Cancer chemotherapy
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Transcript of Cancer chemotherapy
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Cancer
The term cancer refers to the heterogeneous
group of diseases caused by an impairment of
the normal functioning genes which lead to
genetic damage.
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objective of chemotherapy
1. Cure may be solve with aggressive therapy
for a prolonged period of time to eradicate all
disease.Leukemia's is curative approach may
consist of remission , induction, attempting
the maximum cell kill , followed by
consolidation therapy to eradicate all clinically
undetectable disease and to lower tumor cell
burden below 103 ,at which level host
immunological defense may keep the cell in
control
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2- if the goal is palliation , chemotherapy may
be given to decrease a tumor size , control
growth ,and reduce symptoms .palliative
therapy is usually given when complete
eradication of the tumor is considered unlikely
the patient reduces aggressive therapy
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3-adjuvant.
4-neoadjuvnt.
5-salvage.
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dosing
May be based on body weight ,body surface
area(BSA) or area under the concentration
versus time cure (AUC).
BSA is the most frequently used because an
accurate comparison of activity and toxicity
Across species . In addition BSA correlate with
cardiac output which determine renal hepatic
blood flow and thus affect drug elimination
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combination
Usually effective than single agent
Factors consider in combination:
1. Antitumor activity.
2. Different mechanism of action.
3. Minimally overlapping toxicities.
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The reasons for administering
chemotherapy:
1. Overcoming or preventing resistance.
2. Cytotoxicity to resting and dividing cells.
3. Biochemical enhancement of effect.
4. Rescue of normal cells.
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adminsteration
Routes of administration vary ,although
intravenous adminsteration is employed most
commonly.
Other technique include oral, subcutaneous
s, intrathecal, intra-arterial intraperitoneal
,intravesical, continuous iv infusion, bolus iv
infusion, and hepatic artery infusion.
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Response to chemotherapy
1. Complete response.
2. Partial response.
3. Response rate.
4. Stable response.
5. Progression or no response
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Factors affecting response to
chemotherapy
1. Tumor cell heterogenetiy.
2. Drug resistance
3. Dose intensity
4. Patient specific factors.
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Classification of chemotherapeutic
agents
1.
Cytotoxic agents
Alkylating agents, platinums, tumor antibiotics, anti-mitotic agents, anti-metabolites
Hormonal treatment
Anti-Estrogens, GnRH agonists, Androgen receptor blockers
Biologic response modifiers
Interleukin, G-CSF
Targeted agents
Monoclonal antibodies
Tyrosine kinase inhibitors
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• Alkylating Agents:
– Nitrogen Mustards: Mechlorethamine, Cyclophosphamide, Ifosfamide, Melphalan Chlorambucil
– Ethylinimines and Methilinimines: Hexamethylamine, Thiotepa
– Alkyl Sulfonates: Busulfan
– Nitrosoureas: Carmustine, Lomustine, Streptozocin
– Triazines: Dacarbazine, Temozolomide
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• Antimetabolites:
– Folic acid analogs: Methotrexate
– Pyrimidine analogs: 5-FU, Floxuridine, Cytarabine
– Purine analogs: Mercaptopurine, Thioguanine, Cladribine, Fludarabine
• Anti-Mitotic Agents:– Vinca Alkaloids: Vincristine, Vinblastine, Vinorelbine
– Taxanes: Paclitaxel, Docetaxel
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• Topoisomerase-interactive agents:– Topoisomerase I Poison: Camptothecins: Topotecan, Irinotecan
– Topoisomerase II Poison:
• Epipodophyllotoxins: Etoposide, Teniposide
• Anthracyclines: Doxorubicin, Epirubicin, Daunorubicin, Idarubicin (Also classified as tumor antibiotics
• Tumor antibiotics:– Anthracyclines
– Mitomycin
– Bleomycin
– Dactinomycin
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• Platinum compounds:– Cisplatin, Carboplatin, Oxaliplatin
• Miscellaneous:– Mitoxantrone
– Hydroxyurea
– Procarbazine
– Mitotane
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Phase Non-specific:
Alkylating Agents
Tumor antibiotics
Platinum Compounds
Phase Specific:
Cytarabine, Hydroxyurea (S)
Methotrexate, 6-Mercap
Vinca’s and Taxanes (M)
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1-akalyating agent:
The first group of antineoplastic agent
Cause cross linking and abnormal base
pairing of DNA strands which lead to
replication failure.
Examples:
Alteretamine,busulfan,carmustine,chlorabucil,c
isplatin,cyclophosphamide.
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2-Antitumor antibiotics
Most of these antibiotics are obtained from
streptomyces genus.
These agents may act by alkalyation or
intercalation .intercalation is the process by
which the drug slides betweenDNA base pairs
and inhibits synthesis
Examples:
Bleomycin, dactinomycin ,daunorubicin ,
mitomycin C,doxorubicin.
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Ant metabolites:
Are structural analogs of naturally occurring substrates for biochemical reactions
They inhibit DNA synthesis by acting as false substitutions in the production of nucleic acids .these are s-phase specific agents.
They are three main group:
Folate analogs.(e.g. methotrexate)
Pyrimidine analogs(5-flurouracil)
Purine analog (6-mercaptopurine,pentostatin,fludarabine)
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Mitotic inhibitors
The vinca alkloids aresset cell division by
preventing microtubule formation.
The taxanes promote microtubule assembly
and stablization ,thus preventing cell division .
These are M-phase specific.
Examples:
Vinca alkaloids eg vincristine,vinbalstin
Taxanes:pacetaxel,docetaxel.
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Topoisomerase inhibitors:
Inhibits the enzymes topoisomerase 1 or2.
The topoisomerases are necessary for DNA
replication and RNA tranacription.
These are G2 phase specific agents.
Examples :
etopside ,topotecan, teniposide.
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enzymes
Asparginase is an enzyme that cause the
degradtion of essential amino acid
asparagines to aspartic acid and ammonia
,unlike normal cells tumor cells lack the ability
to synthesize asparagines
These agent are G1 –phase specific agent.
examples :Asparginase and
pegaasparginase.
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Protein tyrosine kinase
inhibitors
Imatinib mesylate is aselective tyrosine kinase
inhibitors that causes apoptosis or arrest of
growth in cells expressing the Bcr-Abi
oncoprotein bcr-abi is the product of a specific
chromosomal abnormality(peldilpheia
chromosome)
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miscellaneous
1. Tretinoid
2. Arsenic trioxide.
3. Bexarotene
4. Bortezomib
5. thalidomide
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hormones
• Steroids
• Aromatase Inhibitors
• Anti-Estrogens
• GnRH analogues
• Anti-Androgens
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steroids
• Most commonly used:– Prednisone
– Dexamethasone
• Able to induce remissions in hematologic cancers and responses in solid tumors
• Valuable component in NHL, HL, CLL, ALL
• MOA?- promote apoptosis
• Side effects:– Immunosuppression, glucose intolerance, osteoporosis, water
retention, GI ulcers
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Aromatase inhibitors
• Most commonly used:– Letrozole (Femara)
– Anastrozole (Arimidex)
– Exemestane (Aromasin)
• Inhibits aromatase enzyme that converts androgens to estrogens
• Aromatase enzyme in adrenal glands and adipose tissue.
• Indicated for post-menopausal ER/PR+ breast cancer patients in adjuvant, neoadjuvant, and metastatic setting.
• Side effect: Bone mineral density, bone pains, increased fracture rates.
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Anti-Estrogens
• Tamoxifen: binds to ER receptors preventing binding to DNA
• Eventually decresaes autocrine stimulation of breast cancer cells.
• Has an agonist effect on endometrial cells and increases thrombotic risk
• breast cancer treatment (adjuvant or metastatic) • Side effect: thrombosis risk, endometrial CA, hot
flashes, nausea, vomiting, menstrual irregularities.
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antiandrogen
• Bicalutamide
• Flutamide
• Nilutamide
• Binds to Androgen receptors and causes complete androgen blockade
• Usually given with GnRH analogs
• Side effects: decreased libido, hot flashes, gynecomastia, mastodynia, paradoxical stimulation of androgen receptors
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GnRH analogs:
• Prototypes: Goserelin, Leuprolide
• Administered intramuscularly or subcutaneously
• Initially stimulate FSH and LH production by the pituitary, then later cause negative feedback inhibition.
• Estrogen levels fall to post-menopausal values
• Androgen levels fall to castrate values.
• Used in breast cancer and prostate cancer
• Can have initial ‘flare’ reaction which can be controlled by concomitant anti-androgens or anti-estrogens
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Biological cell response
1. Cytokines
2. Monoclonal antibodies
Target extracellular receptors or
Ligands
1. Immunotoxins
• Interleukin-2:– Not directly cytotoxic
– Expands a T-cell response that is cytolytic for tumor cells
– Uses: Melanoma, Renal cell carcinoma, AML
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Bone Marrow Suppression Neutropenia – Low WBC G-CSF (filgrastim) & GM-CSF (sargramostim)
Thrombocytopenia – Low platelete count Oprelvekin (Neumega)
Anemia – Low RBC Erythropoetin
Digestive Tract Problems Stomatitis – inflammation of oral mucosa Diarrhea – impaired nutrient absorption
Nausea & Vomiting (N/V) Occurs 17 – 98% (Psych factors) Ondansetron (Zofran) and others (handout
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Other
Alopecia – hair loss
Reproductive – sterility in males
Hyperuricemia – increased urination (DNA)
Extravasation of vesicants
Drug-specific (hepatic, coronary, etc)
Carcinogenesis – some patients sensitive