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Page 1: Anti Cancer New Program
Page 2: Anti Cancer New Program

CANCERCANCER• is a disease in which there in

uncontrolled multiplication & spread within the body of abnormal forms of the body’s own cells.

Page 3: Anti Cancer New Program

Special Characteristics of Special Characteristics of Cancer CellsCancer Cells

• Uncontrolled Proliferation

• Dedifferentiation and loss of function

• Invasiveness

• Metastasis

Page 4: Anti Cancer New Program

Management of CancerManagement of Cancer

• Surgical

• Irradiation

• Chemotherapy

Page 5: Anti Cancer New Program

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

Page 8: Anti Cancer New Program

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

Page 9: Anti Cancer New Program

• CCS:

• Hematological malignancies,

• solid tumors in growth fraction

CCNS:

• low groth fraction solid tumors

• high growth fraction tumors

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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

Page 14: Anti Cancer New Program

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

Page 19: Anti Cancer New Program

PLANT ALKALOIDSPLANT ALKALOIDS1. VINBLASTINE

2. VINCRISTINE

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

Page 21: Anti Cancer New Program

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. IMATINIB2. GROWTH FACATOR RECEPTOR

INHIBITORA. CEFUXIMAB

B. GEFITINIB & ERLOTINIB C. BEVACIZUMAB 3. ASPARAGINASE (CRISANTASPASE)4. HYDROXYUREA5. RETINOIC ACID DERIVATIVE (TRETINOIN)6. ARSENIC TRIOXIDE

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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 breakage

RESISTANCE THRU:↑ DNA repair / ↓ 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 /Thiotepa: ovarian ca

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IV. ADVERSE EFFECTS OF ALKYLATING AGENTS

• NAUSEA & VOMITING Myelosuppression

• 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, myelosuppression, hemolytic

anemia, pulmonary reaction, disulfiram like effect, skin rashes, CNS depression

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B.CISPLATIN:

–inorganic metal complex

–In testicular CA, bladder, lung & ovarian CA

–Nausea, vomiting, myelosuppression

–Nephrotoxicity, neurotoxocity, ototoxicity, anaphylaxis

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.METHOTREXATEPHARMACODYNAMICS• Inhibits dihydrofolate reductase…………..>• INTERFERES w/ thymidylate & purine

nucleotide , serine, methionine• …> DNA synthesis & cell division blockRESISTANCE:• 1. ↓ drug accumulation• 2.change in drug sensitivity or activity of

dihydrofolate reductase• 3. ↓ formation of polyglutamates

Page 36: Anti Cancer New Program

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• myelosuppression ; 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” 5FdUTP….> DNA synthesis inhibition

RESISTANCE:

– decreased activation of 5 FU

– increased thymidylate synthase activity

– reduce drug sensitivity of this enzyme

Page 40: Anti Cancer New Program

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 specific

RESISTANCE

• ↓ uptake / ↓ conversion to Ara CTP

CLINICAL USE: acute leukemias

ADVERSE 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

suppression, alopeciaVINCRISTINE: 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

Page 48: Anti Cancer New Program

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

Page 57: Anti Cancer New Program

HORMONAL ANTICANCER AGENTSHORMONAL ANTICANCER AGENTSC. SEX HORMONES ANTAGONISTS

– tamoxifen: estrogen receptor partial 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

Page 60: Anti Cancer New Program

MISCELLANEOUS ANTICANCER

AGENTS

Page 61: Anti Cancer New Program

MISCELLANEOUS ANTICANCER MISCELLANEOUS ANTICANCER AGENTSAGENTS

A. Asparaginase depletes serum asparagines used in leukemias & lymphomas given IV Cause severe hypersensitivity

reactions, neurotoxicity & bleeding

Page 62: Anti Cancer New Program

MISCELLANEOUS ANTICANCER AGENTSMISCELLANEOUS ANTICANCER AGENTS

B. IMATINIBInhibitor of the tyrosine kinase

domain of the Bcr- Abl oncogenes & prevent the phosphorylation of the kinase substrate by ATP

For CML, GIT stromal tumorsN /V/D, Fluid Retention, Myalgia

Page 63: Anti Cancer New Program

GROWTH FACTOR RECEPTOR GROWTH FACTOR RECEPTOR INHIBITORSINHIBITORS

• A. CEFUZIMAB

• Colorectal Ca

• B. GEFITINIB & ERLOTINIB

• NSCLCa

• C. BEVACIZUMAB

• Metastatic colororectal Ca

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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

ALL: induction: vincristine & prednisone

>remission maintenance: mercaptopurine, methotrexate / cyclophosphamide

AML: cytarabine, mitoxantrone or daunorubicin or idarubicin

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2.CHRONIC LEUKEMIA2.CHRONIC LEUKEMIA

CML: Imatinib, busulfan, or interferon

bone marrow transplant CLL: chlorambucil & prednisone fludarabine

Page 73: Anti Cancer New Program

THE LYMPHOMAS THE LYMPHOMAS 1. HODGKIN’S DISEASE

MOPP ABVD

2. NON-HODGKIN’S LYMPHOMA CHOP

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 6 cycles at one month apart; CMF/CAF; tamoxifen in postmenopausal women

• Trastazumab: HER-2/neu receptors

Stage III & IV Palliative

aminoglutethimide, trastuzumab

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CARCINOMA CARCINOMA WILM’S TUMOR: vincristine plus

dactinomycin after surgery & radiotherapy

NEUROBLASTOMA: doxorubicin + cyclophosphamide + vincrisitne

CARCINOMA OF THE PANCREAS: gemcitarabine

POLYCYTHEMIA 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 cisplatin• Colon: 5 FU + leucoverin + oxiplatin

MALIGNANT MELANOMA & MISC SARCOMAS:–dacarbazine & cisplain

BRAIN TUMORS• > carmustine, multimodality therapy

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LUNG CARCINOMALUNG CARCINOMA• Small cell( SCLCa)

• Non-small cell(NSCLCa)75-80%

• 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