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CANCER
• 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
Cancer Cells
• Uncontrolled Proliferation
• Dedifferentiation and loss of
function
• Invasiveness
• Metastasis
Management of Cancer
• Surgical
• Irradiation
• Chemotherapy
PHASES OF CELL
CYCLE
DIFFERENTIATION
Mitosis
M
G2
Synthetic
S
PreSynthetic
G1
Post –
Synthetic
G0
Cell Cycle Non – Specific (CCNS)
Agents
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) Agents
ANTIMETABOLITES
• Capecitabine
• Cladribine
• Cytarabine
• Fluorouracil
• Gemcitabine
• Mercaptopurine
• Methotrexate
• Thioguanine
ANTITUMOR
ANTIBIOTIC
• Bleomycin
EPIPODOPHYLLOTOXINS
• Etoposide
• Teniposide
• TAXANES
• Docetaxel
• Paclitaxel
VINCA
ALKALOIDS
• Vinblastine
• Vincristine
• Vinorelbine
CANCER CHEMOTHERAPEUTIC
AGENTS
I. CYTOTOXIC AGENTS
A. 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
AGENTS
C. CYTOTOXIC ANTIBIOTICS
• microbial in origin
• prevent cell division
D. PLANT DERIVATIVES
• affect microtubules and formation of
mitotic spindle
CANCER CHEMOTHERAPEUTIC
AGENTS
II. HORMONES
• suppress hormone secretion
• antagonize hormone action
III. MISCELLANEOUS AGENTS
CLASSIFICATION OF
ANTI-CANCER
DRUGS
POLYFUNCTIONAL ALKYLATING
AGENTS
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
AGENTS
C.ALKYL SULFONATE
1. BUSULFAN
D.AZIRIDINE
1. THIOTEPA
E. TREOSULPHAN
RELATED DRUGS PROBABLY
ACTING AS ALKYLATING AGENTS
1.
2.
3.
4.
5.
PROCARBAZINE
CISPLATIN
DACARBAZINE
CARBOPLATIN
ALTRETAMINE
ANTIMETABOLITES
A. FOLATE ANTAGONIST
1. METHOTREXATE
B. PURINE ANTAGONIST
1. MERCAPTOPURINE
2. THIOGUANINE
3. CLADRIBINE
4. FLUDARABINE
5. PENTOSTATIN
C. PYRIMIDINE ANTAGONIST
1. FLUOROURACIL
2. CAPECITABINE
3. CYTARABINE
4. GEMCITABINE
PLANT ALKALOIDS
1. VINBLASTINE
2. VINCRISITNE
3. VINORELBINE
4. PODOPHYLLOTOXINS (ETOPOSIDE &
TENIPOSIDE)
5. CAMPTOTHECINS (TOPOTECAN &
IRINOTECAN)
6. TAXANES (PACLITAXEL & DOCETAXEL)
ANTIBIOTICS
1. ANTHRACYCLINES(DOXORUBICIN &
DAUNORUBICIN)
2. DACTINOMYCIN(ACTINOMYCIN D)
3. PLICAMYCIN(METHRAMYCIN
4. MITOMYCIN (MITOMYCIN C)
5. BLEOMYCIN
6. EPIRUBICIN
7. MITOZANTRONE
HORMONAL AGENTS
A. ADRENOCORTICOIDS
1. PREDNISONE
2. HYDROCORTISONE
B. ANDROGENS
1. TESTOSTERONE
2.FLUOXYMESTERONE
C. ESTROGENS
1. DIETHYLSTILBESTROL
2. ETHINYL ESTRADIOL
D. PROGESTINS
1. HYDROXYPROGESTERONE
2.MEDROXYPROGESTERONE
HORMONAL AGENTS
E. ESTROGEN INHIBITOR :
1. TAMOXIFEN
2. TORIMIFENE
F. ANDROGEN INHIBITOR
1. FLUTAMIDE
2.CYPROTERONE
HORMONAL AGENTS
G. GONADOTROPIC RELEASING HORMONE
AGONIST
(GnRH)
1. LEUPROLIDE
2. GOSERELIN
3. NAFERELIN
H. AROMATASE INHIBITORS
1. AMINOGLUTETHIMIDE & TRILOSTANE
2. ANASTROZOLE
3. LETROZOLE
4.EXEMESTANE
MISCELLANEOUS ANTI - CANCER DRUGS
1. ASPARAGINASE (CRISANTASPASE)
2. HYDROXYUREA
3. MITOTANE
4.AMSACRINE
5. RETINOID ACID DERIVATAIVES: TRETINOIN
& ISOTRETINOIN
MISCELLANEOUS ANTI - CANCER
DRUGS
6. BONE MARROW GROWTH FACTORS
• GRANULOCYTE COLONYSTIMULATING FACTOR
(G-CSF, FILGRASTIM)
• GRANULOCYTE-MACROPHAGE
COLONY-STIMULATING
FACTOR
(GM-CSF, SARGAMOSTIM)
• AMI FOSTINE (ETHYOL)
MISCELLANEOUS ANTI - CANCER DRUGS
• MONOCLONAL ANTIBODIES
1. RIFUXIMAB
2. TRASTUZUMAB
• RADIOACTIVE ISOTOPES
• RADIOACTIVE IODINE-TREATMENT OF
THYROID CA
BIOLOGICAL RESPONSE MODIFIER
* INTERFERONS, ALDESLEUKIN, TRETINOIN
ALKYLATING AGENTS
I. 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 breakage
RESISTANCE THRU:
increased DNA repair
decrease drug permeability
production of trapping agents
ALKYLATING AGENTS
III. CLINICAL INDICATIONS
A. CYCLOPHOSPHAMIDE:
non Hodgskin’s lymphoma, breast &
ovarian CA, neuroblastoma
B. MECHLORETHAMINE: Hodgskin ‘s
disease (MOPP)
C. CARMUSTINE & LOMUSTINE: brain
tumors
D. 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 AS
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
.METHOTREXATE
PHARMACODYNAMICS
• Inhibits dihydrofolate reductase…………..>
• INTERFERES w/ thymidylate & purine
nucleotide
• …> DNA synthesis & cell division block
RESISTANCE:
• 1. decrease drug accumulation
• 2.change in drug sensitivity or activity of
dihydrofolate reductase
• 3. decrease formation of polyglutamates
METHOTREXATE
PHARMACOKINETICS: 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) &
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) &
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)
• 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)
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)
• activated to Ara CTP (inhibitor of DNA
polymerase)
• most S specific
RESISTANCE
• 1.decreased uptake
• 2. decreased conversion to Ara CTP
CLINICAL USE: acute leukemias
ADVERSE 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 & VINCRISTINE
CLINICAL USE
VINCRISTINE: MOPP & COP; acute leukemias,
lymphomas, wilm’s tumor, choriocarcinoma
VINBLASTINE: ABVD;, other lymphomas,
neuroblastoma, testicular cancer, Kaposi’s sarcoma
VINORELBINE: advance non- small cell cancer
ADVERSE EFFECTS:
VINBLASTINE: GIT distress, alopecia, bone marrow
suppression
VINCRISTINE: neurotoxicity, areflexia, peripheral
neuritis, paralytic ileus
B. 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 & 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 & 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
ANTIBIOTICS
A. DOXORUBICIN & DAUNORUBICIN
intercalate between base pairs………>
inhibit topoisomerase II….>
generate free radicals …………> block
synthesis of RNA & DNA…>
DNA strand scisision
Given IV; excreted in the bile & urine
A. DOXORUBICIN & DAUNORUBICIN
DAUNORUBICIN: acute leukemias
DOXORUBICIN: ABVD; myelomas,
sarcomas, breast, endometrial, lungs,
ovarian & thyroid cancers
CARDIOTOXICITY ( USE
DEXRAZOXANE, radical scavenger)
Bone marrow suppression, GIT effects,
alopecia
B. BLEOMYCIN
DNA strand breakage …..……>
inhibit DNA synthesis
CCS on G2 phase
USE: testicular cancer & Hodgskin’s
lymphoma, lymphomas, squamous cell
cancer
Hypersensitivity reaction, pulmonary
dysfunction
C. DACTINOMYCIN
binds to double-stranded DNA &
inhibits DNA dependent RNA
synthesis
USE: melanoma & wilm’s tumor
Causes bone marrow suppression,
skin & GIT irritation
D. 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
AGENTS
A. GLUCOCORTICOIDS
• Prednisone/ Hydrocortisone:
•
acute & chronic lymphocytic
leukemias, hodgskin’s disease, other
lymphomas
• Fluid retention, hypertension, diabetes,
Increase susceptibility to infection
HORMONAL ANTICANCER
AGENTS
B. SEX HORMONES
estrogen, progestins, androgens:
hormone dependent cancers to change
the hormone balance
Fluoxymesterone: advanced breast CA
Diethylstilbestrol: prostatic cancer
HORMONAL ANTICANCER AGENTS
C. 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 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 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
AGENTS
A. Asparaginase
depletes serum asparagines
used in leukemias & lymphomas
given IV
may cause severe hypersensitivity
reactions, acute pancreatitis &
bleeding
MISCELLANEOUS ANTICANCER AGENTS
B. Mitoxantrone
alkylation of bases
acute leukemias & breast
cancer
cause myelosuppression, GIT
effects & cardiac arrythmias
MISCELLANEOUS 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 AGENTS
D. Monoclonal Antibodies
RIFUXIMAB
Monoclonal antibody to a surface protein
non- Hodgskin’s lymphoma cells
TRASTUZUMAB: 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
CHEMOTHERAPY
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
CHEMOTHERAPY
. HODGKIN’S DISEASE: MOPP / ABVD
2. NON-HODGKIN’S LYMPHOMA: COP
3. TESTICULAR CARCINOMA: PVB
4. BREAST CANCER: CMF/CAF
CANCER CHEMOTHERAPY ACRONYMS
• ABVD : Doxorubicin (adriamycin),
bleomycin, vinblastine, dacarbazine
• CHOP :Cyclophosphamide, doxorubicin
(hydroxydaunorubicin), vincristine
(oncovin), Prednisone
• MOPP : Melchlorethamine, vincristine
(oncovin), Procarbazine, Prednisone
ACRONYMS
• COP :Cyclophosphamide,
vincristine (oncovin), prednisone
• PEB: Platinuml(cisplatin),
• etoposide bleomycin
• CMF : Cyclophosphamide,
methotrexate,
Fluouracil
• CAF: cyclophosphamide,
adriamycin(doxorubicin) , 5 FU
THE LEUKEMIAS
1. 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 LEUKEMIA
CML: Imatinib, busulfan, or
interferon
in younger patient: bone marrow
transplant
CLL: chlorambucil & prednisone
fludarabine
THE LYMPHOMAS
1. HODGKIN’S DISEASE
MOPP
ABVD
2. NON-HODGKIN’S LYMPHOMA
CHOP
> Mitoxantrone & Paclitaxel
MULTIPLE MYELOMA
melphalan & prednisone
CARCINOMA 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
WILM’S TUMOR: vincristine lus
dactinomycin after surgery
>Methotrexate, cyclophosphamide,
doxorubicin
NEUROBLASTOMA: doxorubicin +
cyclophosphamide + vincrisitne
CARCINOMA OF THE PANCREAS:
gemcitarabine
POLYCYTHEMIA VERA: busulfan,
chlorambucil or cyclophosphamide
CARCINOMA
CHORIOCARCINOMA OF THE UTERUS:
Methotrexate /
Etoposide & Cisplatin
CARCINOMA OF THE OVARY: cisplatin &
paclitaxel
TESTICULAR NEOPLASMS: PEB
CARCINOMA OF THE PROSTATE
Estrogen, leuprolide & Flutamide
CARCINOMA OF THE THYROID
Radioiodine, doxorubicin & cisplatin
CARCINOMA
GASTROINTESTINAL 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 CARCINOMA
•
•
•
•
Small cell( SCLC)
Non-small cell(NSCLC)
CISPLATIN & TAXANES
Others: methotrexate, vincristine,
vinblastine, doxorubicin,
mitomycin C
THANK YOU
VERY MUCH !!!
Cast your burden on the Lord.
And He shall sustain you
He shall never permit the
Righteous to be moved.
Psalm 55 : 22