Cancer chemotherapy
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Transcript of Cancer chemotherapy
CANCER CHEMOTHERAPY Dr.Zulcaif Ahmad
Hajvery University
Cancer
It is an unwanted and uncontrolled growth of cells.
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OverviewOut of the total number of people diagnosed
with cancer, less than one fourth can be cured with Radiotherapy and Surgery While
the rest needs chemotherapy. 10% of those treated gets a cure, otherwise it just adds to the better life quality and life span increase upto 5 years (65%). Cancer is
the 2nd highest death causing disease.
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• PRINCIPLE: Cancer chemotherapy strives to cause a lethal cytotoxic event or apoptosis in the cancer cell that can arrest tumor's progression.
• Indication: Chemotherapy is indicated when neoplasms are disseminated and are not amenable to surgery.
• Goal : Long term disease free survival.
• Tumor Susceptibility: Rapidly proliferating cells are more prone to chemotherapeutic drugs as compared to slow proliferating cells.
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Types of Chemotherapy•Adjuvant Chemotherapy: Used as a
supplement treatment to attack micrometastases following surgery and radiation treatment.
• •Neo adjuvant Chemotherapy: Given
prior to the surgical procedure in an attempt to shrink the cancer.
•Maintenance Chemotherapy: Given in lower doses to assist in prolonging remission.
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Cell Cycle
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CELL CYCLE SPECIFIC DRUGS
CELL CYCLE NON-SPECIFIC…
These are specific to the cells that are traversing the cell cycle and do not act against cells in the non proliferating Go phase.
They target both proliferating (Traversing cell cycle) and non proliferating (in G0 phase) cells without any discrimination.
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Classification of Chemotherapeutic Drugs
ANTI METABOLITES ANTI BIOTICSAlkylating
AgentsMonoclonal Antibodies
Microtubule Inhibitors
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1 - ANTIMETABOLITESAntimetabolites are structurally related to compounds already present in our cells and through variable mechanisms interfere with the availability of normal Purine and Pyrimidine nucleotide precursors.Their maximal toxic effects are in S phase of the cell cycle.These are further sub classed as:a) Folate antagonists.b) Purine antagonists.c) Pyrimidine antagonists.
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(a) METHOTREXATEMOA: •Methotrexate (MTX) is a competitive follic
acid antagonist that binds to the active catalytic site of Dihydrofolate reductase (DHFR) so the reduction of Folic acid to Tetrahydrofolate is interfered.
•Just like Tetrahydrofolate, it becomes polyglutamated in the cell - a process that favour its cellular retention owing to increased negative charge and its polyglutamates also potentially inhibits DHFR.
•Deficiency of this coenzyme in S phase leads to the failure of cell to form Thymidine, adenine, guanine, methionine,serine etc and hence DNA and protein synthesis is depressed that let not cell undergo S phase and the cell dies.
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Follic Acid
Dihydrofollate Reductase
Tetrahydrofollate
Methotrexate
Thymidine, Adenine, Guanine, Methionine,Serine.
DNA
CELL DIES
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(b) 6-Mercaptopurine MOA: It is a purine analog. • 6-MP first converts into nucleotide analog form
i.e 6-MP Ribose Phosphate better known as 6-thioinosinnic acid (TIMP).• TIMP then inhibits the first step of Purine ring
biosynthesis and also blocks the formation of AMP and Xanthinuric acid from inosinic acid.• TIMP also converts into thioguanine
monophosphate (TGMP) which after phosphorylation to di and triphosphates can be incorporated into RNA
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• It also forms deoxy-ribonucleotides that are incorporated in DNA.
As a result, non functional DNA and RNA are formed.
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Hajvery University
6-MPHGPRT
TIMP
Deoxyribonucleotidesthioguanine mono/di/tri phosphate
inosinic acid AMP and Xanthinuric acid
NON FUNCTIONAL DNANON FUNCTIONAL RNA
(c) 5- FluorouracilMOA:
5-Fu is a pro drug and after activation it forms Ribosyl and Deoxyribosyl metabolites which perform following functions:1. 5-Fluoro-2-deoxyuridine-5’-mono phosphate
(FdUMP) : Forms covalently bound ternary complex with the enzyme Thymidyle Synthase and reduced Folate thus inhibiting Thymidylate synthesis which leads to inhibition of DNA due to lack of Thymine – “Thymine less Death.”
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2. 5-Fluorouridine-5’-triphosphate (FUTP) : It is incorporated into the RNA and interferes with RNA processing e.g mRNA translation.3. 5-fluorodeoxyuridine-5’-triphosphate : It is incorporated into cellular DNA resulting in inhibition of cellular DNA function and synthesis.
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Hajvery University
5- Fluorouracil
ACTIVATION
5-Fluoro-2-deoxyuridine-5’-mono phosphate (FdUMP)
5-fluorodeoxyuridine-5’-triphosphate
5-Fluorouridine-5’-triphosphate (FUTP)
NON FUNCTIONAL DNA
NON FUNCTIONAL RNA
Thymine less Death
2. MONOCLONAL ANTIBODIES
Monoclonal antibodies are produced from cloning of Specific hybrid B-cells which produce antibodies for specific (desired) antigen e.g HER2 or EGFR or VEGF.
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(a) RituximabMOA: Its antigen is CD-20 site found in normal and malignant B-Cells and plays role in cell cycle initiation and cell differentiation.The Fab domain of the antibody binds with its antigen while Fc segments recruits immune effector functions i.e through complement and antibody mediated cytotoxicity of B-cells.
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ALKYLATING AGENTS
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• Cyclophosphamide, Melphalan• Chlorambucil,Mechlorethamine
Nitrogen mustards
• Carmustine , lomustine• semustineNitrosourease
• Triethylenemelamine , • TriethylenethiophospharamideAziridines
• BusulfanAlkylsulfonates
• DecarbazineTriazenes
• Procarbazine , Hexamethylmelamine• Pentamethylmelamine, Csplatin
Miscellaneous alkylating agents Hajvery University
MECHANISM OF ACTION • Alkylating agents
exert their cytotoxic effects by covalently binding to nucleophilic groups on various cell constiuents. Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to tumor cell s.
Hajvery University
Hajvery University
NITROGEN MUSTURDS MOA(Cyclophosphamide)
• Kill rapidly proliferating cells as well as non-proliferating cells as a result of alkylation of RNA, DNA and essential protiens.• Most favoured sites for alkylation being 7-nitrogen and
6-oxygen of guanine.• Cross linking, resulting in inhibition of DNA replication.• Mispairing of bases = production of defective protiens• Depurination of DNA = strand break• ADR’s :-• Nausea, Vomitting , Moderate depression of
peripheral blood cell count.Hajvery University
Nitrosoureas (Penetrate CNS)MOA:They exerts cytotoxic effects by an alkylation that inhibit
replication and, eventually, RNA and protien synthesis. Although they alkylate DNA in resting cells, cytotoxicity is expressed priemerly on cells that are actively dividing.
Also inhibit several key enzymatic processes by carbamoylation of aminoacids in protiens in the targeted cells.
ADR’s:- Renal toxicity, pulmonary fibrosis, delayed hematopoietic
depressionHajvery University
Hajvery University
Cyclophosphamide
DNA
RNA
PROTEINS
ALKYLATION
CELL DEATH
Antibiotics• Dactinomycin• Daunorubicin• Bleomycinn• Doxorubicin• Epirubicin• Idarubicin
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Dactinomycin•MOA:• The drug intercalates into the minor groove of the double
helix between guanine-cytosine base pair of DNA forming a stable dactinomysin-DNA complex. The complex interfare primarily with DNA dependent RNA polymerase, although at high doses, dactinomycin hinders DNA synthesis. The drug also causes single-strand breaks, possibly due to action on topoisomerase II or by generation of free radicals.• Resistance:• Resistance is due to an increased efflux of the antibiotic
from the cell via p-glycoprotien.DNA repair may also play a role. Hajvery University
ADR’s• Bone marroe depression • Nausea• Vomitting• Diarrhea• Alopecia
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Bleomycin •MOA: • DNA strand scission and direct oxidation of purine or
pyrimidine bases.• DNA-bleomycin-Fe+2 complex appears to undergo
oxidation to bleomycin-Fe+3. The liberated electrons react with oxygen to form superoxide or hydroxyl radicals, which, in turn, attack the phosphodiester bonds of DNA, Resulting in strand-breakage and chromosomal aberrations.• ADR’s:• Pulmonary toxicity• Cough• Hypertrophic skin changes
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Hajvery University
DNA-bleomycin-Fe+2 complex
bleomycin-Fe+3
superoxide or hydroxyl radicals
phosphodiester bonds of DNA
DNA Lysis
BLEOMYCINE
CONVERSI
ONCONVERSION
Electrons
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3. MICROTUBULE INHIBITORS
Microtubule inhibitors are cell cycle and phase specific drugs that disturb the partitioning equilibrium of DNA into two new daughter cells through disrupting mitotic spindle in the M phase of the cell cycle.
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VINCRISTINE & VINBLASTIN
MOA: Blocks Mitosis in Metaphase.They binds to Tubulin (microtubular protein) through a GTP dependent process thus inhibiting the ability of Tubulin to polymerize to form microtubules. Due to this, paracrystals of Tubulin dimers and the drug are aggregated within the cell and the dysfunctional spindle apparatus freezes in Metaphase and chromosomal segregation and cell proliferation is inhibited.
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Hajvery University
Tubulin Microtubules
Polymerization
Mitotic Spindle Apparatus
Chromosomal Segregation
VINCRISTINE
STEROID HORMONES AND THEIR ANTAGONISTS
Tumors that are hormone sensitive may be either:1- In which tumor regresses following treatment with a specific hormone. (Hormone Sensitive)2- In which removal of a specific hormone triggers regression. (Hormone Responsive)3- Both.
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Hormone Responsive therapy is more palliative and Drugs like Prendisone and Tamoxifin are used that exert their effects by competing intracellular hormones for their receptor binding and resulting in affected gene expression.
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Other Drugs• Asparginase.• Carboplatin.• Cisplatin.• Etoposide.• Interferones.• Imatinib.• Protecan
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Problems associated with Chemotherapy.
Resistance: Some neoplastic cells are inherently
resistant to most of chemotherapeutic drugs.
Others may Acquire Resistannce:• Specific to a drug: Through change in
mitotic apparatus (Gene amplification)• Multi drug Resistance: Through over
expression of MDR1 and MRP1 Hajvery University
Toxicities Common ADRS : • Severe Vomiting• Bone marrow suppression• Alopecia• Stomatitis• Myelosuppression
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Drug Specific ADRs :• Cardiotoxicity ( Doxorubicin)• Pulmonary fibrosis ( Bleomycin)• Bladder toxicity ( Cyclophosphamide )
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