Hormone antagonistsHormone antagonists

3-Immunomodulators3-Immunomodulators

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

ImmunomodulatorsImmunomodulators

ImmunosuppressantImmunosuppressant ImmunostimulantsImmunostimulants

a-Immunosuppressanta-Immunosuppressant1 Glucocorticoids 1 Glucocorticoids 2 Cytotoxic 2 Cytotoxic – a- Alkylating agents a- Alkylating agents – b- Antimetabolites b- Antimetabolites

1 Methotrexate 1 Methotrexate 2.Azathioprine and Mercaptopurine 2.Azathioprine and Mercaptopurine

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

Drugs acting on immunophilinsDrugs acting on immunophilinsCyclosporinCyclosporin is a calcineurin inhibitor. is one of the most widely used immunosuppressive drugs. It is a is a calcineurin inhibitor. is one of the most widely used immunosuppressive drugs. It is a

fungal peptide, composed of 11 amino acids.fungal peptide, composed of 11 amino acids.Cyclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of Cyclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of cyclosporin and immunocompetent lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophilin inhibits calcineurin, which under normal circumstances induces the transcription cyclophilin inhibits calcineurin, which under normal circumstances induces the transcription of interleukin-2. The drug also inhibits lymphokine production and interleukin release, of interleukin-2. The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.leading to a reduced function of effector T-cells.Cyclosporin is used in the treatment of acute rejection reactions, but has been increasingly Cyclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer immunosuppressants, as it is nephrotoxic.substituted with newer immunosuppressants, as it is nephrotoxic.

SirolimusSirolimusSirolimus is a macrolide lactone, produced by the Sirolimus is a macrolide lactone, produced by the Streptomyce hygroscopicusStreptomyce hygroscopicus It is used to It is used to prevent rejection reactions. Although it is a structural analogue of tacrolimus, it acts prevent rejection reactions. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side effects.somewhat differently and has different side effects.Contrary to cyclosporine that affect the first phase of the T lymphocyte activation, sirolimus 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. affects the second one, namely the signal transduction and their clonal proliferation. Therefore, sirolimus acts synergistically with cyclosporine and, in combination with other Therefore, sirolimus acts synergistically with cyclosporine and, in combination with other immunosuppressants, has few side effects. Indirectly it inhibits several T lympohocyte immunosuppressants, has few side effects. Indirectly it inhibits several T lympohocyte kinases and phosphatases, preventing the transmission of signal into their activity and the 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 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 to the plasma cells, which lowers the quantity of IgM, IgG and IgA antibodies produced. It acts immunoregulatory.acts immunoregulatory.

b-Immunostimulantsb-Immunostimulants Biologic therapy, also called immunostimulants, Biologic therapy, also called immunostimulants,

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

1-Monoclonal Antibodies1-Monoclonal Antibodies Monoclonal antibodies are proteins produced in the laboratory from a single 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. 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 When used as a treatment for cancer, there are three general strategies with monoclonal antibodies:monoclonal antibodies:One uses the ability of the antibodies to bind to the cancer cells having the 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 tumor antigens on their surface. The immune system will see the cancer cells marked with bound antibodies as foreign and destroy them.marked with bound antibodies as foreign and destroy them. A second strategy is to use the antibodies to block the binding of cytokines or 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 other proteins that are needed by the cancerous cells to maintain their uncontrolled growth. Monoclonal antibodies designed to work like this bind to uncontrolled growth. Monoclonal antibodies designed to work like this bind to the cytokine receptors that are on the tumor cell surface. the cytokine receptors that are on the tumor cell surface. A final strategy involves special antibodies that are linked (conjugated) to a 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 substance that is deadly to the cancer cells. E.G. radioactive isotopes, have been successfully conjugated to antibodies. The antibodies are then used to been successfully conjugated to antibodies. The antibodies are then used to specifically destroy he tumor cells with the radioactivity or toxic substance. specifically destroy he tumor cells with the radioactivity or toxic substance.

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

2-Biological response modifiers2-Biological response modifiers

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

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

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

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

Side effectSide effectFlu-like symptoms (chills, fever, fatigue) Flu-like symptoms (chills, fever, fatigue) Loss of appetite Loss of appetite Skin problems such as a rash, itchiness, scaling Skin problems such as a rash, itchiness, scaling Cardiac arrhythmias Cardiac arrhythmias Gastrointestinal disturbance, such as nausea and vomiting Gastrointestinal disturbance, such as nausea and vomiting Neurological effects, such as depression and poor concentrationNeurological effects, such as depression and poor concentration

InterferonsInterferonsInterferons are small, natural cytokines that are produced by Interferons are small, natural cytokines that are produced by leucocytes ,T−lymphocytes, and fibroblasts in response to infection and other biological leucocytes ,T−lymphocytes, and fibroblasts in response to infection and other biological stimuli.stimuli.The goal of interferon use is to activate tumor−specific cytotoxic T−lymphocytes. Thus, The goal of interferon use is to activate tumor−specific cytotoxic T−lymphocytes. Thus, tumor cells would be destroyed based on immunotherapy.tumor cells would be destroyed based on immunotherapy.Interferons attach to special receptors on the surface of cell membranes. Then Interferons attach to special receptors on the surface of cell membranes. Then produce variety of functions including enhancing or inhibiting enzymes, decreasing cell produce variety of functions including enhancing or inhibiting enzymes, decreasing cell proliferation, or enhancing the activity of macrophages and T−lymphocytes. There are proliferation, or enhancing the activity of macrophages and T−lymphocytes. There are several different classes of interferons, cancer therapy primarily focuses on alpha several different classes of interferons, cancer therapy primarily focuses on alpha interferons.interferons.Alpha interferons are used to treat cancers such as hairy cell leukemiaAlpha interferons are used to treat cancers such as hairy cell leukemia, , malignant malignant melanoma, and Kaposi's sarcoma (an AIDS−related cancer) as well as many other melanoma, and Kaposi's sarcoma (an AIDS−related cancer) as well as many other cancerscancers

Side effectsSide effectsmuscle aches, unusual metallic taste in the mouth, fever and chills, and general flu−like 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 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 fatigue. To reduce the flu−like symptoms physicians may suggest that the patient take acetaminophen before each dosage.acetaminophen before each dosage.confusion, trouble thinking and focusing, mental depression, nervousness, or confusion, trouble thinking and focusing, mental depression, nervousness, or numbness or tingling of fingers,numbness or tingling of fingers,

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

Side EffectsSide EffectsAllergic reaction. Allergic reaction. Decreased bone marrow function, resulting in fatigue Decreased bone marrow function, resulting in fatigue or signs of infection or signs of infection Problems related to the nervous system, such as Problems related to the nervous system, such as confusion, loss of consciousness, or speech confusion, loss of consciousness, or speech disturbancesdisturbances

3-3-Angiogenesis inhibitorsAngiogenesis inhibitors

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

ThalidomideThalidomide Thalidomide interferes with the growth of rapidly dividing cells.It interferes Thalidomide interferes with the growth of rapidly dividing cells.It interferes with the formation of blood vessels. It is called an antiangiogenic drugwith the formation of blood vessels. It is called an antiangiogenic drug It is used to treat several types of cancers, including kidney, ovarian, and It is used to treat several types of cancers, including kidney, ovarian, and breast cancer. breast cancer.

Side effects :Side effects :

Orthostatic hypotensionOrthostatic hypotensionThalidomide may cause peripheral neuropathy (numbness, tingling, pain, Thalidomide may cause peripheral neuropathy (numbness, tingling, pain, or burning sensations in the feet or hands). or burning sensations in the feet or hands). Thalidomide may cause severe birth defects or fetal death if taken by Thalidomide may cause severe birth defects or fetal death if taken by pregnant women (phocomelia). pregnant women (phocomelia). Rash Rash Lack of bowel movementsLack of bowel movements