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Antiviral drugs are a class of medication used specifically for treating viral infections.Like antibiotics for bacteria, specific antivirals are used for specific viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
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Lecture 10
Cancer Chemotherapy
Lecture 10
Anticancer drugs
Antimetabolites Alkylating agents Antibiotics Microtubule inhibitors Miscellaneous agents
Lecture 10
Antimetabolites
Methotrexate 6-marcaptopurine 5-fluorouracil Cytrabine
Lecture 10
Methotrexate
Structurally related to folic acid Inhibitor of an enzyme dihydrofolate reductase (DHFR) DHFR reduces duhydrofolate (FH2) to tetrahydofolate (FH4)
using NADH as electron donor The affinity of MTX for DHFR is thousand times higher than
that of folate for DHFR Therefore the enzyme is competitively inhibited Acts mainly on S phase.
Lecture 10
Methotrexate
Lecture 10
Methotrexate
Inhibition of DHFR deprive the cell of folic acid Folic acid is required for the de novo synthesis of thymidine Folate is also needed for the synthesis of purine nucleotides MTX therefore, inhibit the synthesis of DNA, RNA,
thymidylates and protieins. MTX acts specifically during DNA and RNA synthesis and
thus cytotoxic during the S-phase of cell cycle and has a great effect on rapidly dividing cells.
Effective against Burkitt’s lymphoma, Breast cancer, Head and neck carcinoma.
Lecture 10
6-Marcaptopurine
Purine analogue, structural analogue of hypoxanthine Inhibits 1st step of de novo prurine biosynthesis, thereby inhibiting
their synthesis The thiol anallogues are also incorporated into DNA and RNA Used in acute lymphoblastic leukemia
Lecture 10
5-Fluorouracil
Pyrimidine analogue, fluorine substituted analogue of uracil Has a stable fluorine at position 5 in place of hydrogen atom Interferes with the conversion of deoxyuridylic acid to thymidylic acid
by inhibiting Thymudylate synthase Inhibits cells ability to synthesize DNA Used in colorectal, ovarian, pancreatic and gastric carcinoma
Lecture 10
Cytrabine
Analogue of 2’ deoxycytidine in which natural ribose is replaced by D-arabinose
Acts as a pryrimidine antagonist Biotransformed to its active form – ara CTP Competitively inhibits DNA polymerase No effect on protein or RNA synthesis Used in acute myelogenous leukemia
Lecture 10
Alkylating agent
Exert their cytotoxic effect by covalently binding with nucleophilic group of various cell constituents.
Act via a reactive alkyl group (R-CH2-CH2+) to form covalent bond
Alkylation of DNA is the crucial cytotoxic reaction that is lethal to tumor cell
They are phase non-specific. Do not discriminate between dividing and resting cells but are most
toxic for rapidly dividing cells.
Alkylating agents include: Cyclophosphamide Nitrosuria Nitrogen mustard
Lecture 10
Cyclophosphamide
Pro-drug, requires metabolic activation Cyt P450 system converts it into a hydroxylated intermediate Alkylation of DNA is considered to be the cytotoxic step Inter- and intra-strand cross-linking of DNA at N7 of guanine causes
cell death Used in Burkitt’s Lymphoma and breast cancer
Lecture 10
Nitrogen mustard
First developed during World War II as a vesicant or blister agent They are transported into the cell by a chloride uptake process The drug lose a chloride ion and forms a reactive intermediate that
alkylates N7 of guanine residue in one or both the strand of DNA Leads to cross-linkages between guanine residues in DNA strands Leads to depurination that facilitates DNA strand breakage Predominantly used in Hodgkin’s disease
Lecture 10
Nitrosurea
Exert cytotoxic effect by alkylation that crosslink DNA strands Inhibits DNA replication Because of their ability to penetrate CNS, they are primarily
used in the treatment of brain tumors Limited in the treatment of other cancer
Lecture 10
Antibiotics
Dactinomycin Doxorubicine and donorubicine
Lecture 10
Dactinomycin
Intercalates into the minor groove of the double helix between G-C base pairs of DNA
Forms a stable dactinomycin-DNA complex Inhibits DNA-dependent RNA synthesis Blocks protein synthesis Used in gastric carcinoma and soft tissue carcinoma
Lecture 10
Doxorubicine and donorubicine
Inserted non-specifically between adjacent base pairs Binds to sugar-phosphate backbone of DNA Causes a local uncoiling of the DNA molecule Blocks DNA and RNA synthesis
Doxorubicin Daunorubicin
Lecture 10
Microtubule inhibitors
Mitotic spindle is a part of cytoskeleton Essential for the internal movement of cytoplasm in all eukaryotic cells It is also essential for the equal partitioning of DNA into daughter cells during cell
division Mitotic spindle consists of chromatin and a protein tubulin Polymerization of tubulin molecule is a necessary step in the formation of mitotic
spindle Several plant alkaloids used as anticancer drugs that disrupt this process by affecting
the equilibrium between polymerized and depolymerized formd of tubulin
Background:
Lecture 10
Microtubule inhibitors
Vincristin and Vinblastin Taxols
Lecture 10
Vincritine and vinblstine
Isolated form a plant Vinca rosea Sometimes referred to as vinca alkaloids Both vincristine and vinblastin binds to tubulin Blocks the ability of tubulin to polymerize An aggregate of tubulin-dimer and the drug is formed Resulting dysfunctional spindle apparatus that are frozen at
metaphase stage Prevents chromosomal segregation and cell proliferation
Lecture 10
Taxol
Isolated for the needle of yew species Binds reversibly to tubulin Unlike vinca alkaloids it promotes tubulin polymerization Stabilize the polymer which is non functional
Lecture 10
Miscellaneous agents
Cisplatin Etoposide Bleomycin
Lecture 10
Cisplatin
The drug is a platinum complex Has synergistic cytotoxicity with radiation and other
chemmotherapeutic agents Mechanism of action is similar to alkylating agents Binds to N7 of guanine
Forms inter- and intra-strand cross-linkage in the DNA strands
Used in Testicular, bladder and ovarian cancer
Lecture 10
Etoposide
A semi-synthetic derivative of the plank alkaloid podophylotoxin
Blocks cell cycle at S -- G2 phase
Major target is topoisomerage II
Lecture 10
Bleomycin
Mixture of different copper chelating glycoproteins
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DNA synthesis
AntimetabolitesAntimetabolites
DNA
DNA transcription DNA duplication
Mitosis
Alkylating agentsAlkylating agents
Spindle poisonsSpindle poisons & &
Microtuble StablizersMicrotuble Stablizers
Intercalating agentsIntercalating agents
Sites of Action of Cytotoxic Agents – Cellular Level
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