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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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The Classification of
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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The Classification of
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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The Classification of
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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The Main Step of Anticancer
Drug Research
Clinical Research:
Phase 1 clinical trialPhase 2 clinical trial
Phase 3 clinical trial
Phase 4 clinical trial
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The Main Step of Anticancer
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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The Main Step of Anticancer
Drug Research
Phase 2 clinical trial
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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The Main Step of Anticancer
Drug Research
Phase 3 clinical trial
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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The Main Step of Anticancer
Drug Research
Phase 4 clinical trial
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
Pyrimidine Antagonists
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
Pyrimidine Antagonists
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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AntibioticsAntibiotics
Classification of Antibiotics: Adriamycin (Anthracyaline Antibiotics)
Mitomycin C
Bleomycin
Actinomycin D
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AntibioticsAntibiotics
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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AntibioticsAntibiotics
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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AntibioticsAntibiotics
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
Tubulin-Binding Agents
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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Anti-Cancer Plant Allaloids
Tubulin-Binding Agents
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
Anti-Cancer Plant Allaloids
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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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Thanks!