cancer chemotherapy
TRANSCRIPT
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CANCER CHEMOTHERAPY
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• CANCER: is disease characterized by loss in normal control mechanism’s that govern cell survival, poliferation and differentiation.
• METASTASIS: is ability of tumor stem cells to migrate to distant sites in body to colonize various organs.
• ONCOGENE: mutant form of normal gene found in naturally occuring tumors w/c when expressed in non-cancerous cells cause them to behave like cancer cells.
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CLASS OF DRUG DRUGS
ALKYLATING AGENT NITROGEN MUSTARDS CyclophosphamideMelphalanMechlorethamine
ALKYL SULFONES Busulfan
NITROSOUREAS CarmustineStreptazocin
TRIAZINES Dacarbazine
PLATINUM COORDINATION COMPOUNDS
CisplatinCarboplatinOxaliplatin
ANTI-METABOLITES FOLIC ACID ANTAGONIST Methotrexate
PYRIMIDINE ANTAGONIST 5-fluorouracilCytarabineGemcitabine
PURINE ANTAGONIST 6-mercaptopurinethioguanine
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NATURAL PRODUCTS VINCA ALKALOIDS VinblastineVincristine
TAXANES PaclitaxelDocetaxel
EPIPODOPHYLLOTOXINS PaclitaxelDocitaxel
ANTIBIOTICS DactinomycinDaunorubinDoxorubicinBleomycin
ENZYMES L-asparginase
MISCELLANEOUS AGENTS SUBSTITUTED UREA DERIVATIVES
Hydroxy urea
PROTEIN TYROSINE KINASE INHIBITOR
imatinib
INTERFERON’S AND CYTOKINE
Interferon α, IL 2
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HORMONES ADRENOCORTICOSTEROIDS
Prednisolone
ANTIESTROGENS Tamoxifen
AROMATASE INHIBITORS AnastrozoleLetrozole
ANTI ANDROGENS Flutamide
GONADOTROPHIN RELEASING HORMONE
leuprolide
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PRINCIPLES OF CANCER CHEMOTHERAPY
• Cause a lethal cytotoxic event or apoptosis in cancer cell that can arrest tumor’s progression.
• Attack is generally directed towards DNA or against metabolic sites essential to cell replication. ( E.G DNA and RNA synthesis w/c have purines and pyrimidines presence).
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TREATMENT STRATEGIES:
• GOAL OF TREATMENT:• 1. ERADICATION OF EVERY NEOPLASTIC CELL.If cure not possible so next step is control of disease
( stop from spreading).Initially the neoplastic cell is reduced ( either by
surgery / radiation) followed by chemotherapy, immunotherapy or combination of treatments.
PALLIATION: alleviation of symptoms + avoidance of life threatening toxicity is goal of advanced stage cancer.
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INDICATIONS FOR TREATMENT:
• 1. chemotherapy is indicated when neoplasm are disseminated and not feasable for surgery.
• 2. also used as supplemental treatment to attack micrometastases following surgery and radiation treatment “ ADJUVANT CHEMOTHERAPY”.
• 3. neo adjuvant chemotherapy is given prior to surgery to shrink cancer.
• 4. maintenance chemotherapy is given in low doses to assist in prolonging remission.
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CELL CYCLE
• PODOPHYLLOTOXIN
• BLEOMYCIN
• Mitotic phase ( cell divides)
• VINCA ALKALOIDS
• Synthesis of enzymes needed for DNA synthesis
• DNA is replicated• ANTIMETABOLITES• PODOPHYLLOTOXIN
G2 M
G1S
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• Rapidly dividing cells are generally more sensitive to anticancer drugs whereas slowly proliferating cells are less sensitive.
• G0 phase cell survive most agents.
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• CELL CYCLE SPECIFICITY OF DRUGS:• NORMAL CELL and cancer cell both go through growth
cycle difference is in number • Chemotherapeutic agents effective only against
replicating cells are called “ CELL CYCLE SPECIFIC”• Antimetabolites• Bleomycin• Antibiotics• Vinca alkaloids• etoposide
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• Effective for high growth fraction malignancies as hematologic cancers.
• NON CELL CYCLE SPECIFIC DRUGS:• More toxicity in cycling cells but are useful against
tumors that have low % of replicating cells e.g• Alkylating agents• Cisplatin• Nitrosoureas• Solid tumors + low + high growth fraction
malignancies.
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TUMOR GROWTH RATE:
• Initially rapid but growth rate decreases as tumor size ↑.
• This occurs b/c of unavailability of nutrients and oxygen caused by ↓ blood circulation.
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TREATMENT REGIMENS AND SCHEDULING:
• LOG KILL:• Destruction of cancer cells by chemotherapeutic
agents follow first order kinetics i.e given dose of drug destroys a constant fraction of cells not constant number of cells.
• Diagnosis of leukemia made when 109 total leukemic cells .
• Five log kill means pt becomes asymptomatic ie is in remission.
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PHARMACOLOGIC SANCTUARIES:
• Leukemic or other tumor cells sometimes find sanctuaries in tissues such as CNS where chemotherapeutic agents cannnot penetrate require IT drugs to eliminate leukemic cells or irradiation of craniospinal axis
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TREATMENT PROTOCOLS:
• Combination drug chemotherapy is more successful than single drug treatment
• COMBINATION OF DRUGS:• Cytotoxic agents with different toxicities,
different molecular sites and MOA are combined.
• Better effects due to potentiated effects.• If similar toxicity drugs combined dose should
be reduced.
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ADVANTAGES OF COMBINATION THERAPY:
• 1. provide maximal cell killing within range of tolerated toxicity.
• 2. are effective against broader range of cell lines in heterogenous tumor population.
• 3. may delay or prevent development of resistant cell lines.
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TOXICITY
• COMMON ADR:• Narrow therapeutic index• Nausea• Vomitting ( anti-emetic)• Stomatitis.• Bone marrow suppression.• Allopecia.• Cardiotoxicity( doxorubicin)• Pulmonary fibrosis( bleomycin)
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MINIMIZING ADR:
• Megaloblastic anemia caused by methotrexate can be overcome by FOLINIC ACID ( LEUCOVORIN)
• Neutropenia ( human granulocyte colony stimulating factor) FILGRASTIM can be given.
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ALKYLATING AGENTS:
• Highly reactive , transfer their alkyl groups to imp cellular constituents DNA or RNA at an electron rich site making them non-functional.
• Alkylation takes place by chemical formation of (+) charged carbonium ion that reacts with functional constituents of DNA.
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NITROGEN MUSTARDS
• MECHLORETHAMINE:• Hodgkins disease ( 3 and 4 stage)• MOPP regimen ( mechlorethamine, oncovin,
procarbazine and prednisolone).• Chronic myelogenous leukemia.• Chronic lymphoblastic leukemia.• 10mg vial reconstituted with 10ml 0.9% NACl
given IV.• ADR: vesicant action.
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CYCLOPHOSPHAMIDE:• Converted to 4-hydroxycyclophosphamide by hepatic
CyP2B enzyme → in tumor cell cleaved to phosphoramide and acrolein
• Phosphoramide mustard is responsible for antitumor activity.
• ADR :• Acrolein causes hemorrhagic cystitis.• Ample fluid should be taken• MESNA ( mercaptoethane sulfonate) is treatment of cystitis
traps acrolein.• allopecia
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• USES:• 1. malignant lymphomas.• 2. Hodgkins disease.• 3. neuroblastoma.• 4. breast and ovarian cancer.• IV dose 50mg/kg divided dose over 2-5 days.• Orally 1-5 mg/kg for initial and maintenace
treatment
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NITROSOUREAS:
• CARMUSTINE:• Lipid soluble• Useful for brain tumor• Metastatic brain tumor• Hodgkins and non hodgkins lymphoma• DOSE: 150-200mg/m2 given IV for 6 weeks as
single dose
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PLATINUM COORDINATION COMPLEXES:
• Cisplatin• Carboplatin• Oxaliplatin.• MOA: they kill tumor cells in all stages of cell
cycle by binding to DNA and preventing its replication by forming intrastrand as well as interstrand crosslinks.
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• USE:• 1. non-small cell and small cell lung cancer.• 2. esophageal and gastric cancer.• 3. head and neck cancer.• 4. genitourinary cancer ( testicular + bladder)• Oxaliplatin in advanced colon cancer.
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• ADR:• Neurotoxic ( peripheral neuropathy)• Nephrotoxic( reduced by hydration and
mannitol)• Carboplatin less nephrotoxic but causes tinnitus
and hearing loss but greater myelosuppression.• DOSE: 20mg/m2 for 5 days.• 75-100mg/m2 once over 4 weeks for ovarian
cancer.
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PROCARBAZINE:
• Is reactive agent that forms hydrogen peroxide w/c generates free radicals that cause DNA strand scission.
• KINETICS: orally active penetrates tissues including CSF
• USE: component regimen for Hodgkins lymphoma
• ADR: myelosuppressant• GI irritation
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ANTIMETABOLITES
• CCS drugs acting primarily in S phase of cell cycle.• METHOTREXATE:• MOA: competitively inhibits enzyme
dihydrofolate reductase w/c catalyzes reduction of dihydrofolate to tetrahydrofolate→ blocks synthesis of purines and pyrimidines→ results in interfering of formation of DNA, RNA and protein
• Polyglutamate derivatives of methotrexate imp for cytotoxic reactions.
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• RESISTANCE:• 1. drug accumulation decreased.• 2. changes in drug sensitivity or activity of dihydrofolate
reductase.• 3. decrease formation of polyglutamate.• KINETICS:• IV and oral good distribution except CNS.• Not metabolized clearance depends on renal function.• Adequate hydration needed to prevent crystallization in
renal tubules.
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• USE:• 1.choriocarcinoma.• 2.acute leukemia.• 3.nonHodgkins• 4 cutaneous T cell lymphoma.• 5 breast cancer• DOSE: 15-30mg/day orally or IV 5 days.
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• Meningiocarcinoma given IT.• ADR:• 1.mucositis.• 2.bone marrow suppression.• 3.bloody diarrhea.• 4.wt loss.• Leucovorin rescue( tetra hydrofolate is accumulated
more readily by normal cells)• It bypasses dihydrofolate reductase step in folic acid
synthesis dose 15mg (10mg/m2 every 6 hrly)
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PYRIMIDINE ANALOGUE:
• 5-FLUOROURACIL:• Prodrug gets converted to → 5-fluoro-2-
deoxyuridine (5dump) w/c binds to enzyme thymidylate synthase and folate cofactors→ covalently preventing formation of thymidylate and inhibits DNA synthesis.
• 5FU forms Futp ( 5 fluorodine 5 tri phosphate) w/c is incorporated into RNA where it interferes with RNA processing and mRNA translation.
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• USES:• Treatment of bladder, breast, colon, head and neck, liver
and ovarian cancers.• DOSE:• 12mg/kg IV for 4 days.• 6 mg/kg on alternate days for 4 doses.• ADR:• Myelosuppression.• ALLOPECIA• jaundice
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PURINE ANTAGONIST:
• 6-MERCAPTOPURINE:• Thiopurine.• Prodrug• Mercaptopurine in presence of hypoxanthine guanine
phosphoribosyl transferase → thioinosine mono phosphate (TIMP) → inhibits purine synthesis.
• TIMP → thiguanine mono phosphate and thioguanine triphosphate .
• Cytotoxic effect of mercaptopurine is result of incorporation of these nucleotides into DNA.
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• USE:• 1. acute lymphoid leukemia• 2. acute myeloid leukemia.• DOSE:• 2.5-5 mg/kg once aday.• ADR:• Myelosuppression ( dose limiting)• Hepatic dysfunction ( jaundice)
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NATURAL PRODUCTS:
• PLANT ALKALOIDS:• VINCA ROSEA: vincristine, vinblastine and
vinorelbine.• Cell cycle specific agents blocks in metaphase of
mitosis.• MOA:• Binds to tubulin monomers inhibiting formation of
microtubules → without microtubules newly replicated chromosomes cannot be seperated→ cell division blocked.
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VINCRISTINE (ONCOVIN)
• USE:• Acute lymphocytic lymphoma 1.4-2mg/m2 IV at
weekly interval.• Choriocarcinoma.• ADR:• Myelosuppression• GI mucosal damage• Allopecia.• Neurotoxic effects( peripheral neuritis)
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ETOPOSIDE:
• Semi-synthetic derivatives of podophyllotoxin• Given IV• MOA:• Inhibit topoisomerase 2 w/c results in breakage
or inhibition of DNA strands and facilitating accumulation of DNA breaks.
• USE:• Testicular and prostrate carcinomas• DOSE: 50-100mg/m2 for 5 days.
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PACLITAXEL:
• Taxanes.• MOA: binds to β tubulin subunit of microtubule ( diff
from vinca)→ promote microtubule polymerization, inhibit depolymerization→ arrested in G2 and M phases.
• USE: ovarian and breast cancer• IV 75mg/m2 over 3 hrs infusion• ADR: neutropenia• Thrombocytopenia• Peripheral neuropathy• Hypersensitivity ( give dexa and H1 antagonist)
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ANTIBIOTICS
• ADRIAMYCIN( DOXORUBICIN , DAUNORUBICIN)• Anthracycline antibiotics• MOA: cause DNA damage by intercalation into
DNA → intercalation interferes with action of topoisomerase 2 resulting in blockade of synthesis of DNA and RNA.
• Intracellular formation of free radicals also cause DNA damage.
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• Given IV• Doxorubicin dose 75mg/m2 repeated after 21 days.• USE• Hodgkins lymphoma• Myeloma• Sarcoma• Breast, endometrial, ovarian• Lung• Thyroid cancers
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• ADR:• Myelosuppression.• Cardiotoxicity ( arrthymia , abnormal ECG)• Brief not cause serious problem.• Dextrazoxane given for it b/c inhibitor of iron
mediated free radical formation.• Liposomal formulation less cardiotoxic.
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BLEOMYCIN:
• Glycopeptide mixture• MOA: binds to DNA cause single strand and
double strand DNA breaks following free radical formation and inhibition of DNA synthesis.
• Cell cycle specific• Active in G2 phase
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• DOSE • IV or IM or SC weekly 10-30units/m2• USE:• Hodgkins lymphoma• Head + neck cancer• Squamous cell cancer of cervix• Testicular cancer.
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• ADR:• Pulmonary dysfunction ( fibrosis , pneumonia)• Dose limiting• Mucocutaneous reaction ( alopecia,
hyperkeratosis)• Hypersensitivity reactions common.
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OTHER ANTI-CANCER AGENTS:
• L-ASPARGINASE:• Is an enzyme used to treat acute lymphocytic leukemia
of childhood.• MOA: • Hydrolyzes asparagine w/c is required for growth of
tumor cell.• Inhibits asparagine → drug shuts off protein + nucleic
acid synthesis.• DOSE: 6000-10,000 IV every 3rd day for 3-4 weeks.• ADR: hypersensitivity, pancreatitis.
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PROTEIN TYROSINE KINASE INHIBITOR
• IMATINIB:• MOA: is specific anticancer drug acts on
specific oncogene.• Inhibits tyrosine kinase activity of protein
product of B cr-Abl oncogene that is expressed in chronic myelogenous leukemia→ as result proliferation of oncogene inhibited→ apoptosis results.
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• USE:• (1) CML• (2) GI stromal tumors ( C-kit tyrosine kinase)• ADR:• Diarrhea.• Fluid retention• DOSE:• 400mg chronic dose QD orally.
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GROWTH RECEPTOR INHIBITOR:
• BEVACIZUMAB:• Is recombinant humanized monoclonal antibody.• MOA:• Inhibits natural protein vascular endothelial
growth factor (VEGF) that stimulates new blood vessel formation.
• When VEGF is targeted and bound to bevacizumab, no growth of blood vessels , tumor do not get oxygen and nutrient for growth.
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• USE:• Metastatic colorectal cancer IV or infusion 5mg/kg
once every 14 days.• ADR:• Myelosuppression• Hypertension• Stroke• Angina• CHF
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INTERFERONS
• Effective in hairy cell leukemia
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GONADAL HORMONE ANTAGONIST:
• TAMOXIFEN:• MOA: acts by binding to estrogen receptors and blocking
estrogen dependent transcription in cells in G phase.• USE: breast cancer• ADR: b/c it has agonist action in endometrium can cause
endometrial hyperplasia• Nausea• Vomitting• Venous thrombosis• Hot flushes.
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• FLUTAMIDE:• Anti-androgen• MOA: bind to androgen receptor inhibit
androgen effects.• USE: prostatic carcinoma.• ADR: hot flushes• Hepatic dysfunction• Gynecomastia.
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AROMATASE INHIBITOR:
• ANASTRAZOLE:• Inhibit aromatase w/c catalyses conversion of
androstenedione (androgenic precursor) to estrone ( estrogenic hormone)
• USE: advanced breast cancer• ADR: hot flushes, bone and back pain• Dyspnea• DOSE: 1mg orally daily
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MONOCLONAL ANTIBODIES:
• RITUXIMAB:• Monoclonal antibody binds to surface protein in
non-hodgkin’s cell induces complement mediated lysis , direct cytotoxicity and induction of apoptosis
• USE: low grade lymphoma.• ADR:• Myelo suppression• Hypersensitivity.
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REGIMEN
• MOPP → HODGKIN’S • Mechlorethamine• Vincristine• Procarbazine• Prednisolone.
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• ABVD HODGKIN’S• Doxorubicin• Bleomycin• Vinblastine• Dacarbazine.
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• CMF BREAST• Cyclophosphamide• Methotrexate• 5FU
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• CHOP non hodgkin’s • Carcinoma stomach• Cyclophosphamide• Doxorubicin• Vincristine• Prednisolone.