CANCER is a disease in which there in uncontrolled multiplication & spread within the body of...

CANCERCANCER• is a disease in which there in

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

Special Characteristics of Special Characteristics of Cancer CellsCancer Cells

• Uncontrolled Proliferation

• Dedifferentiation and loss of function

• Invasiveness

• Metastasis

Management of CancerManagement of Cancer

• Surgical

• Irradiation

• Chemotherapy

PHASES OF CELL PHASES OF CELL CYCLECYCLE

Mitosis

M

Synthetic

S

Pre-

Synthetic

G1

Pos

t –S

ynth

etic

G2

DIFFEREN-TIATION

G0

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

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

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

CANCER CHEMOTHERAPEUTIC CANCER CHEMOTHERAPEUTIC AGENTSAGENTS

C. CYTOTOXIC ANTIBIOTICS

• microbial in origin

• prevent cell division

D. PLANT DERIVATIVES

• affect microtubules and formation of mitotic spindle

CANCER CHEMOTHERAPEUTIC CANCER CHEMOTHERAPEUTIC AGENTSAGENTS

II. HORMONES• suppress hormone secretion

• antagonize hormone action

III. MISCELLANEOUS AGENTS

CLASSIFICATION OF CLASSIFICATION OF ANTI-CANCER ANTI-CANCER

DRUGSDRUGS

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

POLYFUNCTIONAL ALKYLATING POLYFUNCTIONAL ALKYLATING AGENTSAGENTS

C.ALKYL SULFONATE1. BUSULFAN

D.AZIRIDINE 1. THIOTEPA

E. TREOSULPHAN

RELATED DRUGS PROBABLY RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTSACTING AS ALKYLATING AGENTS

1. PROCARBAZINE

2. CISPLATIN

3. DACARBAZINE

4. CARBOPLATIN

5. ALTRETAMINE

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

PLANT ALKALOIDSPLANT ALKALOIDS1. VINBLASTINE

2. VINCRISITNE

3. VINORELBINE

4. PODOPHYLLOTOXINS (ETOPOSIDE & TENIPOSIDE)

5. CAMPTOTHECINS (TOPOTECAN & IRINOTECAN)

6. TAXANES (PACLITAXEL & DOCETAXEL)

ANTIBIOTICSANTIBIOTICS1. ANTHRACYCLINES(DOXORUBICIN &

DAUNORUBICIN)

2. DACTINOMYCIN(ACTINOMYCIN D)

3. PLICAMYCIN(METHRAMYCIN

4. MITOMYCIN (MITOMYCIN C)

5. BLEOMYCIN

6. EPIRUBICIN

7. MITOZANTRONE

HORMONAL AGENTSHORMONAL AGENTSA. ADRENOCORTICOIDS

1. PREDNISONE2. HYDROCORTISONE

B. ANDROGENS1. TESTOSTERONE2.FLUOXYMESTERONE

C. ESTROGENS1. DIETHYLSTILBESTROL2. ETHINYL ESTRADIOL

D. PROGESTINS1. HYDROXYPROGESTERONE2.MEDROXYPROGESTERONE

HORMONAL AGENTSHORMONAL AGENTS

E. ESTROGEN INHIBITOR :

1. TAMOXIFEN

2. TORIMIFENE

F. ANDROGEN INHIBITOR

1. FLUTAMIDE

2.CYPROTERONE

HORMONAL AGENTSHORMONAL AGENTSG. GONADOTROPIC RELEASING HORMONE

AGONIST (GnRH)

1. LEUPROLIDE 2. GOSERELIN3. NAFERELIN

H. AROMATASE INHIBITORS1. AMINOGLUTETHIMIDE & TRILOSTANE2. ANASTROZOLE3. LETROZOLE4.EXEMESTANE

MISCELLANEOUS ANTI - CANCER DRUGSMISCELLANEOUS ANTI - CANCER DRUGS1. ASPARAGINASE (CRISANTASPASE)

2. HYDROXYUREA

3. MITOTANE

4.AMSACRINE

5. RETINOID ACID DERIVATAIVES: TRETINOIN & ISOTRETINOIN

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)

MISCELLANEOUS ANTI - CANCER DRUGSMISCELLANEOUS ANTI - CANCER DRUGS

• MONOCLONAL ANTIBODIES1. RIFUXIMAB2. TRASTUZUMAB

• RADIOACTIVE ISOTOPES• RADIOACTIVE IODINE-TREATMENT OF

THYROID CABIOLOGICAL RESPONSE MODIFIER

* INTERFERONS, ALDESLEUKIN, TRETINOIN

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

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

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

IV. ADVERSE EFFECTS OF ALKYLATING AGENTS

• Myelosuppression/ N & V• hemorrhagic cystitis

(cyclophosphamide)• peripheral neuropathy

(altretamine))• adrenal insufficiency, pulmonary

fibrosis & skin pigmentation (busulfan)

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

B.CISPLATIN:

–inorganic metal complex

–In testicular CA, bladder, lung & ovary CA

–Nausea, vomiting, myelosuppression

–Nephrotoxicity, neurotoxocity,ototoxicity, anaphylaxis

.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

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

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

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

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

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

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

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

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

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

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

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

ANTIBIOTICSANTIBIOTICS

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

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

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

C. DACTINOMYCINC. DACTINOMYCINbinds to double-stranded DNA &

inhibits DNA dependent RNA synthesis

USE: melanoma & wilm’s tumorCauses bone marrow suppression,

skin & GIT irritation

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

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

HORMONAL ANTICANCER HORMONAL ANTICANCER AGENTSAGENTS

B. SEX HORMONESestrogen, progestins, androgens:

hormone dependent cancers to change the hormone balance

Fluoxymesterone: advanced breast CADiethylstilbestrol: prostatic cancer

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

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

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

MISCELLANEOUS ANTICANCER

AGENTS

MISCELLANEOUS ANTICANCER MISCELLANEOUS ANTICANCER AGENTSAGENTS

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

reactions, acute pancreatitis & bleeding

MISCELLANEOUS ANTICANCER AGENTSMISCELLANEOUS ANTICANCER AGENTS

B. Mitoxantronealkylation of basesacute leukemias & breast

cancercause myelosuppression, GIT

effects & cardiac arrythmias

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

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

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.

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

CANCER CHEMOTHERAPY ACRONYMSCANCER CHEMOTHERAPY ACRONYMS• ABVD : Doxorubicin (adriamycin),

bleomycin, vinblastine, dacarbazine• CHOP :Cyclophosphamide, doxorubicin

(hydroxydaunorubicin), vincristine

(oncovin), Prednisone• MOPP : Melchlorethamine, vincristine

(oncovin), Procarbazine, Prednisone

ACRONYMSACRONYMS• COP :Cyclophosphamide,

vincristine (oncovin), prednisone• PEB: Platinuml(cisplatin),• etoposide bleomycin• CMF : Cyclophosphamide,

methotrexate, Fluouracil• CAF: cyclophosphamide,

adriamycin(doxorubicin) , 5 FU

THE LEUKEMIASTHE LEUKEMIAS

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

2.CHRONIC LEUKEMIA2.CHRONIC LEUKEMIA

CML: Imatinib, busulfan, or interferon

in younger patient: bone marrow transplant

CLL: chlorambucil & prednisone fludarabine

THE LYMPHOMAS THE LYMPHOMAS 1. HODGKIN’S DISEASE

MOPP ABVD

2. NON-HODGKIN’S LYMPHOMA CHOP > Mitoxantrone & Paclitaxel

MULTIPLE MYELOMA melphalan & prednisone

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

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

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

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

LUNG CARCINOMALUNG CARCINOMA• Small cell( SCLC)

• Non-small cell(NSCLC)

• CISPLATIN & TAXANES• Others: methotrexate, vincristine,

vinblastine, doxorubicin, mitomycin C

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