Anti-Cancer Drugs22

8/7/2019 Anti-Cancer Drugs22

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Anti-Cancer Drugs

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Overview

Introduction

Malignant disease accounts for a high proportionof deaths in industrialised countries.

The treatment of anticancer drug is to give

palliation, induce remission and, if possible, cure.


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Overview

Introduction

Cancer occurs after normal cells hav

e beentransformed into neoplastic cells through alteration oftheir genetic material and the abnormal expression ofcertain genes. Neoplastic cells usually exhibitchromosomal abnormalities and the loss of their

differentiated properties. These changes lead touncontrolled cell division and many result in theinvasion of previously unaffected organs, a processcalled metastasis.


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Advances in Cancer Chemotherapy

Treatment options of cancer:

Surgery: before 1955

Radiotherapy: 1955~1965

Chemotherapy: after 1965

Immunotherapy and Gene therapy


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Adv

ances in Cancer Chemotherapy

The treatment of a patient with cancer mayaim to:

give palliation, for example prompt relief ofunpleasant symptoms such as superior vena cavaobstruction from a mediastinal tumor

induce remission so that all macroscopic and

microscopic features of the cancer disappear,though disease is known to persist cure, for which all the cells of the clone must be

destroyed.


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Cancer Chemotherapy

Disease Name 5 Years Survival Rate

Childhood Acute Lymphoblastic Leukemia 50~80%

Adult Acute Lymphoblastic Leukemia 20~60%

Childhood Acute Myeloblastic Leukemia 20~60%

Adult Acute Myeloblastic Leukemia 10~20%

Breast Cancer

Premenopausal

10~20%

Breast CancerPostmenopausal 0~15%

Hodgkin s lymphoma * 40~80%


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Cancer Chemotherapy

Disease Name 5 Years Survival Rate Small Cell Lung Cancer Limited Stage 10~20% E

xtensiv

e Stage

0~5% Non-Hodgkin s lymphoma * 40~65% Ovarian Cancer 40~60% Children Solid TumorNephroblastoma, Rhabdomyosarcoma

LymphomaOsteosarcoma* 60~90% Trophoblastoma Chorion Epithelioma** 80~90%

Seminoma of Testis** 60~90% Embryonic Carcinoma of Testis 60~80%Note* Combination with other therapeutics

**Chemotherapy Level of our country is high


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The Classification of

Anticancer Drugs

According to chemical structure andAccording to chemical structure and

resource of the drug;; According toAccording to biochemistry mechanisms of

anticancer action;;

According to the cycle or phasespecificity of the drug


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Anticancer Drugs

According to chemical structure andAccording to chemical structure and

resource of the drug::Alkylating Agents,, Antimetabolite,,

Antibiotics, Plant ExtractsAntibiotics, Plant ExtractsHormones

OthersOthers


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Anticancer Drugs

According toAccording to biochemistry mechanisms of

anticancer action:BlockBlock nucleic acid biosynthesis

Direct influence the structure and function ofthe structure and function ofDNADNA

Interfere transcription and block RNA synthesisInterfere protein synthesis and function

Influence hormone homeostasis

Others


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Anticancer Drugs

According to the cycle or phase

specificity of the drug:cell cycle nonspecific agents (CCNSA)

cell cycle specific agents (CCSA)


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The Basic Concept of

Cell Generation Cycle

The cycle of cell replication includes:

MMitosisphaseG1Gap1, period before Sphase

SDNA synthesisphase

G2Gap2,period after Sphase

Growth Fraction (GF


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Growth Fraction (GF)

GFProliferating cell groupProliferating cell group

Total tumor cell groupTotal tumor cell group

CCNSACCNSAdrugs that are activedrugs that are active

throughout the cell cycle.throughout the cell cycle.CCSA:CCSA: drugs that act during a specificdrugs that act during a specific

phase of the cell cycle.phase of the cell cycle.


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Cell cycle specific agents and Cell cycle

Non-specific agents

Cell Cycle Nonspecific Agents (CCNSA)

drugs that are active throughout the celldrugs that are active throughout the cellcyclecycle

Alkylating Agents

Platinum Compounds

AntibioticsAntibiotics


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Cell cycle specific agents and Cell cycle

Non-specific agents

Cell Cycle Specific Agents (CCSA)drugsdrugs thatthat actact duringduring aa specificspecific phasephase ofofthethe cellcell cyclecycleS Phase Specific Drug:

Antimetabolites, Topoisomerase InhibitorsM Phase Specific Drug:

Vinca Alkaloids, TaxanesG2 Phase Specific Drug:

Bleomycin


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Mechanism of Anticancer Drugs

Block nucleic acid (DNA, RNA) biosynthesis

Directly destroy DNA and inhibit DNAreproduction

Interfere transcription and block RNA synthesis

Interfere protein synthesis and function Influence hormone homeostasis


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Block Nucleic Acid (DNA, RNA)

BiosynthesisAntimetabolites:

Folic Acid Antagonist: inhibit dihydrofolate

reductase (methotrexate) Pyrimidine Antagonist: inhibit thymidylate

synthetase (fluorouracil) ; inhibit DNA

polymerase (cytarabine)

Purine Antagonist: inhibit interconversion of

purine nucleotide (mercaptopurine)

Ribonucleoside Diphosphate Reductase Antagonist:

(hydroxyurea)


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Interfere Protein Synthesis

Antitubulin: vinca alkaloids and taxanes;

Interfere the function of ribosome:harringtonines

Influence amino acid supply: L-asparaginase

Bind tubulin, destroy spindle to producemitotic arrest.


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Interfere Transcription and

Block RNA Synthesis

Bind with DNA to block RNA production.

doxorubicin


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Influence the Structure andFunction of DNA

Alkylating Agent: mechlorethamine,cyclophosphamide andthiotepa

Platinum: cis-platinium

Antibiotic: bleomycin andmitomycin C

Topoismerase inhibitor: camptothecine and

podophyllotoxin


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Influence Hormone Homeostasis

These drugs bind to hormone receptors to blockthe actions of the sex hormones which results in

inhibition of tumor growth. Estrogens and estrogen antagonistic drug Androgens and androgen antagonistic drug Progestogen drug

Glucocorticoiddrug gonadotropin-releasing hormone inhibitor:

leuprolide, goserelin aromatase inhibitor: aminoglutethimide,

anastrazole


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The Long Roadof a New Medicine


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The Main Step of Anticancer

Drug Research

Non-clinical Research

1.Anticancer Drug Screen:in vitrotumor cell culture, tumorinhibitor/kill test

in vivoanimal xenograft model e.g.Ehrlich

ascites tumor, S180 lymphosarcoma2. Pharmacodynamics, pharmacokinetics and

toxicology test


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Drug Research

Clinical Research:

Phase 1 clinical trialPhase 2 clinical trial

Phase 3 clinical trial



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Drug ResearchPhase 1 clinical trial

In Phase 1 clinical trials, researchers test a new

drug or treatment in a small group of people

(20-80) for the first time to evaluate its

safety, determine a safe dosage range, and

identify side effects.

TOLERANCE

PHARMACOKINETICS


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Drug Research


In Phase 2 clinical trials, the study drug ortreatment is given to a larger group of people

(40-100) to see if it is effective and to further

evaluate its safety.


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Drug Research


In Phase 3 studies, the study drug or treatment

is given to large groups of people (more than 200)

to further determine its effectiveness, monitor

side effects, compare it to commonly used

treatments, and collect information that will

allow the drug or treatment to be used safely.


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Drug Research


Phase 4 studies are done after the drug ortreatment has been marketed. These studies

continue testing the study drug or treatment to

collect information about their effect in various

populations and any side effects associated with

long-term use.


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Anticancer Drugs

Alkylating Agent Antimetabolite

Antibiotics

Alkaloid Hormones

Otherscis-platinumcarboplatinlobaplatin


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Alkylating Agents One of the frightening developments of World

War I was the introduction of chemical warfare.

These compounds were known as the nitrogen

mustard gases. The nitrogen mustards were

observed to inhibit cell growth, especially of

bone marrow. Shortly after the war, thesecompounds were investigated and shown to inhibit

the growth of cancer cells.


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Alkylating Agents

Mechanism of Action

Nitrogen mustards inhibit cell reproduction by

binding irreversibly with the nucleic acids (DNA).The specific type of chemical bonding involved is

alkylation. After alkylation, DNA is unable to

replicate and therefore can no longer synthesize

proteins andother essential cell metabolites.Consequently, cell reproduction is inhibited and

the cell eventually dies from the inability to

maintain its metabolic functions.


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Resistance of Alkylating Agents

Resistance to alkylating agents has severalcauses:

Membrane transport may be decreased.

The drug may be bound by glutathione (GSH)via GSH-S-transferase or metallothioneins

in the cytoplasm and inactivated. The drug may be metabolized to inactive

species.


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Adverse Effects of Alkylating Agents

Myelosuppression is the dose-limitingadverse effect for alkylating agents.

Nausea andvomiting are common as areteratogenesis and gonadal atrophy,although in the latter cases these are

variable, according to the drug, itsschedule, and route of administration.

Treatment also carries a major risk ofleukemogenesis and carcinogenesis.


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Alkylating AgentsMustine

Mustine must be injected intravenouslybecause it is highly reactive. Itdisappears very rapidly from the blood,the activity of Mustine lasts only a fewminutes.

The main indication for Mustine is intreatment of Hodgkins disease andlymphomas, but it may also be useful inother malignancies.


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Alkylating Agents

CyclophosphamideCyclophosphamide can also be given orally.Indications

It is used in the treatment of chronic lymphocycticleukemia, non-Hodgkins lymphomas, breast andovarian cancer, and a variety of other cancers.

It is also a potent immunosuppressant, it is used inthe management of rheumatoid disorders and

autoimmune nephritis.Adverse Effects: Alopecia, nausea, vomiting, myelosuppression, and

hemorrhagic cystitis.


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Alkylating AgentsNitrosoureas

Carmustine, Lomustine, Semustine

Pharmacokinetics:

Nitrosoureas are highly lipophilic andreach cerebrospinal fluid concentrationsthat are about 30% of plasmaconcentrations.

Indications:

Because of their excellent CNSpenetration, carmustine and lomustine

have been used to treat brain tumors.


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Alkylating Agents

Phenylalanine Nitrogen Mustard

Melphalan is a nitrogen mustard that is

primarily used to treat multiple myeloma(plasma cell myeloma), breast cancer, and

ovarian cancer.


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Alkylating Agents

AlkysulfonatesBusulfan [Myleran]Indications: Busulfan is administeredorally to treat chroic

granulocytic leukemia andothermyeloproliferative disorders.

Adverse Effects:

Busulfan produces advers effects related tomyelosuppression. It only occasionally producesnausea andvomitting. In high doses, it producesa rare but sometimes fatal pulmonaryfibrosis, busulfan lung.


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Alkylating AgentsThiotepa

Thiotepa is converted rapidly by liver

mixed-function oxidases to its activemetabolite triethylenephosphoramide

(TEPA); it is active in bladder cancer.


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Antimetabolites

General Characteristics

Antimetabolites are S phase-specificdrugs that are structural analogues of

essential metabolites and that interfere

with DNA synthesis.Myelosuppression is the dose-limiting

toxicity for all drugs in this class.


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Classification of Antimetabolites

Folic acid Antagonists: MTX

Purine Antagonists: 6MP6TG

Pyrimidine Antagonists5FU

araC

HU


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Antimetabolites

Folic Acid AntagonistMethotrexate MTX

Mechanism of Action

The structures of MTX and folic acid are

similar. MTX is actively transported into

mammalian cells and inhibits dihydrofolate

reductase, the enzyme that normally convertsdietary folate to the tetrahydrofolate form

required for thymidine and purine synthesis.


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Antimetabolites

Folic Acid AntagonistMethotrexate MTX

Indications

The use of MTX in the treatment of

choriocarinoma, a trophoblastic tumor, was the

first demonstration of curative chemotherapy.

It is especially effective for treating acutelymphocytic leukemia and for treating the

meningeal metastases of a wide range of tumors.


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Antimetabolites

Folic Acid AntagonistMethotrexate MTXAdverse Effects

MTX is myelosuppressive, producing severeleukopenia, bone marrow aplasia, andthrombocytopenia.

This agent may produce severe gastrointestinal

disturbances. Renal toxicity may occur because of precipitation

(crystalluria) of the 7-OH metabolite of MTX.


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Antimetabolites

Purine Antagonists6-Mercapapurine6-MP

The drugs are believed to act similarly to inhibitpurine base synthesis, although their exact

mechanisms of action are still uncertain.Indications: Mercaptopurine is used primarily for the maintenance

of remission in patients with acute lymphocyticleukemia and is given in combination with MTX for

this purpose.Adverse Effects: Well tolerate. Myelosuppression is generally mild with

thioguanine.Long-term mercaptopurine use may cause

hepatotoxicity.


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Antimetabolites

Pyrimidine Antagonists

5-Fluorouracil (5-FU)Mechanism of Action

Fluorouracil is an analogue of thymine in which the

methyl group is replaced by a fluorine atom. It has

two active metabolites: 5-FdUMP and 5-FdUTP. 5-

FdUMP inhibits thymidylate synthetases and preventsthe synthesis of thymidine, a major building block of

DNA. 5-FdUTP is incorporated into RNA by RNA

polymerase and interferes with RNA function.


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Antimetabolites


5-Fluorouracil (5-FU)

Indications Fluorouracil is exclusively used to treat

solid tumors, especially breast, colorectal,

and gastric tumors and squamous celltumors of the head and neck.


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Antimetabolites

Pyrimidine Antagonists5-Fluorouracil (5-FU)Adverse Effects Fluorouracil may cause nausea andvomiting,

myelosuppression, andoral and gastrointestinalulceration. Nausea andvomitting are usually mild.

With fluorouracil, myelosuppression is more

problematic after bolus injections, whereasmucosal damage is dose-limiting with continuousinfusions.


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Antimetabolites


CytarabineIndications Cytarabine has a narrow clinical spectrum and is

primarily used in combination with daunorubicin orthioguanine for the treatment of acutenonlymphocytic leukemia.

Adverse Effects: High doses of cytarabine can damage the liver,

heart, and other organs.


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Classification of Antibiotics: Adriamycin (Anthracyaline Antibiotics)

Mitomycin C

Bleomycin

Actinomycin D


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Adriamycin and DaunorubicinProperties:

Adriamycin and Daunorubicin are tetracycline ringswith the sugar daunosamine. They are DNAintercalating agents that block the synthesis of DNAand RNA.

These agents are primarily toxic during the S phaseof cell cycle.

These agents imparts a red tinge to the urine.

Adramycin is used to treat acute leukemias, lymphoma,

and a number of solid tumors.


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Mitomycin C:Mechanism: Mitomycin C is an antineoplastic antibiotic that

alkylates DNA and thereby causes strandbreakage and inhibition of DNA synthesis.

Indications: It is primarily used in combination with

vinvristine as salvage therapy for breast cancer.Adverse Effects: Mitomycin produces delays and prolonged

myelosuppression that preferentially affectsplatelets and leukocytes.


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Actinomycin D: Actinomycin D intercalates DNA and thereby

prevents DNA transcription andmessenger RNAsynthesis.

The drug is given intravenously, and its clinicaluse is limited to the treatment of trophoblastic

(gestational) tumors and the treatment ofpediatric tumors, such as Wilms tumor andEwings sarcoma.


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AntibioticsAntibioticsBleomycin:Mechanism: The drug has its greatest effect on neoplastic

cell in the G2 phase of the cell replication

cycle.Although bleomycin intercalates DNA, themajor cytotoxicity is believed to result fromironcatalyzed free radical formation and DNAstrand breakage.

Indications: It is useful in Hodgkins and non-Hodgkins

lymphomas, testicular cancer, and several othersolid tumors.

Adverse Effects: Bleomycin produces very little myelosuppression.

The most serious toxicities of Bleomycin are

pulmonary and mucocutaneous reactions.


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Anti-Cancer Plant Allaloids

Tubulin-Binding Agents

Vinca Alkaloids: The cellular mechanism of

action of vinca alkaloids is the prevention of

microtubule assembly, causing cells to arrest

in the late G2 phase by preventing formation

of mitotic filaments for nuclear and cell

division.


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Anti-Cancer Plant AllaloidsAnti-Cancer Plant Allaloids


Vinca alkaloids:

Vinblastine,vincristin, vindesine and vinorelbine are allalkaloids derived from the periwinkle plant (Vinca rosea).

Indications:

Vinblastine is used in combination with Bleomycin

and Cisplatin for metastatic testicular tumors. Vincristine is used in combination with prednisone

to induce remission in childhood leukemia.

Vinorelbine is used to treat non-small-cell lung

cancer and breast cancer.


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Paclitaxel:

Taxanes enhance all aspects of tubulinpolymerization, an action that is the opposite tothat of vinca alkaloids, but they are alsocytotoxic, emphasizing the dynamic importance of

tubulin polymerization as a target for cytotoxicdrugs.

Paclitaxel, Taxotere


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Interfere the Function of Ribosome:

Cephalotaxus Alkaloids :

Harringtonine

Homoharringtonine



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Platinum Compound

Cisplatin:Mechanism of Action:

Cisplatin binds to guanine in DNA and

RNA, and the interaction isstabilized by

hydrogen bonding. The molecular

mechanism of action is unwinding andshortening of the DNA helix.


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Platinum CompoundCisplatin:Indications:

Cisplatin has efficacy against a wide range ofneoplasms. It is given intravenously as a first-line drug for testicular, ovarian, and bladdercancer, and it is also useful in the treatment ofmelanoma and a number of other soild tumors.

Adverse Effect: Cisplatin produces relatively little

myelosuppression but can cause severe nausea,vomiting, and nephrotoxicity.


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Hormones

Several types of hormone-dependent cancer(especially breast, prostate, and endometrial

cancer) respond to treatment with theircorresponding hormone antagonists.

Estrogen antagonists are primarily used in thetreatment of breast cancer, whereas androgen

antagonists are used in the treatment ofprostate cancer. Corticosteroids are particularlyuseful in treating lymphocytic leukemias andlymphomas.


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Hormones

Estrogens:

Estrogens inhibit the effects of endogenous

androgens and androgen-dependent metastatic

prostatic carcinoma. Diethylstilbestrol is usually

the agent of choice.

Cardiac and cerebrovascular complications andcarcinoma of the male breast are potential

adverse effects.


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Hormones

Progenstins:

Progestins are useful in the management of

endometrial carcinoma and back-up therapy for

metastatic hormone-dependent breast cancer.


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Hormones

Antiestrogen: Tamoxifen Tamoxifen is the drug of choice in

postmenopausal women with or recovering frommetastatic breast cancer. It is most effective inpatients who have estrogen receptor-positivetumors.

Tamoxifen is also used as adjun

vcti

ve therapy tooophorectomy to leuprolide or goserelin in

premenopausal women with estrogen receptor-positive tumors.


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Hormones

Androgens: Androgen activity in breast cancer is similar to

that of estrogens, perhaps for the samemechanistic reasons.

Virilizing effects and hepatic toxicity make themunacceptable to most patients.

Fluoxymesterone is the most widely used agent. Danazol has use in hematology in aplastic anemia

and congenital anemias.


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Hormones

Glucocorticoids: They are integral components of curative therapy

for acute lymphoblastic leukemia, non-Hodgkinslymphoma, andHodgkins disease.

Glucocorticoids have essential roles in theprevention of allergic reaction, emesis control,relief of intracranial hypertension or spinal cordcompression in neurologic complications, and painrelief.


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Problems With Cancer

Chemotherapy

Drug Resistance Drug Toxicity


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Drug Resistance

De novo Resistance

Acquired Resistance Multidrug Resistance (MDR)


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Drug Resistance

De novo resistance:

De novo resistance can be de novo genetic (i.e.

the cells are initially inherently resistant), or can

arise because drugs are unable to reach the

target cells because of permeability barriers

such as the blood-brain barrier.


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Drug Resistance

Acquired Resistance:

Acquireddrug resistance may result fromgenomic mutations, such as the induction ordeletion of enzymes involved in drug inactivationor drug activation, respectively.


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Drug Resistance

Multidrug Resistance (MDR):

P-glycoprotein transports many naturally

occurring drugs out of neoplastic cells, and its

induction may lead to multidrug resistance.

As scientific understanding of the mechanisms of

drug resistance increases, new treatments maybe developed to counteract resistance.


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Drug Toxicity

The most common toxicities of antineoplastic

drugs result fr

om inhibiti

on

of cell replicati

on in

the bone marrow, gastrointestinal epithelium, and

hair follicles. Many antineoplastic drugs also

stimulate the chemoreceptor trigger zone in the

medulla and thereby elicit nausea andvomiting.


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Immunomodulating DrugsImmunomodulating Drugs

Immunosuppressive Agents:

Act to suppress immune mechanisms and are usedto treat autoimmune diseases or to prevent graft

rejection following tissue transplantation.

Ciclosporin, Tacrolimus, adrenocortical hormones,antimetabolites, alkylating agent, antilymphocyte

globulin, Mycophenolate Mofetil


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Immunomodulating DrugsImmunomodulating Drugs

Immunopotentiator :

Enhance antitumor immunity and are used to

treat neoplastic disease.

Recombinant Interferons and Cytokines.


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Adjunct Agents

Filgastrim

Salgastrim


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