anticancer 2003
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Anticancer drugs
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INTRODUCTION
Cancer occurs after normal cells have been transformed into neoplastic cells through alteration of their genetic material and the abnormal expression of certain genes.
Neoplastic cells usually exhibit chromosomal abnormalities and the loss of their differentiated properties.
These changes lead to uncontrolled cell division and many result in the invasion of previously unaffected organs, a process called metastasis.
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Treatment options for Cancer:
Surgery before:1955
Radiotherapy: 1955~1965
Chemotherapy: after 1966
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The Classification of Anticancer Drugs
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The Classification of Anticancer Drugs
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The Classification of Anticancer Drugs
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Block Nucleic Acid (DNA, RNA) Biosynthesis
Antimetabolites:
• 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 Transcription and Block RNA Synthesis
• Bind with DNA to block RNA production.
Doxorubicin
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Influence the Structure and Function of DNA
• Alkylating Agent: Mechlorethamine,
Cyclophosphamide and Thiotepa
• Platinum: Cis-platinium
• Antibiotic: Bleomycin and Mitomycin C
• Topoismerase inhibitor: Camptothecine and
Podophyllotoxin Visit :www.bpharmstuf.com
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Influence Hormone Homeostasis
• Estrogens and estrogen antagonistic drug
• Androgens and androgen antagonistic drug
• Progestogen drug
• Glucocorticoid drug
• Gonadotropin-releasing hormone inhibitor: leuprolide, goserelin
• Aromatase inhibitor: aminoglutethimide, anastrazoleVisit :www.bpharmstuf.com
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Anticancer Drugs
• Alkylating agent
• Antimetabolite
• Antibiotics
• Alkaloid
• Hormones
• Others(Cis-platinum, carboplatin,lobaplatin)
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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, these
compounds were investigated and shown to
inhibit the growth of cancer cells.Visit :www.bpharmstuf.com
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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 and other 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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Classification of Alkylating Agents
Bis Chloroethyl Amines :
Cyclo phosphamide, Chlormethine, Chlorambucil,
Sarcolysine
Nitrosoureas :
Carmustine,Lomustine
Ethyleneammonium or Aziridines :
Thiotepa,triethylene melamine
Alkylsulfonates : Busulfan
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Alkylating Agents-Cyclophosphamide Indications
It is used in the treatment of chronic lymphocyctic leukemia,
breast and ovarian cancer, and a variety of other cancers.
It is also a potent immunosuppressant, it is used in the
management of rheumatoid disorders and autoimmune nephritis.
Adverse Effects:
Alopecia, nausea, vomiting, myelosuppression, and hemorrhagic
cystitis.
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Alkylating Agents——Nitrosoureas
Carmustine, Lomustine, Semustine
Pharmacokinetics:
Nitrosoureas are highly lipophilic and reach cerebrospinal fluid
concentrations that are about 30% of plasma concentrations.
Indications:
Because of their excellent CNS penetration, carmustine and
lomustine have been used to treat brain tumors.
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Alkylating agents - Alkylsulfonates
Busulfan [Myleran] Indications:
Busulfan is administered orally to treat chroicgranulocyticleukemia and other myeloproliferative disorders.
Adverse Effects:
Busulfan produces adverse effects related to myelosuppression. It only occasionally produces nausea and vomiting. In high doses, it produces a rare but sometimes fatal pulmonary fibrosis, ”busulfan lung”.
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Alkylating Agents——Thiotepa
Thiotepa is converted rapidly by liver
mixed-function oxidases to its active
metabolite triethylenephosphoramide
(TEPA); it is active in bladder cancer.
THIOTEPAOXIDASES
TEPA
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Antimetabolites
General Characteristics
Antimetabolites are S phase-specific drugs
that are structural analogues of essential
metabolites and that interfere with DNA
synthesis.
Myelosupression is the dose-limiting
toxicity for all drugs in this class.Visit :www.bpharmstuf.com
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Classification of Antimetabolites
Folic acid Antagonists: MTX
Purine Antagonists: 6MP
Pyrimidine Antagonists:5FU,Cytarabine
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Antimetabolites - Folic Acid Antagonist - Methotrexate
Dihydropteorate diphosphate + PABA
Dihydropteroicacid
Dihydropteroatesynthase
Dihydrofolicacid
Tetrahydrofolicacid
Dihydrofolatereductase
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Antimetabolites-Folic Acid Antagonist
Methotrexate (MTX) Indications
The use of MTX in the treatment of choriocarinoma, a
trophoblastic tumour, was the first demonstration of
curative chemotherapy.
It is especially effective for treating acute lymphocytic
leukemia and for treating the meningeal metastasis of a
wide range of tumors.
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Antimetabolites-FolicAcidAntagonist
Methotrexate (MTX)
Adverse Effects
MTX is myelosuppressive, producing severe leukopenia, bone marrow aplasia, and thrombocytopenia.
This agent may produce severe git disturbances.
Renal toxicity may occur because of precipitation (crystalluria) of the 7-OH metabolite of MTX.
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Antimetabolites - PurineAntagonists 6-Mercaptopurine
The drugs are believed to act similarly to inhibit purine 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 lymphocytic leukemia and is given in combination with MTX for this purpose.
Adverse Effects: Myelosuppression is generally mild with
thioguanine.Long-term mercaptopurine use may cause hepatotoxicity. Visit :www.bpharmstuf.com
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Antimetabolites-PyrimidineAntagonists
5-Fluorouracil (5-FU) Mechanism of Action Fluorouracil is an analogue of thymine in which the
methylgroup is replaced by a fluorine atom. It has two active metabolites: 5-FdUMP and 5-FdUTP. 5-FdUMP inhibits thymidylate synthetases and prevents the 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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AntibioticsAntibiotics
Classification of Antibiotics:Adriamycin Mitomycin C BleomycinActinomycin D
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AntibioticsAntibioticsAdriamycin and Daunorubicin
Properties:
Adriamycin and Daunorubicin are tetracycline rings with the sugar daunosamine. They are DNA intercalating agents that block the synthesis of DNA and RNA.
These agents are primarily toxic during the S phase of 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. Visit :www.bpharmstuf.com
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AntibioticsAntibiotics
Mitomycin C:Mechanism:Mitomycin C is an antineoplastic antibiotic that
alkylates DNA and thereby causes strand breakage and inhibition of DNA synthesis.
Indications:It is primarily used in combination with vincristine
as salvage therapy for breast cancer.Adverse Effects:Mitomycin produces delays and prolonged
myelosuppression that preferentially affects platelets and leukocytes.
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AntibioticsAntibiotics
Actinomycin D Actinomycin D intercalates DNA and
thereby prevents DNA transcription and messenger RNA synthesis.
The drug is given intravenously, and its clinical use is limited to the treatment of trophoblastic (gestational) tumors and the treatment of pediatric tumors, such as Wilms’ tumor and Ewing’s sarcoma.
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AntibioticsAntibiotics
BleomycinMechanismThe drug has its greatest effect on neoplastic cell in the
G2 phase of the cell replication cycle.Although bleomycin intercalates DNA, the major cytotoxicity is believed to result from iron catalyzed free radical formation and DNA strand breakage.
IndicationsIt is useful in Hodgkin’s and non-Hodgkin’s lymphomas,
testicular cancer, and several other solid tumors.Adverse EffectsBleomycin produces very little myelosuppression. The
most serious toxicities of Bleomycin are pulmonary and mucocutaneous reactions.
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Anti-Cancer Plant Alkaloids
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 Alkaloids
Tubulin-Binding AgentsPaclitaxel:Taxanes enhance all aspects of tubulin
polymerization, an action that is the opposite to that of vinca alkaloids, but they are also cytotoxic, emphasizing the dynamic importance of tubulin polymerization as a target for cytotoxic drugs.
Eg: Paclitaxel, Taxotere
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Platinum Compound
Cisplatin:Mechanism of Action:Cisplatin binds to guanine in DNA
and RNA, and the interaction is stabilized by hydrogen bonding. The molecular mechanism of action is unwinding and shortening of the DNA helix.
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Platinum Compound
Cisplatin
Indications:
Cisplatin has efficacy against a wide range of neoplasms. It is given intravenously as a first-line drug for testicular, ovarian, and bladder cancer, and it is also useful in the treatment of melanoma and a number of other soild tumours.
Adverseeffect:
Cisplatin produces relatively little myelosuppression but can cause severe nausea, vomiting, and nephrotoxicity.Visit :www.bpharmstuf.com
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HormonesSeveral types of hormone-dependent
cancer (especially breast, prostate, and endometrial cancer) respond to treatment with their corresponding hormone antagonists.
Estrogen antagonists are primarily used in the treatment of breast cancer, whereas androgen antagonists are used in the treatment of prostate cancer. Corticosteroids are particularly useful in treating lymphocytic leukemias and lymphomas.
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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 and carcinoma of the male breast are potential adverse effects.
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Hormones
ProgestinsProgestins 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 from metastatic breast cancer. It is most effective in patients who have estrogen receptor-positive tumors.
Tamoxifen is also used as adjunvctive therapy to oophorectomy 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 same mechanistic reasons.
Virilizing effects and hepatic toxicity make them unacceptable to most patients.
Fluoxymesterone is the most widely used agent.
Danazol has use in hematology in aplastic anaemia and congenital anaemias. Visit :www.bpharmstuf.com
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Hormones
Glucocorticoids: They are integral components of curative therapy
for acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, and Hodgkin’s disease.
Glucocorticoids have essential roles in the prevention of allergic reaction, emesis control, relief of intracranial hypertension or spinal cord compression in neurologic complications, and pain relief.
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REFERENCES
• Medical pharmacology by Tripathi
• Phamacology by Rang and Dale
• Phamacology by V.N Sharma• www.wikipedia.org• Foye’s principles of medicinal
chemistry• www.lippincott.com• Pharmacology by Goodmann
and GillmannVisit :www.bpharmstuf.com
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