anticancer and chemotherapy by: mohamed fahad al-ajmi
Post on 21-Dec-2015
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INTRODUCTION
Definition:
Under the influence of chemicals in the environment, radiation or viruses, the DNA in normal cells may be transformed, possibly by a single alteration or substitution of one of the constituent purine bases, in such a way that the normal control mechanisms, which restrict cell proliferation are removed.
INTRODUCTION Cancer incidence and death by organ sites
Most common new cancer cases:Male: Female:
Prostate (29%) Breast (30%)Lung (15%) Lung (13%)Colon/rectum (10%) Colon/rectum (11%)
Leading cancer deaths:Male: Female:Lung (32%) Lung (25%)Prostate (13%) Breast (16%)Colon/rectum (9%) Colon/rectum
(11%)
INTRODUCTION
Terminology Hypertrophy:is the increase in size of a
tissue or organ through increase in the size of the consistuent cells.Hyperplasia:is the increase in organ or
tissue size through increase in cell number. Both hypertrophy and
hyperplasia are reversible on removal of the growth stimuli
CARCINOGENESIS
Before discussing the details of molecular basis of CARCINOGENESIS we need to now how a normal cell divide (cell cycle).
The eukaryotic cell cycle
M
G0
G1
S
G2
M: Mitosis
S: Synthesis
G1, G2: Gaps between M and S
G0: Quiescent phase
Checkpoints: Point in the eukaryotic cell cycle where progress through the cycle can be halted until conditions are suitable for the cell to proceed to the next stage.
M
G0
G1
S
G2
DNA damageIncomplete
DNA replication
Chromosomes Unattached to the spindle
DNA damageUnfavorable
growth conditions
G1 checkpoint
G2 checkpoint
Mitotic checkpoint
CARCINOGENESIS
Causes of cancer: Radiation
Ionizing radiationUV light.
VirusesPapelloma virus AIDS virusHepatitis virus
Major classes of anti-cancer drugs
Alkylating agents
Antimetabolites
Antibiotics
Antimitotics
Hormones and antagonists
Molecularly-targeted therapy
Alkylating agents
Damage DNA in resting and cycling cells Most toxic to rapidly proliferating cells
Cell-cycle nonspecific. Toxicities include bone marrow
suppression, acute and delayed GI effects Example: cyclophosphamide (Cytoxan)
May cause hemorrhagic cystitis, particularly in dogs
Keep well hydrated, encourage drinking
Alkylating agents
Mechanism of action: cross-link 2 strands of DNA leading to impairment of DNA replication and RNA transcription.
Alkylating agents: examples
cyclophosphamide: creates guanine adducts that block cell proliferation.
cisplatin and its analogues, such as oxaliplatin: form DNA adducts and create inter or intrastrand crosslinks that disrupt DNA synthesis.
Antimetabolites
Analogues of normal metabolites, incorporated into DNA or RNA, resulting in abnormal nucleic acids and inhibition of enzymes involved in nucleotide biosynthesis
Purine Synthesis
Pyrimidine Synthesis
Ribonucleotides Deoxyribonucleotides DNA
RNA
Antimetabolites
Act the S phase: inhibit DNA synthesis Example: methotrexate
Mimics folic acid, which is needed for synthesis of DNA, RNA and some amino acids
Toxicities include delayed GI effects and bone marrow suppression
Antimetabolites: examples
Methotrexate: a folate analog inhibits dihydrofolate reductase (DHFR), the enzyme essential for nucleic acid synthesis.
5-fluorouracil (5-FU): a pyrimidine analog that inhibits thymidylate synthase and also interferes with RNA synthesis and function.
Gemcitabine: a pyrimidine analog that inhibits DNA polymerase.
FH2: dihydrofolateFH4: tetrahydrofolate TMP: thymidine monophosphatedUMP: deoxyuridine monophosphate
5-FU
Methotrexate
DNA
Antibiotics Bacterial or fungal derivatives, Mechanism of action:
intercalates within the DNA, causes single and double strand breaks, and inhibits topoisomerase II.
Damage DNA in cycling and noncycling cells.
Examples:1- Bleomycin:
Antibiotics
2- doxorubicin (Adriamycin) Rapid IV administration causes histamine release, severe pruritis and swelling (facial). Pretreat with H1 and H2
receptor antagonistsProduces free radicals that damage heart muscle, particularly in dogsVesicant
Inhibitors of topoisomerases
Topoisomerases: Cleavage, unwinding and re-annealing of DNA, necessary for DNA replication and RNA transcription
Etoposide (VP-16): Inhibits topoisomerase II, leading to double-strand DNA breaks
Etoposide
Antimitotics
Mechanism of action: natural products that interfere with
microtubule synthesis and degradation, leading to inhibition of cell division.
Cell-cycle specific.
Examples: 1- Paclitaxel (Taxol): stabilizes
microtubules, inhibit the cell cycle during mitosis.
Antimitotics
2- Vinca (plant) alkaloids Act in M phase to inhibit mitosis Vincristine and vinblastine Both can cause bone marrow
suppression and neurotoxicity Vesicants: cause blisters on contact
with skin, extravasation causes tissue necrosis
Protective gear absolutely essential
Hormones and antagonists
Mechanism of action: inhibits synthesis or effects of the steroid
hormones that are necessary for growth of certain tumors, such as breast and prostate tumors.
Examples: Tamoxifen: binds to estrogen receptors (ER) as an
antagonist inhibitor of estrogen. Anastrozole: inhibits aromatase, the enzyme that
catalyzes the final step in estrogen production.
STI-571 (Gleevec, Imatinib)
A small molecule that inhibits Bcr-Abl tyrosine kinase
Targets this enzyme which is over-expressed in CML (chronic myeloid leukemia)
Taken by mouth daily for treatment of refractory CML
Gefitinib (Iressa)
It inhibits the intracellular tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR).
Recent research indicates that it inhibits growth of cancer cells with mutations of the TK domain of EGFR.
It is approved for treatment of non-small cell lung cancer refractory to standard chemotherapy. (~10% patients have EGFR mutations)
Antibodies
Herceptin (Trastuzumab)
A recombinant monoclonal antibody against epidermal growth factor receptor 2 (Her2); used for treating refractory breast cancer over-expressing HER2 protein
Avastin (Bevacizumab)
A recombinant monoclonal antibody against VEGF, which plays an important role in blood vessel formation (angiogenesis); used for treatment of colon cancer
Enzymes
L-asparaginase Breaks down blood asparagine – needed
by some cancer cells for protein synthesis Used against lymphomas and some
leukemias Antigenic (large protein): hypersensitivity
reactions common
Common toxicities of chemotherapy
Organs with active cell division are affected: Bone marrow GI tract mucosa Hair follicles
These side-effects are often reversible.
Common toxicities
Bone marrow suppression:
Leukopenia, thrombocytopenia and anemia
Caused by most anti-cancer drugs except: Bleomycin, vincristine, hormones, and most of the molecularly-targeted agents.
Common toxicities Gastrointestinal toxicity:
Nausea and vomiting: cisplatin and anthracyclines Diarrhea: 5-FU, topotecan Mucositis: 5-FU
Alopecia (Hair loss): Paclitaxel, carboplatin, anthracyclines.
Renal toxicity: Cisplatin
Pulmonary toxicity: Bleomycin (pulmonary fibrosis)
Peripheral neuropathy: Cisplatin, oxaliplatin and paclitaxel
Long-term complications
Cardiomyopathy: Anthracyclines (Incidence exceeds
5% for high-dose of doxorubicin)
Leukemia: high-dose etoposide
Infertility: Alkylating agents
Management of side-effects
Use antiemetics to prevent nausea/emesis e.g. Zofran; a serotonin antagonist
Anemia Blood transfusion and/or erythropoietin (Epogen)
Neutropenia: Granulocyte-colony-stimulating factor (G-CSF,
Neuprogen) To shorten duration of neutropenia
Thrombocytopenia: Platelet transfusion and/or thrombopoietin
Guidelines for handling/administering chemotherapeutic agents
Wear latex gloves, surgical mask, goggles, protective clothing (eg, lab coat) when handling
Dilute or mix drugs under laminar flow hood (if available) or in low-traffic area without air currents. This helps prevent aerosolization of particles
Try to use drugs available as preservative-free solutions to avoid having to dilute them
Guidelines for handling/administering chemotherapeutic agents
If drug must be diluted, use needle guard (available from manufacturers)
Never “prime” needle by squirting drug into air
Never use mouth to remove needle cap Administer drugs through IV catheter to
avoid extravasation Place carefully and check throughout infusion
Guidelines for handling/administering chemotherapeutic agents
Guidelines for handling/administering chemotherapeutic agents
Pregnant women should not handle/administer antineoplastic agents
Thoroughly wash hands before and after handling/administering antineoplastic agents
Prevent contact of agent with skin or mucous membranes. If this occurs, wash area immediately with large volumes of water, document the contact and seek medical assistance
Guidelines for handling/administering antineoplastic agents
Place absorbent pad under patient’s leg If drug spills, allows disposal of pad
without contaminating table Wear latex gloves when disposing of
vomit, urine or feces from animals receiving antineoplastic agents
Maintain record of all exposure during preparation, administration, clean-up and spills