cancer is a disease in which there in uncontrolled multiplication & spread within the body of...
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CANCERCANCER• is a disease in which there in
uncontrolled multiplication & spread within the body of abnormal forms of the body’s own cells.
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Special Characteristics of Special Characteristics of Cancer CellsCancer Cells
• Uncontrolled Proliferation
• Dedifferentiation and loss of function
• Invasiveness
• Metastasis
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Management of CancerManagement of Cancer
• Surgical
• Irradiation
• Chemotherapy
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PHASES OF CELL PHASES OF CELL CYCLECYCLE
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Mitosis
M
Synthetic
S
Pre-
Synthetic
G1
Pos
t –S
ynth
etic
G2
DIFFEREN-TIATION
G0
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Cell Cycle Non – Specific (CCNS) Cell Cycle Non – Specific (CCNS) AgentsAgents
ALKYLATING
AGENTS• Busulfan• Carmustine• Cyclophosphamide• Lomustine• Mechlorethamine• Melphalan• Thiothepa
ANTHRACYCLINES• Daunorubicin• Doxorubicin• Epirubicin• Idarubicin• Mitoxantrone
ANTI TUMOR
ANTIBIOTICS• Dactinomycin• Mitomycin
CAMPTOTHECINS
• Irinotecan
• Topotecan
PLATINUM ANALOGS
• Carboplatin
• Cisplatin
• Oxaliplatin
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Cell Cycle Specific (CCS) AgentsCell Cycle Specific (CCS) Agents
ANTIMETABOLITES• Capecitabine• Cladribine• Cytarabine• Fluorouracil• Gemcitabine• Mercaptopurine• Methotrexate• Thioguanine
ANTITUMOR ANTIBIOTIC
• BleomycinEPIPODOPHYLLO-TOXINS• Etoposide• Teniposide• TAXANES• Docetaxel• Paclitaxel
VINCA ALKALOIDS
• Vinblastine
• Vincristine
• Vinorelbine
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CANCER CHEMOTHERAPEUTIC CANCER CHEMOTHERAPEUTIC AGENTSAGENTS
I. CYTOTOXIC AGENTSA. ALKYLATING AGENTS AND RELATED
COMPOUNDS
• form covalents bonds with DNA
• impede DNA replication
B. ANTIMETABOLITES
• block or subvert one or more of the metabolic pathways involved in DNA synthesis
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CANCER CHEMOTHERAPEUTIC CANCER CHEMOTHERAPEUTIC AGENTSAGENTS
C. CYTOTOXIC ANTIBIOTICS
• microbial in origin
• prevent cell division
D. PLANT DERIVATIVES
• affect microtubules and formation of mitotic spindle
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CANCER CHEMOTHERAPEUTIC CANCER CHEMOTHERAPEUTIC AGENTSAGENTS
II. HORMONES• suppress hormone secretion
• antagonize hormone action
III. MISCELLANEOUS AGENTS
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CLASSIFICATION OF CLASSIFICATION OF ANTI-CANCER ANTI-CANCER
DRUGSDRUGS
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POLYFUNCTIONAL ALKYLATING POLYFUNCTIONAL ALKYLATING AGENTSAGENTS
A. NITROGEN MUSTARD
1. CYCLOPHOPHAMIDE
2. CHLORAMBUCIL
3. MECHLORETHAMINE
4. IFOSFAMIDE
5. MELPHALAN
6. ESTRAMUSTINE
B. NITROSOUREA
1. CARMUSTINE(BNCU)
2. SEMUSTINE (methyl CCNU)
3.LOMUSTINE( CCNU)
4.STREPTOZOCIN
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POLYFUNCTIONAL ALKYLATING POLYFUNCTIONAL ALKYLATING AGENTSAGENTS
C.ALKYL SULFONATE1. BUSULFAN
D.AZIRIDINE 1. THIOTEPA
E. TREOSULPHAN
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RELATED DRUGS PROBABLY RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTSACTING AS ALKYLATING AGENTS
1. PROCARBAZINE
2. CISPLATIN
3. DACARBAZINE
4. CARBOPLATIN
5. ALTRETAMINE
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ANTIMETABOLITESANTIMETABOLITESA. FOLATE ANTAGONIST
1. METHOTREXATE
B. PURINE ANTAGONIST1. MERCAPTOPURINE 4. FLUDARABINE
2. THIOGUANINE 5. PENTOSTATIN
3. CLADRIBINE
C. PYRIMIDINE ANTAGONIST1. FLUOROURACIL 3. CYTARABINE
2. CAPECITABINE 4. GEMCITABINE
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PLANT ALKALOIDSPLANT ALKALOIDS1. VINBLASTINE
2. VINCRISITNE
3. VINORELBINE
4. PODOPHYLLOTOXINS (ETOPOSIDE & TENIPOSIDE)
5. CAMPTOTHECINS (TOPOTECAN & IRINOTECAN)
6. TAXANES (PACLITAXEL & DOCETAXEL)
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ANTIBIOTICSANTIBIOTICS1. ANTHRACYCLINES(DOXORUBICIN &
DAUNORUBICIN)
2. DACTINOMYCIN(ACTINOMYCIN D)
3. PLICAMYCIN(METHRAMYCIN
4. MITOMYCIN (MITOMYCIN C)
5. BLEOMYCIN
6. EPIRUBICIN
7. MITOZANTRONE
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HORMONAL AGENTSHORMONAL AGENTSA. ADRENOCORTICOIDS
1. PREDNISONE2. HYDROCORTISONE
B. ANDROGENS1. TESTOSTERONE2.FLUOXYMESTERONE
C. ESTROGENS1. DIETHYLSTILBESTROL2. ETHINYL ESTRADIOL
D. PROGESTINS1. HYDROXYPROGESTERONE2.MEDROXYPROGESTERONE
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HORMONAL AGENTSHORMONAL AGENTS
E. ESTROGEN INHIBITOR :
1. TAMOXIFEN
2. TORIMIFENE
F. ANDROGEN INHIBITOR
1. FLUTAMIDE
2.CYPROTERONE
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HORMONAL AGENTSHORMONAL AGENTSG. GONADOTROPIC RELEASING HORMONE
AGONIST (GnRH)
1. LEUPROLIDE 2. GOSERELIN3. NAFERELIN
H. AROMATASE INHIBITORS1. AMINOGLUTETHIMIDE & TRILOSTANE2. ANASTROZOLE3. LETROZOLE4.EXEMESTANE
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MISCELLANEOUS ANTI - CANCER DRUGSMISCELLANEOUS ANTI - CANCER DRUGS1. ASPARAGINASE (CRISANTASPASE)
2. HYDROXYUREA
3. MITOTANE
4.AMSACRINE
5. RETINOID ACID DERIVATAIVES: TRETINOIN & ISOTRETINOIN
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MISCELLANEOUS ANTI - CANCER MISCELLANEOUS ANTI - CANCER DRUGSDRUGS
6. BONE MARROW GROWTH FACTORS
• GRANULOCYTE COLONY-STIMULATING FACTOR
(G-CSF, FILGRASTIM)
• GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF, SARGAMOSTIM)
• AMI FOSTINE (ETHYOL)
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MISCELLANEOUS ANTI - CANCER DRUGSMISCELLANEOUS ANTI - CANCER DRUGS
• MONOCLONAL ANTIBODIES1. RIFUXIMAB2. TRASTUZUMAB
• RADIOACTIVE ISOTOPES• RADIOACTIVE IODINE-TREATMENT OF
THYROID CABIOLOGICAL RESPONSE MODIFIER
* INTERFERONS, ALDESLEUKIN, TRETINOIN
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ALKYLATING AGENTSI. PHARMACOKINETICS
– oral or parenteral administration– hepatic microsome P450 mediated
cyclophosphamide ACROLEIN…….MESNA
–nitrosoureas: highly lipid soluble–unchanged form in urine (cisplatin)–terminated via hepatic metabolism:
procarbazine
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II. PHARMACODYNAMICS OF ALKYLATING AGENTS CCNS Form reactive molecules…> alkylation
(N7 guanine)………> Cross linking of bases, abnormal
base pairing & DNA strand breakageRESISTANCE THRU:increased DNA repairdecrease drug permeabilityproduction of trapping agents
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ALKYLATING AGENTSIII. CLINICAL INDICATIONS
A. CYCLOPHOSPHAMIDE: non Hodgskin’s lymphoma, breast
& ovarian CA, neuroblastomaB. MECHLORETHAMINE: Hodgskin ‘s disease (MOPP)C. CARMUSTINE & LOMUSTINE: brain tumorsD. BUSULFAN: chronic myelogenous leukemia
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IV. ADVERSE EFFECTS OF ALKYLATING AGENTS
• Myelosuppression/ N & V• hemorrhagic cystitis
(cyclophosphamide)• peripheral neuropathy
(altretamine))• adrenal insufficiency, pulmonary
fibrosis & skin pigmentation (busulfan)
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RELATED DRUGS PROBABLY ACTING RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTSAS ALKYLATING AGENTS
A. PROCARBAZINE• in Hodgkin’s lymphoma• leukemogenic, teratogenic,
mutagenic• N & V, myelosyppression, hemolytic
anemia, pulmonary reaction, disulfiram like,skin rashes, CNS depression
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B.CISPLATIN:
–inorganic metal complex
–In testicular CA, bladder, lung & ovary CA
–Nausea, vomiting, myelosuppression
–Nephrotoxicity, neurotoxocity,ototoxicity, anaphylaxis
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.METHOTREXATEPHARMACODYNAMICS• Inhibits dihydrofolate reductase…………..>• INTERFERES w/ thymidylate & purine
nucleotide • …> DNA synthesis & cell division blockRESISTANCE:• 1. decrease drug accumulation• 2.change in drug sensitivity or activity of
dihydrofolate reductase• 3. decrease formation of polyglutamates
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METHOTREXATEMETHOTREXATEPHARMACOKINETICS: Oral, IV. IM, intrathecal CLINICAL USE: choriocarcinoma, acute
leukemias, nonHodgskins and cutaneous T cell lymphomas, breast CA; rheumatoid arthritis, psoriasis & abortifacient
ADVERSE EFFECTS; N & V & D, mucositis• bone marrow suppression ; skin effects• reduced by folinic acid (leukoverin rescue)• enhance by salicylates, NSAID, sulfonamides,
sulfonylureas
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MERCAPTOPURINE (6 MP) & MERCAPTOPURINE (6 MP) & THIOGUANINE (6 TG)THIOGUANINE (6 TG)
• 6 THIOINOSINIC ACID….activated by hypoxanthine - guanine phosphoribosyltransferase (HGPRT)….>
• inhibit enzymes involved in purine metabolism
RESISTANCE:• decrease HGPRT activity
• increase alkaline phosphatases that inactivate the toxic nucleotides
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MERCAPTOPURINE (6 MP) & MERCAPTOPURINE (6 MP) & THIOGUANINE (6 TG)THIOGUANINE (6 TG)
PHARMACOKINETCS: oral; urine• 6MP metabolism inhibited by allopurinol
CLINICAL INDICATIONS• acute leukemias ; chronic myelocytic leukemias
ADVERSE EFFECTS:• myelosuppression, immunosuppression,
hepatotoxicity
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FLUOROURACIL ( 5FU)FLUOROURACIL ( 5FU)• Uracil, interferes with DTMP
• ( 5 FDUMP)………..> thymidylate synthase….> “thymineless death”………..> DNA synthesis inhibition
RESISTANCE:
– decreased activation of 5 FU
– increased thymidylate synthase activity
– reduce drug sensitivity of this enzyme
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FLUOROURACIL ( 5FU)FLUOROURACIL ( 5FU)
PHARMACOKINETICS : IV• widely distributed; hepatic metabolism
CLINICAL USES: colorectal, stomach, pancreas, esophagus, liver, bladder, breast, head and neck, liver & ovarian cancers
• topical: keratoses & basal cell cancer
ADVERSE EFFECTS: myelosuppression, GIT effects & alopecia, hand & foot syndrome, neurotoxicity
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CYTARABINE (ARA-C)CYTARABINE (ARA-C)
• activated to Ara CTP (inhibitor of DNA polymerase)
• most S specificRESISTANCE• 1.decreased uptake• 2. decreased conversion to Ara CTPCLINICAL USE: acute leukemiasADVERSE EFFECTS: myelosuppression & GIT
irritation; neurotoxicity & peripheral neuritis
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A. VINBLASTINE & VINCRISTINE* Periwinkle plant
– spindle poisons– prevent assembly of tubulin dimmers
into microtubules– block formation of mitotic spindle– act on M phase– RESISTANCE: increase efflux of the drug
PHARMACOKINETICS• Parenterally• Hepatic metabolism
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A. VINBLASTINE & VINCRISTINEA. VINBLASTINE & VINCRISTINECLINICAL USE
VINCRISTINE: MOPP & COP; acute leukemias, lymphomas, wilm’s tumor, choriocarcinomaVINBLASTINE: ABVD;, other lymphomas, neuroblastoma, testicular cancer, Kaposi’s sarcomaVINORELBINE: advance non- small cell cancer
ADVERSE EFFECTS:VINBLASTINE: GIT distress, alopecia, bone marrow
suppressionVINCRISTINE: neurotoxicity, areflexia, peripheral
neuritis, paralytic ileus
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B. ETOPOSIDE & TENIPOSIDEB. ETOPOSIDE & TENIPOSIDE• Podophyllotoxins from May apple root
• interacts w/ topoisomerase II….>inhibits mitochondrial electron transport….> increase degradation of DNA
• late S and early G2 phase
• oral; elimination thru the kidneys
• small cell lung CA, prostate & testicular CA
• cause bone marrow suppression, GIT effects, alopecia
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C. TOPOTECAN & IRINOTECANC. TOPOTECAN & IRINOTECAN
• from Comptotheca acuminate tree
• inhibit topoisomerase I
• DNA damage
• Topotecan: advanced ovarian cancer, small cell lung cancer
• Irinotecan: ,metastatic colorectal CA
• Cause: myelosuppression & diarrhea
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D. PACLITAXEL & DOCETAXELD. PACLITAXEL & DOCETAXEL– Taxanes from Western yew
– Prevent microtubule disassembly into tubulin monomers; by IV
– Advanced breast and ovarian cancers
– Paclitaxel: N & V, myelosuppression, peripheral neuropathy, hypersensitivity rx
– Docetaxil: neurotoxicity & bone marrow suppression, fluid retention, rash
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ANTIBIOTICSANTIBIOTICS
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A. DOXORUBICIN & DAUNORUBICINA. DOXORUBICIN & DAUNORUBICIN
intercalate between base pairs………> inhibit topoisomerase II….>
generate free radicals …………> block synthesis of RNA & DNA…>
DNA strand scisisionGiven IV; excreted in the bile & urine
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A. DOXORUBICIN & DAUNORUBICINA. DOXORUBICIN & DAUNORUBICIN
DAUNORUBICIN: acute leukemiasDOXORUBICIN: ABVD; myelomas,
sarcomas, breast, endometrial, lungs, ovarian & thyroid cancers
CARDIOTOXICITY ( USE DEXRAZOXANE, radical scavenger)
Bone marrow suppression, GIT effects, alopecia
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B. BLEOMYCINB. BLEOMYCINDNA strand breakage …..……>
inhibit DNA synthesis CCS on G2 phaseUSE: testicular cancer & Hodgskin’s
lymphoma, lymphomas, squamous cell cancer
Hypersensitivity reaction, pulmonary dysfunction
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C. DACTINOMYCINC. DACTINOMYCINbinds to double-stranded DNA &
inhibits DNA dependent RNA synthesis
USE: melanoma & wilm’s tumorCauses bone marrow suppression,
skin & GIT irritation
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D. MITOMYCIND. MITOMYCIN
• Activated to form an alkylating agent…> cross links DNA
• IV given; hepatic metabolism
• USE: adenocarcinoma of the cervix, stomach, pancreas & lungs
• Causes myelosuppression
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HORMONAL ANTICANCER HORMONAL ANTICANCER AGENTSAGENTS
A. GLUCOCORTICOIDS• Prednisone/ Hydrocortisone:• acute & chronic lymphocytic
leukemias, hodgskin’s disease, other lymphomas
• Fluid retention, hypertension, diabetes, Increase susceptibility to infection
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HORMONAL ANTICANCER HORMONAL ANTICANCER AGENTSAGENTS
B. SEX HORMONESestrogen, progestins, androgens:
hormone dependent cancers to change the hormone balance
Fluoxymesterone: advanced breast CADiethylstilbestrol: prostatic cancer
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HORMONAL ANTICANCER AGENTSHORMONAL ANTICANCER AGENTSC. SEX HORMONES ANTAGONISTS
– tamoxifen: estrogen receptor oartial agonist
– may cause nausea & vomiting, hot flushes, vaginal bleeding, hypercalcemia, ocular, dysfunction& peripheral edema
– Flutamide: prostatic cancer– Cause:gynecomastia, hot flushes,
hepatic dysfunction
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HORMONAL ANTICANCER AGENTSHORMONAL ANTICANCER AGENTS
D. GONADOTROPIN-RELEASING HORMONE ANALOGS (GnRh ANALOG)–Leuprolide, Goserelin & nafarellin– inhibit release of pituitary LH & FSH–prostatic cancer–may cause: bone pain, gynecomastia,
hematuria, impotence & testicular atrophy
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HORMONAL ANTICANCER AGENTSHORMONAL ANTICANCER AGENTS
E. AROMATASE INHIBITORS–anastrozole & leterozole– inhibit enzyme that catalyzes the
conversion of androstenedione to estrone–advanced breast cancer–diarrhea, nausea, hot flushes, bone &
back pain, peripheral edema
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MISCELLANEOUS ANTICANCER
AGENTS
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MISCELLANEOUS ANTICANCER MISCELLANEOUS ANTICANCER AGENTSAGENTS
A. Asparaginase depletes serum asparagines used in leukemias & lymphomas given IV may cause severe hypersensitivity
reactions, acute pancreatitis & bleeding
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MISCELLANEOUS ANTICANCER AGENTSMISCELLANEOUS ANTICANCER AGENTS
B. Mitoxantronealkylation of basesacute leukemias & breast
cancercause myelosuppression, GIT
effects & cardiac arrythmias
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MISCELLANEOUS ANTICANCER AGENTSMISCELLANEOUS ANTICANCER AGENTS
C. Interferons endogenous glycoproteins with
antineoplastic, immunosuppresion & antiviral actions
Use in hairy cell leukemias, chronic myelogenous leukemia, T cell lymphomas
Cause myelosuppression & neurologic dysfunction
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MISCELLANEOUS ANTICANCER AGENTSMISCELLANEOUS ANTICANCER AGENTS
D. Monoclonal AntibodiesRIFUXIMABMonoclonal antibody to a surface protein
non- Hodgskin’s lymphoma cellsTRASTUZUMAB: monoclonal antibody to a
surface protein in breast cancers that over express the HER2 protein
Toxicity: hypersensitivity reactions & myelosuppression
Cardiac dysfunction with trastuzumab
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STRATEGIES IN CANCER STRATEGIES IN CANCER CHEMOTHERAPYCHEMOTHERAPY
I. Each drug should be active when used alone against the particular cancer
II. The drug should have different mechanism of action
III. Cross resistant between drugs should be minimal.
IV. The drugs should have different toxic effects.
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SAMPLES OF COMBINATION SAMPLES OF COMBINATION CHEMOTHERAPYCHEMOTHERAPY
. HODGKIN’S DISEASE: MOPP / ABVD
2. NON-HODGKIN’S LYMPHOMA: COP
3. TESTICULAR CARCINOMA: PVB
4. BREAST CANCER: CMF/CAF
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CANCER CHEMOTHERAPY ACRONYMSCANCER CHEMOTHERAPY ACRONYMS• ABVD : Doxorubicin (adriamycin),
bleomycin, vinblastine, dacarbazine• CHOP :Cyclophosphamide, doxorubicin
(hydroxydaunorubicin), vincristine
(oncovin), Prednisone• MOPP : Melchlorethamine, vincristine
(oncovin), Procarbazine, Prednisone
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ACRONYMSACRONYMS• COP :Cyclophosphamide,
vincristine (oncovin), prednisone• PEB: Platinuml(cisplatin),• etoposide bleomycin• CMF : Cyclophosphamide,
methotrexate, Fluouracil• CAF: cyclophosphamide,
adriamycin(doxorubicin) , 5 FU
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THE LEUKEMIASTHE LEUKEMIAS
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1. ACUTE LEUKEMIA1. ACUTE LEUKEMIA
CHILDHOOD LEUKEMIA
> ALL: induction: vincristine & prednisone
>remission maintenance: mercaptopurine, methotrexate & cyclophosphamide in various combination
ADULT LEUKEMIA
> AML: cytarabine, mitoxantrone or daunorubicin or idarubicin
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2.CHRONIC LEUKEMIA2.CHRONIC LEUKEMIA
CML: Imatinib, busulfan, or interferon
in younger patient: bone marrow transplant
CLL: chlorambucil & prednisone fludarabine
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THE LYMPHOMAS THE LYMPHOMAS 1. HODGKIN’S DISEASE
MOPP ABVD
2. NON-HODGKIN’S LYMPHOMA CHOP > Mitoxantrone & Paclitaxel
MULTIPLE MYELOMA melphalan & prednisone
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CARCINOMA OF THE BREASTCARCINOMA OF THE BREAST
Stage I SURGERY
Stage II: positive lymph nodes: SURGERY plus cytotoxic chemo in 8 cycles at one month apart; CMF/CAF; tamoxifen in postmenopausal women
Stage III & IV Palliative
aminoglutethimide, trastuzumab
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CARCINOMA CARCINOMA WILM’S TUMOR: vincristine lus
dactinomycin after surgery>Methotrexate, cyclophosphamide,
doxorubicinNEUROBLASTOMA: doxorubicin +
cyclophosphamide + vincrisitneCARCINOMA OF THE PANCREAS:
gemcitarabinePOLYCYTHEMIA VERA: busulfan,
chlorambucil or cyclophosphamide
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CARCINOMACARCINOMACHORIOCARCINOMA OF THE UTERUS:
Methotrexate / Etoposide & Cisplatin
CARCINOMA OF THE OVARY: cisplatin & paclitaxel
TESTICULAR NEOPLASMS: PEB
CARCINOMA OF THE PROSTATEEstrogen, leuprolide & Flutamide
CARCINOMA OF THE THYROIDRadioiodine, doxorubicin & cisplatin
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CARCINOMACARCINOMAGASTROINTESTINAL CARCINOMAS
• Stomach: 5FU plus doxorubicin & mitomycin
• Colon: 5 FU plus leucoverin or interferon
MALIGNANT MELANOMA & MISC SARCOMAS:
–dacarbazine & cisplain
BRAIN TUMORS
• > carmustine, multimodality therapy
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LUNG CARCINOMALUNG CARCINOMA• Small cell( SCLC)
• Non-small cell(NSCLC)
• CISPLATIN & TAXANES• Others: methotrexate, vincristine,
vinblastine, doxorubicin, mitomycin C
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THANK YOU THANK YOU VERY MUCH !!!VERY MUCH !!!
Cast your burden on the Lord.Cast your burden on the Lord.And He shall sustain youAnd He shall sustain youHe shall never permit theHe shall never permit theRighteous to be moved.Righteous to be moved.
Psalm 55 : 22Psalm 55 : 22