Chapter 54Chapter 54Cancer ChemotherapyCancer Chemotherapy

BackgroundBackground

It is the second most common cause of death It is the second most common cause of death in the developed nations in the developed nations

One in three people will be diagnosed with One in three people will be diagnosed with cancer during their lifetimecancer during their lifetime

The terms The terms cancercancer, , malignant neoplasmmalignant neoplasm and and malignant tumourmalignant tumour are synonymous are synonymous

Both benign and malignant tumours manifest Both benign and malignant tumours manifest uncontrolled proliferation, but the latter are uncontrolled proliferation, but the latter are distinguished by their capacity for distinguished by their capacity for dedifferentiationdedifferentiation, their invasiveness and their , their invasiveness and their ability to ability to metastasisemetastasise (spread to other parts of (spread to other parts of the bodythe body

BackgroundBackground

Cancer:Cancer: is a disease in which there is is a disease in which there is uncontrolled multiplication & spread within uncontrolled multiplication & spread within the body of abnormal forms of body’s own the body of abnormal forms of body’s own cellscells

Cancer cells manifest, to varying degrees, Cancer cells manifest, to varying degrees, four characteristics that distinguish them four characteristics that distinguish them from normal cells:from normal cells:1)1) Uncontrolled proliferationUncontrolled proliferation2)2) Dedifferentiation & loss of functionDedifferentiation & loss of function3)3) InvasivenessInvasiveness4)4) MetastasiMetastasiss

CausesCauses

A normal cell turns into a cancer cell b/c of one A normal cell turns into a cancer cell b/c of one or more mutation in its DNA, which can be or more mutation in its DNA, which can be inherited or acquired , which can be inherited or inherited or acquired , which can be inherited or acquired, usually through exposure to viruses or acquired, usually through exposure to viruses or carcinogenscarcinogens (e.g. tobacco products, asbestos) (e.g. tobacco products, asbestos)

2 main categories of genetic changes:2 main categories of genetic changes:– Induce of oncogenic transformation Induce of oncogenic transformation – Inactivation of tumour suppressor genesInactivation of tumour suppressor genes

About 30 tumour suppressor genes and 100 About 30 tumour suppressor genes and 100 dominant oncogenes have been identifieddominant oncogenes have been identified

CausesCauses

Incidence, geographical distribution, & Incidence, geographical distribution, & behaviour of specific types of cancer are behaviour of specific types of cancer are related to: age, sex, race, genetic related to: age, sex, race, genetic predisposition, & exposure to environmental predisposition, & exposure to environmental carcinogenscarcinogens

Principles of cancer Principles of cancer chemotherapychemotherapy

• Drug therapy is used in patients with Drug therapy is used in patients with cancer to:cancer to:

1.1. Eradicate the diseaseEradicate the disease

2.2. Induce a remissionInduce a remission

3.3. Control symptomsControl symptoms Ideal anticancer drugs would eradicate cancer Ideal anticancer drugs would eradicate cancer

cells without harming normal tissuescells without harming normal tissues Unfortunately, most currently available agents Unfortunately, most currently available agents

do not specifically recognize neoplastic cells do not specifically recognize neoplastic cells but affect all kind of proliferating cellsbut affect all kind of proliferating cells

Principles of cancer chemotherapyPrinciples of cancer chemotherapy

The treatment of cancer patients requires a The treatment of cancer patients requires a skillful interdigitation of pharmacotherapy with skillful interdigitation of pharmacotherapy with other modalities of treatment (e.g., surgery other modalities of treatment (e.g., surgery and irradiation)and irradiation)

In biochemical terms, cancer cells and normal In biochemical terms, cancer cells and normal cells are so similar in most respects that it is cells are so similar in most respects that it is more difficult to find general, exploitable, more difficult to find general, exploitable, biochemical differences between thembiochemical differences between them

Principles of cancer chemotherapyPrinciples of cancer chemotherapy

Individual patient characteristics determine Individual patient characteristics determine the choice of modalitiesthe choice of modalities

Not all patients can tolerate drugs, and not all Not all patients can tolerate drugs, and not all drug regimens are appropriate for a given drug regimens are appropriate for a given patientpatient

Renal and hepatic function, bone marrow Renal and hepatic function, bone marrow reserve, general performance status, and reserve, general performance status, and concurrent medical problems all come into concurrent medical problems all come into consideration in making a therapeutic planconsideration in making a therapeutic plan

Principles of Drug TreatmenPrinciples of Drug Treatmentt

The log cell kill hypothesis: The log cell kill hypothesis: cytotoxic effect cytotoxic effect of anticancer drugs follow log-cell kinetics: a of anticancer drugs follow log-cell kinetics: a given dose would be predicted to kill a given dose would be predicted to kill a constant constant proportion/fractionproportion/fraction of cellsof cells

For example: if an individual drug leads to a 3 For example: if an individual drug leads to a 3 log kill of cancer cells and reduces the tumor log kill of cancer cells and reduces the tumor burden from 10burden from 101010 to 10 to 1077 cells, the same dose cells, the same dose used at a tumor burden of 10used at a tumor burden of 1055 cells reduces cells reduces the tumor mass to 10the tumor mass to 1022 cells cells

Cell kill is, therefore, proportional, regardless Cell kill is, therefore, proportional, regardless of tumor burdenof tumor burden

Benefits of combination therapyBenefits of combination therapy

Combination-drug chemotherapy is more Combination-drug chemotherapy is more successful than single-drug treatment in most of successful than single-drug treatment in most of the cancers for which chemotherapy is effective the cancers for which chemotherapy is effective b/c:b/c:

1)1) It provides maximal cell kill within the range of It provides maximal cell kill within the range of toxicity tolerated by the host for each drug toxicity tolerated by the host for each drug

2)2) It provides a broader range of interaction between It provides a broader range of interaction between drugs and tumor cells with different genetic drugs and tumor cells with different genetic abnormalities in a heterogeneous tumor populationabnormalities in a heterogeneous tumor population

3)3) It may prevent or slow the subsequent It may prevent or slow the subsequent development of cellular drug resistancedevelopment of cellular drug resistance

Benefits of combination therapyBenefits of combination therapy

Certain principles have been used in designing Certain principles have been used in designing such treatmentssuch treatments

Efficacy: Efficacy: each drug should have some individual each drug should have some individual therapeutic activity against the particular tumor therapeutic activity against the particular tumor being treatedbeing treated

Toxicity: Toxicity: Drugs with different dose-limiting Drugs with different dose-limiting toxicities should be used to avoid overlapping toxicities should be used to avoid overlapping toxicities toxicities

Optimum scheduling: Optimum scheduling: Intensive intermittent Intensive intermittent schedules should allow time for recovery from the schedules should allow time for recovery from the acute toxic effects, primarily bone marrow toxicityacute toxic effects, primarily bone marrow toxicity

Benefits of combination therapyBenefits of combination therapy

Drugs that act by different mechanisms may Drugs that act by different mechanisms may have additive or synergistic therapeutic have additive or synergistic therapeutic effects. Combination therapy will thus increase effects. Combination therapy will thus increase log cell kill and diminish the probability of log cell kill and diminish the probability of emergence of resistant clones of tumor cellsemergence of resistant clones of tumor cells

Several cycles of treatment should be given, Several cycles of treatment should be given, since one or two cycles of therapy are rarely since one or two cycles of therapy are rarely sufficient to eradicate a tumor. Most curable sufficient to eradicate a tumor. Most curable tumors require at least six to eight cycles of tumors require at least six to eight cycles of therapytherapy

Benefits of combination therapyBenefits of combination therapy

Example of combination therapy of advanced Example of combination therapy of advanced Hodgkin’s disease:Hodgkin’s disease:– MOPPMOPP (mechlorethamine, Oncovin (mechlorethamine, Oncovin

[vincristine sulfate], procarbazine, [vincristine sulfate], procarbazine, prednisone)prednisone)

– ABVDABVD (Adriamycin [doxorubicin (Adriamycin [doxorubicin hydrochloride], bleomycin,vinblastine, hydrochloride], bleomycin,vinblastine, dacarbazine), has resulted in cure rates of dacarbazine), has resulted in cure rates of 50 to 60%50 to 60%

Cell-cycle specificity of drugsCell-cycle specificity of drugs

Both normal cells & tumor cells go through Both normal cells & tumor cells go through growth cyclegrowth cycle

The number of cells that are in various stages The number of cells that are in various stages of the cycle may differ in the normal & of the cycle may differ in the normal & neoplastic tissuesneoplastic tissues

The normal cell cycle consists of a definable The normal cell cycle consists of a definable sequence of events that characterize the sequence of events that characterize the growth and division of cells growth and division of cells

Cell-cycle specificity of drugsCell-cycle specificity of drugs

Cell cycle specific (CCS) drugs: Cell cycle specific (CCS) drugs: effective effective only against replicating cells (most effective only against replicating cells (most effective against hematological malignancies & in solid against hematological malignancies & in solid tumors in which large proportion of the cells tumors in which large proportion of the cells are proliferating)are proliferating)

Cell-cycle nonspecific (CCNS) drugs: Cell-cycle nonspecific (CCNS) drugs: many many bind to cellular DNA. Useful against low growth bind to cellular DNA. Useful against low growth and high growth tumors (e.g., carcinomas of and high growth tumors (e.g., carcinomas of the colon or non–small cell lung cancer) the colon or non–small cell lung cancer)

ResistanceResistance

Primary resistance (inherent drug Primary resistance (inherent drug resistance):resistance): melanoma, renal cell cancer, melanoma, renal cell cancer, & brain cancer& brain cancer

Acquired resistance: Acquired resistance: genetic mutation genetic mutation particularly after prolonged administration particularly after prolonged administration of suboptimal doses (minimized by short of suboptimal doses (minimized by short term, intensive, intermittent therapy term, intensive, intermittent therapy administration or by drug combinations)administration or by drug combinations)

Possible mechanisms of Anticancer Drug Possible mechanisms of Anticancer Drug ResistanceResistance

MechanismMechanism Chemotherapy AgentsChemotherapy Agents

Improved proficiency in repair of DNAImproved proficiency in repair of DNA Cisplatin, cyclophosphamide, melphalan, Cisplatin, cyclophosphamide, melphalan, mitomycin, mechlorethaminemitomycin, mechlorethamine

In drug activationIn drug activation Cytarabine, doxorubicin, fluorouracil, Cytarabine, doxorubicin, fluorouracil, mercaptopurine, methotrexate, thioguaninemercaptopurine, methotrexate, thioguanine

in drug inactivationin drug inactivation Cytarabine, mercaptopurineCytarabine, mercaptopurine

In cellular uptake of drugIn cellular uptake of drug Methotrexate, melphalanMethotrexate, melphalan

In efflux of drug (multidrug In efflux of drug (multidrug resistance)resistance)

Doxorubicin, daunorubicin, etoposide, Doxorubicin, daunorubicin, etoposide, vincristine, vinblastine, teniposide, vincristine, vinblastine, teniposide, docetaxel, paclitaxel, vinorelbinedocetaxel, paclitaxel, vinorelbine

Alternative biochemical pathwaysAlternative biochemical pathways Cytarabine, fluorouracil, methotrexateCytarabine, fluorouracil, methotrexate

Alterations in target enzymes (DHFR, Alterations in target enzymes (DHFR, topoisomerase II)topoisomerase II)

Fluorouracil, hyroxyurea, mercaptopurine, Fluorouracil, hyroxyurea, mercaptopurine, methotrexate, thioguanine, teniopside, methotrexate, thioguanine, teniopside, doxorubicin, daunoruricin, idarubicindoxorubicin, daunoruricin, idarubicin

Multidrug resistanceMultidrug resistance

Tumor cells may become generally resistant to Tumor cells may become generally resistant to a variety of cytotoxic drugs on the basis of a variety of cytotoxic drugs on the basis of decreased uptake or retention of the drugsdecreased uptake or retention of the drugs

It is the major form of resistance to a broad It is the major form of resistance to a broad range of structurally unrelated anticancer range of structurally unrelated anticancer agents, including the anthracyclines, vinca agents, including the anthracyclines, vinca alkaloids, taxanes, camptothecins, alkaloids, taxanes, camptothecins, epipodophyllotoxinsepipodophyllotoxins

It is associated with increased expression of It is associated with increased expression of the MDR1 gene, which encodes a cell surface the MDR1 gene, which encodes a cell surface transporter glycoprotein (P-glycoprotein)transporter glycoprotein (P-glycoprotein)

Multidrug resistanceMultidrug resistance

Associated with increased expression of a Associated with increased expression of a normal gene (the MDR1 gene) for a cell normal gene (the MDR1 gene) for a cell surface glycoprotein (P-glycoprotein) involved surface glycoprotein (P-glycoprotein) involved in drug effluxin drug efflux

Multidrug resistance can be reversed Multidrug resistance can be reversed experimentally by calcium channel blockers, experimentally by calcium channel blockers, such as verapamil, and a variety of other such as verapamil, and a variety of other drugs, which inhibit the transporterdrugs, which inhibit the transporter

The multidrug resistance gene MDR1, which encodes the cell-surface molecule P-glycoprotein (PGP), can confer resistance to a wide variety of drugs. PGP transports drugs out of the cell, which is a process that requires the presence of two ATP-binding domains. These domains are a defining characteristic of this family of ATP-binding cassette (ABC) transporters. The exact mechanism of drug efflux is not well understood, but might involve either direct transport out of the cytoplasm or redistribution of the drug as it transverses the plasma membrane. Some cytotoxic drugs that are

known substrates for PGP include etoposide, daunomycin, taxol, vinblastine and doxorubicin. PGP is modified by sugar moieties (black) on the external surface of the protein

Toxicity of cancer chemotherapyToxicity of cancer chemotherapy

Most anticancer s have a narrow Most anticancer s have a narrow therapeutic indextherapeutic index

Therapy aimed at killing rapidly dividing Therapy aimed at killing rapidly dividing cancer cells also affects normal cells cancer cells also affects normal cells undergoing rapid proliferation (for undergoing rapid proliferation (for example, cells of the buccal mucosa, example, cells of the buccal mucosa, bone marrow, gastrointestinal (GI) bone marrow, gastrointestinal (GI) mucosa, and hair), contributing to the mucosa, and hair), contributing to the toxic manifestations of chemotherapytoxic manifestations of chemotherapy

Common ADEsCommon ADEs

1)1) Bone marrow suppression Bone marrow suppression that that predisposes to infectionspredisposes to infections

2)2) GIT: GIT: – N & VN & V: : phenothiazines and other centrally actingphenothiazines and other centrally acting– Damage to the the GIT muycosa: Damage to the the GIT muycosa: stomatitis, stomatitis,

dysphagia, and diarrhea dysphagia, and diarrhea

3)3) AlopeciaAlopecia

4)4) SterilitySterility

5)5) HyperuricemiaHyperuricemia (tumor lysis syndrome) (tumor lysis syndrome)

Drugs used in cancer Drugs used in cancer chemotherapychemotherapy

1)1) Alkylating agents Alkylating agents and related and related compoundscompounds

2)2) AntimetabolitesAntimetabolites

3)3) Cytotoxic antibioticsCytotoxic antibiotics

4)4) Plant derivatives Plant derivatives (vinca alkaloids, (vinca alkaloids, taxanes, campothecins) taxanes, campothecins)

5)5) HormonesHormones

6)6) Miscellaneous agentsMiscellaneous agents

ALKYLATING AGENTS ALKYLATING AGENTS The alkylating agents are the largest class of The alkylating agents are the largest class of

anticancer agentsanticancer agents1)1) Nitrogen mustards:Nitrogen mustards: chlorambucil, chlorambucil,

cyclophosphamide, mechlorethaminecyclophosphamide, mechlorethamine2)2) Nitrosureas:Nitrosureas: carmistine, lomustinecarmistine, lomustine3)3) Alkylsulfonates: Alkylsulfonates: busulfanbusulfan4)4) Platinum analogs: Platinum analogs: cisplatin, carboplatin, and cisplatin, carboplatin, and

oxaliplatinoxaliplatin5)5) Other Alkylating AgentsOther Alkylating Agents: dacarbazine, : dacarbazine,

procarbazine, & bendamustineprocarbazine, & bendamustine

Mechanism of actionsMechanism of actions

Form reactive molecular species/ intermediate Form reactive molecular species/ intermediate that that transfer of their alkyl groups to various transfer of their alkyl groups to various cellular constituentscellular constituents

The macromolecular sites of alkylation The macromolecular sites of alkylation damage include DNA, RNA, proteins, and damage include DNA, RNA, proteins, and various enzymesvarious enzymes

Alkylations of DNA within the nucleus Alkylations of DNA within the nucleus represent the major interactions that lead to represent the major interactions that lead to cell deathcell death

The major site of alkylation within DNA is the The major site of alkylation within DNA is the N7 position of guanineN7 position of guanine

Most major alkylating agents are bifunctional, with two reactive groups

ALKYLATING AGENTSALKYLATING AGENTS Are cell cycle-Are cell cycle-nonnonspecificspecific, but cells are , but cells are

most susceptible to alkylation in late G1 & most susceptible to alkylation in late G1 & S phases S phases

Used in combination with other agents to Used in combination with other agents to treat a wide variety of lymphatic and solid treat a wide variety of lymphatic and solid cancercancer

Mutagenic & carcinogenic and can lead to Mutagenic & carcinogenic and can lead to secondary malignancies, such as acute secondary malignancies, such as acute leukemialeukemia

Drug resistanceDrug resistance

1)1) Increase capability to repair DNA lesionsIncrease capability to repair DNA lesions

2)2) Decrease permeability of the cell to the Decrease permeability of the cell to the alkylating agentsalkylating agents

3)3) Increase production/activity of glutathione of Increase production/activity of glutathione of glutathione S-transferase, which can glutathione S-transferase, which can conjugate with and detoxify electrophilic conjugate with and detoxify electrophilic intermediatesintermediates

A. CyclophosphamideA. Cyclophosphamide

Pro-drug that needs hepatic activation by Pro-drug that needs hepatic activation by CYP450 (4-hydroxy cyclophosphamide):CYP450 (4-hydroxy cyclophosphamide):The The active compounds, are active compounds, are phosphoramide phosphoramide mustard mustard and and acroleinacrolein

Clinical usesClinical uses: : 1)1) Cyclophosphamide has a wide spectrum of Cyclophosphamide has a wide spectrum of

antitumor activity: antitumor activity: Breast cancer, ovarian cancer, Breast cancer, ovarian cancer, non-Hodgkin's lymphoma, CLL, soft tissue non-Hodgkin's lymphoma, CLL, soft tissue sarcoma, neuroblastoma, Wilms' tumor, sarcoma, neuroblastoma, Wilms' tumor, rhabdomyosarcomarhabdomyosarcoma

2)2) Alternative to azathioprine in suppressing Alternative to azathioprine in suppressing immunological rejection of transplant organsimmunological rejection of transplant organs

A. CyclophosphamideA. Cyclophosphamide

Specific ADE:Specific ADE: Hemorrhagic cystitis: Hemorrhagic cystitis: Dysuria and decreased Dysuria and decreased

urinary frequencyurinary frequency Due to acrolein in the urine Due to acrolein in the urine Can be minimized by vigorous hydration & by use Can be minimized by vigorous hydration & by use

of sodium 2-mercaptoethane sulfonate (MESNA) of sodium 2-mercaptoethane sulfonate (MESNA) which “traps” acroleinwhich “traps” acrolein

Other common ADEs:Other common ADEs: AlopeciaAlopecia NVDNVD Bone marrow suppressionBone marrow suppression

B. MechlorethamineB. Mechlorethamine

Originally developed as a vesicant Originally developed as a vesicant (nitrogen mustard) during world war I(nitrogen mustard) during world war I

IV administered IV administered The major indication for mechlorethamine The major indication for mechlorethamine

is Hodgkin’s disease; the drug is given in is Hodgkin’s disease; the drug is given in the MOPP regimenthe MOPP regimen

B. MechlorethamineB. Mechlorethamine

Specific ADEs: Specific ADEs: Marked vesicant action (blistering agent): care should be Marked vesicant action (blistering agent): care should be

taken to avoid extravasation into Sc tissues or even taken to avoid extravasation into Sc tissues or even spillage onto the skinspillage onto the skin

Reproductive toxicity includes amenorrhea and inhibition Reproductive toxicity includes amenorrhea and inhibition of oogenesis and spermatogenesisof oogenesis and spermatogenesis

Common ADEs:Common ADEs: Bone marrow suppressionBone marrow suppression Immunosuppression (herpes zoster infections, especially Immunosuppression (herpes zoster infections, especially

in patients with lymphomas)in patients with lymphomas) AlopeciaAlopecia NVDNVD

C. Nitrosureas: Carmustine (IV) & C. Nitrosureas: Carmustine (IV) & Lomustine (orally)Lomustine (orally)

Are highly lipid-soluble and are able to Are highly lipid-soluble and are able to cross the BBB, making them effective in cross the BBB, making them effective in the treatment of brain tumorsthe treatment of brain tumors

Both alkylation and carbamoylation Both alkylation and carbamoylation contribute to the therapeutic and toxic contribute to the therapeutic and toxic effects of the nitrosoureaseffects of the nitrosoureas

C. Nitrosureas: Carmustine (IV) & C. Nitrosureas: Carmustine (IV) & Lomustine (orally)Lomustine (orally)

ADEs:ADEs: – Bone marrow depression: 4 to 5 weeksBone marrow depression: 4 to 5 weeks– Severe nausea and vomitingSevere nausea and vomiting– Pulmonary toxicity, manifested by Pulmonary toxicity, manifested by

cough, dyspnea, and interstitial fibrosiscough, dyspnea, and interstitial fibrosis (long term)(long term)

– Less frequent: Less frequent: alopecia, stomatitis, and alopecia, stomatitis, and mild abnormalities of liver functionmild abnormalities of liver function

– Potentially, mutagenic, teratogenic, and Potentially, mutagenic, teratogenic, and carcinogeniccarcinogenic

Streptozocin (STZ)Streptozocin (STZ)

Sugar-containing nitrosoureaSugar-containing nitrosourea It has a high affinity for cells of the islets of It has a high affinity for cells of the islets of

Langerhans & is transported into the cell Langerhans & is transported into the cell by the glucose transport protein GLUT2by the glucose transport protein GLUT2

CClinical use: linical use: insulin-secreting islet cell insulin-secreting islet cell carcinoma of the pancreas carcinoma of the pancreas

ADEs: ADEs: – Abnormal glucose tolerance (hypoglycemic coma)Abnormal glucose tolerance (hypoglycemic coma)– Renal tubular damage in 5 to 10% of patientsRenal tubular damage in 5 to 10% of patients

D. Platinum analogs (cisplatin, D. Platinum analogs (cisplatin, carboplatin, & oxaliplatin)carboplatin, & oxaliplatin)

1)1) First generation: First generation: CisplatinCisplatin Clinical uses: solid tumors (non-small cell and Clinical uses: solid tumors (non-small cell and

small cell lung cancer, esophageal and gastric small cell lung cancer, esophageal and gastric cancer, head and neck cancer, and cancer, head and neck cancer, and genitourinary cancers, particularly testicular, genitourinary cancers, particularly testicular, ovarian, and bladder cancer)ovarian, and bladder cancer)

ADEs: ADEs: – Renal toxicity (major)Renal toxicity (major)– N and VN and V– Anemia: require transfusions of RBCsAnemia: require transfusions of RBCs– Hearing loss (10 to 30% of patients)Hearing loss (10 to 30% of patients)

D. Platinum analogs (cisplatin, D. Platinum analogs (cisplatin, carboplatin, & oxaliplatin)carboplatin, & oxaliplatin)

2)2) Second generation: Second generation: CarboplatinCarboplatin MOA, mechanisms of resistance, and clinical MOA, mechanisms of resistance, and clinical

uses are identical to cisplatinuses are identical to cisplatin it exhibits significantly less renal toxicity and it exhibits significantly less renal toxicity and

IT toxicity, peripheral nerves, and hearing lossIT toxicity, peripheral nerves, and hearing loss It is more myelosuppressive than cisplatinIt is more myelosuppressive than cisplatin

3)3) Third generation: Third generation: oxaliplatinoxaliplatin Similar to cisplatin and carboplatin, but with Similar to cisplatin and carboplatin, but with

significant activity against colorectal cancersignificant activity against colorectal cancer ADEs: Neurotoxicity manifested by a ADEs: Neurotoxicity manifested by a

peripheral sensory neuropathyperipheral sensory neuropathy

Other Alkylating AgentsOther Alkylating Agents

Procarbazine:Procarbazine: Activated by hepatic CYPs to highly reactive Activated by hepatic CYPs to highly reactive

alkylating species that methylate DNA alkylating species that methylate DNA Oxidative metabolism of this drug by Oxidative metabolism of this drug by

microsomal enzymes generates microsomal enzymes generates azoprocarbazine and Hazoprocarbazine and H22OO22, which may be , which may be responsible for DNA strand scissionresponsible for DNA strand scission

ItIt is commonly used in combination regimens is commonly used in combination regimens for Hodgkin's and non-Hodgkin's lymphoma for Hodgkin's and non-Hodgkin's lymphoma and brain tumorsand brain tumors

Other Alkylating AgentsOther Alkylating Agents

1.1. Procarbazine:Procarbazine: Procarbazine is a weak MAOI: hypertensive Procarbazine is a weak MAOI: hypertensive

reactions may result from its use concurrently reactions may result from its use concurrently with sympathomimetic agents, TCA, or with sympathomimetic agents, TCA, or ingestion of foods with high tyramine contentingestion of foods with high tyramine content

CNS toxicity with neuropathy, ataxia, CNS toxicity with neuropathy, ataxia, lethargy, and confusionlethargy, and confusion

The carcinogenic potential of procarbazine is The carcinogenic potential of procarbazine is thought to be higher than that of most other thought to be higher than that of most other alkylating agentsalkylating agents

Other Alkylating AgentsOther Alkylating Agents

2.2. DacarbazineDacarbazine It is used in the treatment of malignant It is used in the treatment of malignant

melanomamelanoma It is a potent vesicant, and care must be It is a potent vesicant, and care must be

taken to avoid extravasationtaken to avoid extravasation

Other alkylating agentsOther alkylating agents

1. Dacarbazine

2.2. Temzolomide (brain tumor)Temzolomide (brain tumor)

3.3. MelphalanMelphalan

4.4. ChlorambucilChlorambucil

5.5. BusulfanBusulfan

6.6. BendamustineBendamustine

7.7. ThiotepaThiotepa

8.8. AltretamineAltretamine

ANTIMETABOLITES (Structural Analogs) ANTIMETABOLITES (Structural Analogs)

Are structurally similar to endogenous Are structurally similar to endogenous compoundscompounds, such as vitamins, amino , such as vitamins, amino acids,and nucleotidesacids,and nucleotides

These drugs can compete for binding These drugs can compete for binding sites on enzymes or can themselves sites on enzymes or can themselves become incorporated into DNA or RNA become incorporated into DNA or RNA and thus interfere with cell growth and and thus interfere with cell growth and proliferationproliferation

ANTIMETABOLITES (Structural Analogs) ANTIMETABOLITES (Structural Analogs)

The antimetabolites in clinical use include:The antimetabolites in clinical use include:- Folic acid analoguesFolic acid analogues: methotrexate : methotrexate - Purine analogues:Purine analogues: mercaptopurine, mercaptopurine,

thioguaninethioguanine- Pyrimidine analoguesPyrimidine analogues: fluorouracil, : fluorouracil,

cytarabinecytarabine CCS drugs acting primarily in S phaseCCS drugs acting primarily in S phase Are also used as immunosuppressantsAre also used as immunosuppressants

Folate antagonistFolate antagonistMethotrexate (MTX)Methotrexate (MTX)

Folic acid is an essential dietary factor that is Folic acid is an essential dietary factor that is converted by enzymatic reduction to a series converted by enzymatic reduction to a series of tetrahydrofolate (FH4) cofactors that of tetrahydrofolate (FH4) cofactors that provide methyl groups for the synthesis of provide methyl groups for the synthesis of precursors of DNA (thymidylate and purines) precursors of DNA (thymidylate and purines) and RNA (purines)and RNA (purines)

Interference with FH4 metabolism reduces the Interference with FH4 metabolism reduces the cellular capacity for one-carbon transfer and cellular capacity for one-carbon transfer and the necessary methylation reactions in the the necessary methylation reactions in the synthesis of purine ribonucleotides and synthesis of purine ribonucleotides and thymidine monophosphate (TMP), thereby thymidine monophosphate (TMP), thereby inhibiting DNA replicationinhibiting DNA replication

Folate antagonistFolate antagonistMethotrexate (MTX)Methotrexate (MTX)

MoAMoA: : Cellular uptake of the drug is by carrier-Cellular uptake of the drug is by carrier-

mediated active transportmediated active transport

MXT competitively inhibits the binding of MXT competitively inhibits the binding of folic acid to the enzyme dihydrofolate folic acid to the enzyme dihydrofolate reductase (DHFR), interfering with the reductase (DHFR), interfering with the synthesis of tetrahydrofolate (FHsynthesis of tetrahydrofolate (FH44), which ), which serves as the key one-carbon carrier for serves as the key one-carbon carrier for enzymatic processes involved in de novo enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionineand the amino acids serine and methionine

Folate (Diet)

FH2

DHFR

FH4

N5, N10- Ch2FH4

DHFR

Purine biosynthesis

dUMP

dTMP

Methotrexate

Folate antagonistFolate antagonistMethotrexate (MTX)Methotrexate (MTX)

MTX is metavolized to polyglutamte MTX is metavolized to polyglutamte derivatives which are derivatives which are retained in the cell retained in the cell and are also potent inhibitors DHFRand are also potent inhibitors DHFR

Clearance depends on renal functionClearance depends on renal function

Drugs such as aspirin, penicillin, Drugs such as aspirin, penicillin, cephalosporins, and NSAIDs inhibit the cephalosporins, and NSAIDs inhibit the renal excretion of MTXrenal excretion of MTX

Folate antagonistFolate antagonistMethotrexate (MTX)Methotrexate (MTX)

Resistance:Resistance:(1) Decrease drug transport(1) Decrease drug transport(2) Decrease formation of cytotoxic MTX (2) Decrease formation of cytotoxic MTX polyglutamatespolyglutamates(3) Increase levels of DHFR (3) Increase levels of DHFR (4) Alter DHFR protein with reduced (4) Alter DHFR protein with reduced affinity for MTXaffinity for MTX

Folate antagonistFolate antagonistMethotrexate (MTX)Methotrexate (MTX)

Clinical usesClinical uses– Cancer: Cancer: Breast cancer, head and Breast cancer, head and

neck cancer, osteogenic sarcoma, neck cancer, osteogenic sarcoma, primary central nervous system primary central nervous system lymphoma, non-Hodgkin's lymphoma, lymphoma, non-Hodgkin's lymphoma, bladder cancer, choriocarcinomabladder cancer, choriocarcinoma

– Immunosuppressive agentImmunosuppressive agent in severe in severe rheumatoid arthritis rheumatoid arthritis

Folate antagonistFolate antagonistMethotrexate (MTX)Methotrexate (MTX)

Specific ToxicitySpecific Toxicity1.1. Common toxicities Common toxicities

- GIT (NVD & ulcerative mucositis), stomatitis, GIT (NVD & ulcerative mucositis), stomatitis, melosuppressionmelosuppression, alopecia, and dermatitis, alopecia, and dermatitis

- Prevented or reveresed by administration of Prevented or reveresed by administration of folinic acid (leucovorin) “leucovorin rescue”folinic acid (leucovorin) “leucovorin rescue”

2.2. Renal damage:Renal damage: – High doses of MTX and its 7-OH metabolite, High doses of MTX and its 7-OH metabolite,

which can ppt in the renal tubuleswhich can ppt in the renal tubules– Alkalinization of the urine and adequate Alkalinization of the urine and adequate

hydration can helphydration can help

Folate (Diet)

FH2

DHFR

FH4

N5, N10- Ch2FH4

DHFR

Purine biosynthesis

dUMP

dTMP

Methotrexate

Leucovorin

Folate antagonistFolate antagonistMethotrexate (MTX)Methotrexate (MTX)

Specific ToxicitySpecific Toxicity3.3. Hepatotoxicity: Hepatotoxicity: long term use may lead long term use may lead

to cirrhosisto cirrhosis

4.4. Pulmonary toxicity Pulmonary toxicity (cough, dyspnea, (cough, dyspnea, fever, & cyanosis fever, & cyanosis

5.5. Neurologic toxicities Neurologic toxicities (intrathecal (intrathecal adminiosrtation):adminiosrtation): stiff neck, headach, stiff neck, headach, meningeal irritationmeningeal irritation

Folate antagonistFolate antagonistPemetrexedPemetrexed

A new antifolate therapeutic agent that A new antifolate therapeutic agent that inhibits enzymes within the pyrimidine and inhibits enzymes within the pyrimidine and purine cyclepurine cycle

It works by inhibiting DHFR & thymidylate It works by inhibiting DHFR & thymidylate synthasesynthase

It also inhibits glycinamide ribo-nucleotide It also inhibits glycinamide ribo-nucleotide formyl transferase (GARFT), an enzyme formyl transferase (GARFT), an enzyme that is involved in purine synthesis and that is involved in purine synthesis and therefore reduces purine productiontherefore reduces purine production

Sites of Action of Pemetrexed. Actions of pemetrexed on purine and pyrimidine pathways in DNA synthesis. dUMP, Deoxyuridine Monophosphate; TMP, Thymidine Monophosphate; CH2FH2, Methylenetetrahydrofolate; CHOFH4, 10-Formyltetrahydrofolate; FH2, Dihydrofolate; FH4, Tetrahydrofolate; DHFR, Dihydrofolate Reductase; GARFT, Glycinamide Ribonucleotide Formyl Transferase.

Folate antagonistFolate antagonistPemetrexedPemetrexed

Clinical uses: Clinical uses: in combination with cisplatin in in combination with cisplatin in the treatment of mesothelioma & as first-line the treatment of mesothelioma & as first-line treatment of non-small cell lung cancer, as a treatment of non-small cell lung cancer, as a single agent in the second-line therapy of non-single agent in the second-line therapy of non-small cell lung cancersmall cell lung cancer

ADEs: myelosuppression, skin rash, mucositis, ADEs: myelosuppression, skin rash, mucositis, diarrhea, fatigue, & hand-foot syndromediarrhea, fatigue, & hand-foot syndrome

Toxicity is reduced by the coadministration of Toxicity is reduced by the coadministration of folic acid, vitamin B12 and dexamethasonefolic acid, vitamin B12 and dexamethasone

Purine analogesPurine analoges6-thiopurine: 6- Mercaptopurine (6-MP) & 6-6-thiopurine: 6- Mercaptopurine (6-MP) & 6-

thioguanine (6-TG)thioguanine (6-TG)

a.a. 6-MP6-MP Analogue of hypoxanthineAnalogue of hypoxanthine Inactive and is activated intracellularly Inactive and is activated intracellularly by hypoxanthine-by hypoxanthine-

guanine phosphoribosyltransferases (HGPRT) to guanine phosphoribosyltransferases (HGPRT) to to form to form the monophosphate nucleotide 6-thioinosinic acid (TIMP)the monophosphate nucleotide 6-thioinosinic acid (TIMP)

TIMP: TIMP: – Inhibits several enzymes of Inhibits several enzymes of de novo de novo purine nucleotide purine nucleotide

synthesissynthesis– Incorporation into nucleic acids: the monophosphate Incorporation into nucleic acids: the monophosphate

form is eventually metabolized to the triphosphate form, form is eventually metabolized to the triphosphate form, which can then get incorporated into both RNA and DNAwhich can then get incorporated into both RNA and DNA

Purine analogesPurine analoges6-thiopurine: 6- Mercaptopurine (6-MP) & 6-6-thiopurine: 6- Mercaptopurine (6-MP) & 6-

thioguanine (6-TG)thioguanine (6-TG)

a.a. 6-MP6-MP Clinical use: acute myelogenous leukemiaClinical use: acute myelogenous leukemia Potential D-D interaction with xanthine Potential D-D interaction with xanthine

oxidase inhibitor (allopurinol):oxidase inhibitor (allopurinol): the dose of the dose of mercaptopurine must be reduced by 50–75%mercaptopurine must be reduced by 50–75%

Specific toxicitySpecific toxicity: : hepatic dysfunction hepatic dysfunction (cholestasis jaundice, necrosis)(cholestasis jaundice, necrosis)

Bone marrow is the principle toxicityBone marrow is the principle toxicity

Purine analogesPurine analoges6-thiopurine: 6- Mercaptopurine (6-MP) & 6-6-thiopurine: 6- Mercaptopurine (6-MP) & 6-

thioguanine (6-TG)thioguanine (6-TG)

b.b. 6-TG6-TG Analogue of the natural purine guanineAnalogue of the natural purine guanine 6-TG is converted intracellularly by the 6-TG is converted intracellularly by the

enzyme hypoxanthine guanine–enzyme hypoxanthine guanine–phosphoribosyltransferase (HGPRTase) to 6-phosphoribosyltransferase (HGPRTase) to 6-TGMPTGMP

TGMP is further converted to the di- and TGMP is further converted to the di- and triphosphates, thioguanosine diphosphate triphosphates, thioguanosine diphosphate and thioguanosine triphosphate, which then and thioguanosine triphosphate, which then inhibit the biosynthesis of purinesinhibit the biosynthesis of purines

Purine analogesPurine analoges6-thiopurine: 6- Mercaptopurine (6-MP) & 6-6-thiopurine: 6- Mercaptopurine (6-MP) & 6-

thioguanine (6-TG)thioguanine (6-TG)

b.b. 6-TG6-TG Clinical use: Clinical use: with cytarabine in the treatment with cytarabine in the treatment

of adult acute leukemiaof adult acute leukemia Interaction does not occur with allopurinolInteraction does not occur with allopurinol Specific toxicitySpecific toxicity: : hepatic dysfunction hepatic dysfunction

(cholestasis jaundice, necrosis)(cholestasis jaundice, necrosis) less common less common than with mercaptopurinethan with mercaptopurine

Bone marrow is the principle toxicityBone marrow is the principle toxicity

Pyrimidine analogesPyrimidine analoges1-1-Fluorouracil (5-FU)Fluorouracil (5-FU)

Halogenated pyrimidine analogue that Halogenated pyrimidine analogue that must be activated metabolically:must be activated metabolically:

1)1) 5-fluoro-2’-deoxyuridine-5’-5-fluoro-2’-deoxyuridine-5’-monophosphate (5-FdUMP): monophosphate (5-FdUMP): forms a forms a covalently ternary complex with the covalently ternary complex with the enzyme thymidylate synthase and the enzyme thymidylate synthase and the 5,10-methylenetetrahydrofolate5,10-methylenetetrahydrofolate

2)2) 5-fluorouridine-5'-triphosphate 5-fluorouridine-5'-triphosphate (FUTP):(FUTP):incorporate into RNA, where it incorporate into RNA, where it interferes with RNA processing and mRNA interferes with RNA processing and mRNA translationtranslation

Pyrimidine analogesPyrimidine analoges1-1-Fluorouracil (5-FU)Fluorouracil (5-FU)

Clinical uses: Clinical uses: Colorectal cancer, anal cancer, Colorectal cancer, anal cancer, breast cancer, gastroesophageal cancer, head and breast cancer, gastroesophageal cancer, head and neck cancer, hepatocellular cancerneck cancer, hepatocellular cancer

IV administered b/c of its severe toxicity to the GITIV administered b/c of its severe toxicity to the GIT Resistance:Resistance:

Depletion of enzymes (especially uridine kinase) that Depletion of enzymes (especially uridine kinase) that activate 5-fluorouracil to nucleotidesactivate 5-fluorouracil to nucleotides

Increased thymidylate synthase levelIncreased thymidylate synthase level Altered affinity of thymidylate synthetase for FdUMPAltered affinity of thymidylate synthetase for FdUMP Increase in the pool of the normalIncrease in the pool of the normal metabolite deoxyuridylic acid (dUMP)metabolite deoxyuridylic acid (dUMP) Increase in the rate of catabolism of 5-fluorouracilIncrease in the rate of catabolism of 5-fluorouracil

Pyrimidine analogesPyrimidine analoges1-1-Fluorouracil (5-FU)Fluorouracil (5-FU)

ADEsADEs 1.1. MyelosuppressionMyelosuppression2.2. GIT (mucositis and diarrhea)GIT (mucositis and diarrhea)3.3. Skin toxicity manifested by the hand-foot Skin toxicity manifested by the hand-foot

syndromesyndrome4.4. NeurotoxicityNeurotoxicity

Hand-foot syndrome is a side effect of some types of chemotherapy that causes redness, swelling, and pain on the palms of the hands and/or the soles of the feet. Hand-foot syndrome occurs when small amounts of chemotherapy leak out of the capillaries (small blood vessels) in the hands and feet. Once out of the blood vessels, the chemotherapy damages the surrounding tissues

http://www.cancer.net

Pyrimidine analogesPyrimidine analoges2-2-CapecitabineCapecitabine

Prodrug that is enzymatically converted to 5-Prodrug that is enzymatically converted to 5-FU in the tumorFU in the tumor

Adv: Adv: orally administeredorally administered Clinical use: Clinical use: metastatic breast cancer that is metastatic breast cancer that is

resistant to first line drugs & colorectal cancerresistant to first line drugs & colorectal cancer ADEs:ADEs:

– Main: diarrhea and the hand-foot syndromeMain: diarrhea and the hand-foot syndrome– Myelosuppression, NV, and mucositis: the Myelosuppression, NV, and mucositis: the

incidence is significantly less than that seen incidence is significantly less than that seen with IV 5-FUwith IV 5-FU

Pyrimidine analogesPyrimidine analoges3-3-Cytarabine (cytosine arabinoside, Ara-C)Cytarabine (cytosine arabinoside, Ara-C)

It is a CCS (S-phase)It is a CCS (S-phase) MOA:MOA: Is an analogue of the pyrimidine nucleosides Is an analogue of the pyrimidine nucleosides

cytidine and deoxycytidinecytidine and deoxycytidine Is activated by kinases to AraCTP: an inhibitor of Is activated by kinases to AraCTP: an inhibitor of

DNA polymerases which will incorporate into DNA DNA polymerases which will incorporate into DNA and can retard chain elongationand can retard chain elongation

This agent has absolutely no activity in solid This agent has absolutely no activity in solid tumorstumors

Its activity is limited exclusively to hematologic Its activity is limited exclusively to hematologic malignancies (e.g. acute myelogenous leukemia malignancies (e.g. acute myelogenous leukemia and non-Hodgkin's lymphoma)and non-Hodgkin's lymphoma)

Pyrimidine analogesPyrimidine analoges3-3-Cytarabine (cytosine arabinoside, Ara-C)Cytarabine (cytosine arabinoside, Ara-C)

ResistanceResistance Defect in the transport processDefect in the transport process Changes in the kinase enzymes activityChanges in the kinase enzymes activity Increased deamination of the drug Increased deamination of the drug

Specific ToxicitySpecific Toxicity Leukoenphalopathy: high doses with Leukoenphalopathy: high doses with

intrathecal administrationintrathecal administration

Pyrimidine analogesPyrimidine analoges4-4-GemcitabineGemcitabine

MOA: MOA: Activated to 2',2'-difluorodeoxycytidine Activated to 2',2'-difluorodeoxycytidine triphosphate which will inhibit DNA triphosphate which will inhibit DNA synthesis by being incorporated into sites synthesis by being incorporated into sites in the growing strand that ordinarily would in the growing strand that ordinarily would contain cytosinecontain cytosine

Pyrimidine analogesPyrimidine analoges4-4-GemcitabineGemcitabine

Resistance: Resistance: Alteration in the deoxycytidine kinaseAlteration in the deoxycytidine kinase Increase tumor production of Increase tumor production of

endogenous deoxycytidineendogenous deoxycytidine Clinical use: Clinical use:

First-line treatment of locally advanced or First-line treatment of locally advanced or metastatic adenocarcinoma of the pancreasmetastatic adenocarcinoma of the pancreas

Non-small cell lung cancer, bladder cancer, Non-small cell lung cancer, bladder cancer, ovarian cancer, soft tissue sarcoma, and non-ovarian cancer, soft tissue sarcoma, and non-Hodgkin's lymphomaHodgkin's lymphoma

PLANT ALKALOIDSPLANT ALKALOIDS

These classes differ in their structures and MOA but These classes differ in their structures and MOA but share the multidrug resistance mechanism, since share the multidrug resistance mechanism, since they are all substrates for the multidrug transporter they are all substrates for the multidrug transporter P- glycoproteinP- glycoprotein

Cell cycle specific agentsCell cycle specific agents

Vinca alkaloidsVinca alkaloids (vinblastine, vincristine)(vinblastine, vincristine)PodophyllotoxinsPodophyllotoxins (etoposide, teniposide) (etoposide, teniposide)CamptothecinsCamptothecins (Topotecan & Irinotecan) (Topotecan & Irinotecan) TaxanesTaxanes (paclitaxel, docetaxel) (paclitaxel, docetaxel)

AA. Vinca alkaloids: Vinblastine, . Vinca alkaloids: Vinblastine, Vincristrine, & vinorelbineVincristrine, & vinorelbine

Structurally related compounds derived from Structurally related compounds derived from Vinca rosea Vinca rosea (Vinblastine & vincristrine) (Vinblastine & vincristrine)

Vinorelbine is a semi-synthetic derivativeVinorelbine is a semi-synthetic derivative Despite their structural similarity, there are Despite their structural similarity, there are

significant differences between them in regard to significant differences between them in regard to clinical usefulness and toxicityclinical usefulness and toxicity

MOA: MOA: The vinca alkaloids bind avidly to tubulinThe vinca alkaloids bind avidly to tubulin & & inhibition tubulin polymerization, which disrupts inhibition tubulin polymerization, which disrupts assembly of microtubules. This inhibitory effect assembly of microtubules. This inhibitory effect results in mitotic arrest in metaphase (M)results in mitotic arrest in metaphase (M) preventprevent, and cell division cannot be completed, and cell division cannot be completed

A. Vinca alkaloids: Vinblastine, A. Vinca alkaloids: Vinblastine, Vincristrine, & vinorelbineVincristrine, & vinorelbine

ResistanceResistance::– Decreased rate of drug uptake Decreased rate of drug uptake – Increased drug efflux : multidrug resistance Increased drug efflux : multidrug resistance

& cross-resistance usually occurs with & cross-resistance usually occurs with anthracyclines, dactinomycin, and anthracyclines, dactinomycin, and podophyllotoxinspodophyllotoxins

A. Vinca alkaloids: Vinblastine, A. Vinca alkaloids: Vinblastine, Vincristrine, & vinorelbineVincristrine, & vinorelbine

ADRsADRsVinblastineVinblastine:: NV, NV, bone marrow suppressionbone marrow suppression, alopecia, & , alopecia, &

vesicantvesicantVincristineVincristine:: NeurotoxicityNeurotoxicity: peripheral sensory neuropathy: peripheral sensory neuropathy Syndrome of inappropriate secretion of Syndrome of inappropriate secretion of

antidiuretic hormone (SIADH)antidiuretic hormone (SIADH)Vinorelbine:Vinorelbine: Bone marrow suppression with neutropeniaBone marrow suppression with neutropenia

B. Taxanes: Paclitaxel, Docetaxel, & B. Taxanes: Paclitaxel, Docetaxel, & IxabepiloneIxabepilone

Cell cycle specific (G2/M phase of the cell Cell cycle specific (G2/M phase of the cell cycle)cycle)

MoAMoA:: They bind reversibly to the β-tubulin They bind reversibly to the β-tubulin subunit promoting polymerization and subunit promoting polymerization and stabilization of the polymer rather than stabilization of the polymer rather than disassembly. Thus, they shift the disassembly. Thus, they shift the depolymerization-polymerization process to depolymerization-polymerization process to accumulation of microtubules. The overly accumulation of microtubules. The overly stable microtubules formed are nonfunctional, stable microtubules formed are nonfunctional, and chromosome desegregation does not and chromosome desegregation does not occur. This results in death of the celloccur. This results in death of the cell

Mackler NJ and Pienta KJ (2005) Drug Insight: use of docetaxel in prostate and urothelial cancers. Nat Clin Pract Urol 2: 92–100 doi:10.1038/ncpuro0099

Figure 1 Mechanism of action of docetaxel

B. Taxanes: Paclitaxel, Docetaxel, & B. Taxanes: Paclitaxel, Docetaxel, & IxabepiloneIxabepilone

Resistance: Resistance: Multidrug resistant P-glycoprotein Multidrug resistant P-glycoprotein Mutation in the tubulin structureMutation in the tubulin structure

Clinical uses: Clinical uses: advanced ovarian cancer and advanced ovarian cancer and metastatic breast cancer. Non-small cell in metastatic breast cancer. Non-small cell in combination with cisplatincombination with cisplatin

B. Taxanes: Paclitaxel, Docetaxel, & B. Taxanes: Paclitaxel, Docetaxel, & IxabepiloneIxabepilone

ADEs:ADEs: Neutropenia:Neutropenia: treatment with colony treatment with colony

stimulating factor (Filgrastim) can helpstimulating factor (Filgrastim) can help Peripheral neuropathyPeripheral neuropathy Transient, asymptomatic bradycardia:Transient, asymptomatic bradycardia:

PaclitaxelPaclitaxel Fluid retention: Fluid retention: DocetaxelDocetaxel Serious hypersensitivty:Serious hypersensitivty: patients are pre- patients are pre-

treated with dexamethazone, treated with dexamethazone, diphenylhydramine, and an Hdiphenylhydramine, and an H22 blocker blocker

C. podophyllotoxins: Etoposide & C. podophyllotoxins: Etoposide & TeniposideTeniposide

Cell cycle specific Cell cycle specific ((most active in the most active in the late S to Glate S to G22 phase of the cell cycle) phase of the cell cycle)

MoAMoA: : Both drugs bind to the Both drugs bind to the topoisomerase II topoisomerase II -DNA complex and -DNA complex and prevent resealing of the break that prevent resealing of the break that normally follows topoisomerase binding normally follows topoisomerase binding to DNAto DNA

The enzyme remains bound to the free The enzyme remains bound to the free end of the broken DNA strand, leading to end of the broken DNA strand, leading to an accumulation of DNA breaks and cell an accumulation of DNA breaks and cell deathdeath

Mechanism of action of etoposide

D. Camptothecins: Topotecan & D. Camptothecins: Topotecan & IrinotecanIrinotecan

CCell cycle specific (ell cycle specific (most active in the S most active in the S phase)phase)

MoA: MoA: Interfere with activity of Interfere with activity of

topoisomerase I, the enzyme topoisomerase I, the enzyme responsible for cutting & religating responsible for cutting & religating single DNA strands. Inhibition of the single DNA strands. Inhibition of the enzyme enzyme results in results in DNA damageDNA damage

Binding of CPT to topo I and DNA

Topoisomerase I

DNA

CPT

Action of Type I DNA topoisomerases

http://en.wikipedia.org/wiki/Camptothecin

ANTITUMOR ANTIBIOTICS ANTITUMOR ANTIBIOTICS

Antitumor antibiotics produce their Antitumor antibiotics produce their effect mainly by direct action on DNA, effect mainly by direct action on DNA, leading to disruption of the DNA leading to disruption of the DNA functionfunction

All the anticancer antibiotics now All the anticancer antibiotics now being used in clinical practice are being used in clinical practice are products of various strains of the soil products of various strains of the soil microbe microbe StremptomycesStremptomyces

Cell cycle non-specificCell cycle non-specific

A. Anthracyclin antibioticsA. Anthracyclin antibiotics

Agents:Agents: DoxorubicinDoxorubicin, , daunorubicindaunorubicin, , idarubcinidarubcin, , epirubicinepirubicin, , & & mitoxantronemitoxantrone

MoA: MoA: a.a. Inhibitoin of topoisomerase IIInhibitoin of topoisomerase IIb.b. Intercalation in the DNA: block the synthesis Intercalation in the DNA: block the synthesis

of DNA and RNA, and DNA strand scissionof DNA and RNA, and DNA strand scissionc.c. BBinding to cellular membranes to alter inding to cellular membranes to alter

fluidity and ion transportfluidity and ion transportd.d. GGeneration of semiquinone free radicals and eneration of semiquinone free radicals and

oxygen free radicals through an iron-oxygen free radicals through an iron-dependent, enzyme-mediated reductive dependent, enzyme-mediated reductive processprocess

Doxorubicin–DNA complex

Doxorubicin

A. Anthracyclin antibioticsA. Anthracyclin antibiotics

SpecificSpecific ToxicityToxicity:: CardiotoxicityCardiotoxicity:: arrhythmias and conduction arrhythmias and conduction

abnormalities, pericarditis, and myocarditisabnormalities, pericarditis, and myocarditiso Results from the generation of free radical and lipid Results from the generation of free radical and lipid

peroxidation peroxidation o Reduced with:Reduced with:

Lower weekly doses or continuous infusions of Lower weekly doses or continuous infusions of doxorubicin doxorubicin

Treatment with the iron-chelating agent Treatment with the iron-chelating agent dexrazoxane dexrazoxane

Liposomal-encapuslated formulations of doxorubicinLiposomal-encapuslated formulations of doxorubicin

A. Anthracyclin antibioticsA. Anthracyclin antibiotics

Radiation recall reaction with erythema Radiation recall reaction with erythema and desquamation of the skin observed at and desquamation of the skin observed at sites of prior radiation therapysites of prior radiation therapy

Doxorubicin will impart a reddish color to Doxorubicin will impart a reddish color to the urine for 1 or 2 days after the urine for 1 or 2 days after administrationadministration

Bone marrow suppressionBone marrow suppression Hyperpigmentation of nail beds and skin Hyperpigmentation of nail beds and skin

creases, and conjunctivitiscreases, and conjunctivitis

B. Mitomycin (mitomycin C)B. Mitomycin (mitomycin C)

It is sometimes classified as an alkylating It is sometimes classified as an alkylating agent b/c it undergoes metabolic activation agent b/c it undergoes metabolic activation through an to generate an alkylating agent through an to generate an alkylating agent that cross-links DNAthat cross-links DNA

ADRs:ADRs:– Hemolytic-uremic syndrome: Hemolytic-uremic syndrome:

microangiopathic hemolytic anemia, microangiopathic hemolytic anemia, thrombocytopenia, and renal failurethrombocytopenia, and renal failure

C. BleomycinC. Bleomycin

It is a small peptide that contains a DNA-binding It is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite region and an iron-binding domain at opposite ends of the moleculeends of the molecule

CCS drug active in G2 phaseCCS drug active in G2 phase MOA:MOA: It acts by binding to DNA, which results in It acts by binding to DNA, which results in

single-strand and double-strand breaks single-strand and double-strand breaks following free radical formation, and inhibition following free radical formation, and inhibition of DNA biosynthesis. The fragmentation of DNA of DNA biosynthesis. The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe(II) is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrationscomplex and leads to chromosomal aberrations

C. BleomycinC. Bleomycin

Specific Toxicity:Specific Toxicity: Cause: Bleomycin hydrolase, which Cause: Bleomycin hydrolase, which

inactivates bleomycin, virtually absent in inactivates bleomycin, virtually absent in lungs and skin lungs and skin

Pulmonary toxicity: Pulmonary toxicity: pneumonitis with cough, pneumonitis with cough, dyspnea, dry inspiratory crackles on physical dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest x-rayexamination, and infiltrates on chest x-ray

Skin toxicity: Skin toxicity: hyperpigmentation, hyperpigmentation, erythematosus rashes, and thickening of the skin erythematosus rashes, and thickening of the skin over the dorsum of the hands and at dermal over the dorsum of the hands and at dermal pressure points, such as the elbowspressure points, such as the elbows

MISCELLANEOUS MISCELLANEOUS ANTICANCER DRUGS ANTICANCER DRUGS

L-AsparaginaseL-Asparaginase

Enzyme that depletes serum L-asparagineEnzyme that depletes serum L-asparagine to aspartic acid and ammoniato aspartic acid and ammonia

It is used in treatment of childhood acute It is used in treatment of childhood acute lymphocytic leukemialymphocytic leukemia

ADEs: ADEs: hypersensitivity reactions, decrease hypersensitivity reactions, decrease in clotting factors, liver abnormalities, in clotting factors, liver abnormalities, pancreatitis, seizures, and coma due to pancreatitis, seizures, and coma due to ammonia toxicityammonia toxicity

Because tumor cells lack asparagine synthetase, they require an exogenous source of L-asparagine. Thus, depletion of L-asparagine results in effective inhibition of protein synthesis