Download Doxorubicin

Breast Regimen – AC->T (Adriamycin/cyclophosphamide followed by Taxol)
Doxorubicin
60 mg/m2
IV over 5-15min
Q 21 days
Cyclophosphamide
600 mg/m2
IV over 30 min
Q21 days
80 mg/m2
IV over 30 min
Q 7 days
Day 1 x 4 cycles
Followed by
Paclitaxel
Day 1 weekly x 12
cycles
Antimetabolites – analogs of purine/pyrimidine synthesis

Inhibits enzymes catalyzing DNA synthesis
Antimetabolites
6-thioguanine &
Mercaptopurine
Methotrexate
MOA
Purine analog
Use
Leukemias
PK
Oral admin  by food
Converted to
nucleotide by catalyst
 impairs DNA
synthesis
Tumor cell can develop
resistance by deleting
this enzyme
Structure similar to
Childhood leukemia
folic acid  inhibit
dihydrofolate
*Osteosarcoma
reductase (required
for T & purine
RA
synthesis)
Lupus erythematosus
AE
Bone marrow
suppression
Additional Info
DI – allopurinol
Hepatotoxicity
Carcinogenic
A: variable
D: variable in body
water
Doesn’t cross BBB –
can be administered
intrathecally
E: primarily as parent
cmpnd in urine
Bone marrow
suppression
GI mucosa – mouth
ulcers
Long term 
hepatotoxicity
May crystallize in urine
*Leucovorin –
rescue necessary in
lethal/high dose tx
Degraded in intestine
& liver
5-FU
Binds to thymidylate
synthase
Cancers of head & neck
& throughout GI system

Leukemias

Blocks cell repair
Fludarabine,
Cladribine,
Clofarabine,
Nelarabine
Premetrexed
Hydroxyurea
DNA damage &
apoptosis
Metabolites
incorporated into
developing DNA
Gene termination
Antifolate  Inhibits
tetrahydrofolatedependent enzymes
Ribonucleotide
inhibitor  stops
DNA synthesis
Low-grade nonHodgkin’s lymphoma
Lung
Pancreatic
M: rapidly
metabolized to active
polyglutamate form
Colorectal
Leukemia
Bone marrow
suppression
 toxicity by giving
folic acid & B12

Ovarian cancer
Melanoma
Cytarabine,
Fluorouracil,
Capecitabine,
Gemcitabine
Pyrimidine analogs
Cytarabine:
Incorporated into DNA
 stop replication
Fluorouracil:
Blocks synthesis of
thymidine & RNA
Gemcitabine:
S-phase inhibitor
Sickle Cell anemia (
fetal hgb)
Cytarabine:
Leukemia
Fluorouracil:
Solid tumors
 Breast
 Colorectal & liver
metastasis
 Gastric
 Squamous cell tumors
of head & neck
Capecitabine:
Elimination by
metabolism
Bone marrow
suppression
Diarrhea
Colon
Breast
Floxuridine colorectal
Gemcitabine:
Pancreatic
Non-small-cell lung
Biliary tract gallbladder
Breast
Ovarian
Alkylating Agents – cross-links DNA strands by covalent bonds b/w alkyl groups of drug & guanine bases

Nonspecific to state of cell cycle
Antimetabolites
Nitrogen Mustard
*no longer used*
MOA
First chemotherapy
Use
PK
AE
Hodgkin’s lymphoma
Effect rapid growing
lymphoid cells
Cyclophosphamide
Leukemia
(most widely used),
Non-Hodgkin’s
lymphoma
Ifosfamide
Breast
Prodrugs converted
to active agent by
hepatic CYP 450
Alopecia
Nausea
Vomiting
Lung
Bone marrow
suppression
Ovarian
Hemorrhagic cystitis
Immunosuppressant:
 RA
 Autoimmune nephritis
 Pre-transplantation
Other Nitrogen
Mustards:
Chlorambucil,
Additional Info
Mechlorethamine:
Converted in body
fluid to alkylating
Ifosfamide  2nd line
for: testicular & sarcoma
Chlorambucil:
Oral – leukemia
Chlorambucil:
 Bone marrow
suppression
Mesna = antidote
for cystitis –
administered w/
chemo
Meclorethamine,
Melphalan
Nitrosourea:
Carmustine,
Lomustine,
Streptozocin
intermediate
Melphalan:
Multiple myeloma
Carmustine/lomustine: Crosses BBB
 Brain tumors
M: extensively
 Lymphoma
Carmustine:
 Melanoma
 Multiple myeloma
Streptozocin:
 Carcinoid tumor
 Pancreatic islet tumor
Platinum
Compounds:
Cisplatin,
Carboplatin,
Oxaliplatin
 Sterility
 Secondary leukemia
Mechlorethamine:
 Hodgkin’s lymphoma
 Non-Hodgkin’s
lymphoma
1st line for:
 Testicular
 Ovarian
 Cervical
 Bladder
 Lung
E: renally
Mechlorethamine:
*NOT commonly used
due to toxicity
Myelosuppression
(delayed & prolonged)
w/ recovery of bone
marrow at 6-8 wks.
Thrombocytopenia –
most severe
Nausea & vomiting
Pulmonary toxicity w/
high doses
#1 drug to cause
nausea & vomiting
Melanoma
Carboplatin:
 Lung
 Ovarian
Busulfan
Oxaliplatin:
 Colorectal
Myeloid leukemia
Nausea
Mild vomiting
Myelosuppression
Pulmonary fibroses (5
Dacarbazine
m. survival)
Nausea
Hodgkin’s Disease
Vomiting
Mitomycin
Myelosuppression
Myelosuppression
Breast (salvage)
Non-small-cell lung
Severe pulmonary
damage
Pancreatic
Hemolytic uremic
syndrome
Stomach
Anthracycline
Drugs:
Doxorubicin,
Daunorubicin,
Idarubicin
Bright red color
Intercalation of DNA
 inhibit
topoisomerase
Undergo reducation
rxn  form highly
destructive hydroxyl
radicals  DNA
damage
Anthracycline:
Doxorubicin – very
broad:
 Hodgkin’s
 Bladder
 Ovarian
 Gastric
 Some hematologic
D: rapidly to all body
tissues except CNS
M: extensively in
liver – some
metabolites are
active
Long t1/2
Active at G2 phase of
cell cycle
Myelosuppression
Cardiac damage
Nausea & vomiting
Alopecia
Mucosal ulceration
Breast
Extravasation 
severe tissue
ulceration/necrosis
Less potent free
radical formation 
less cardiotoxicity
Hodgkin’s lymphoma
D: widely
*less AE overall
compared to other
Anthracyclines
Pulmonary toxicity
Non-Hodgkin’s
lymphoma
Inactivated in cells by
aminohydrolase – in
skin & lung 
location of some
Acute myeloid leukemia
Mitoxantrone
Bleomycin
Bladder
Dauno & Ida:
 Myeloid leukemia
Testicular
Mucocutaneous
Skin
hyperpigmentation
Potent, very good
drug
Stop immediately if
drug is causing
heart problems
toxicities
Erythema
E: renal
Dactinomycin
Mitotic Inhibitors
Vinca alkaloids:
Vincristine,
Vinblastine,
Vinorelbine
Antibiotic – prevents
DNA transcription &
mRNA synthesis
MOA
Binds to tubulin &
blocks polymerization
Edema
Choriocarcinoma
Pediatric tumors –
Wilms’ tumor, Ewing’s
sarcoma
Use
PK
AE
Vincristine:
 Hodgkin’s lymphoma
 Non-Hodgkin’s
lymphoma
 Leukemia
 Multiple myeloma
 Small-cell lung
 Neuroblastoma
 Sarcoma
Vinblastine:
 Lymphomas
 Bladder
 Breast
 Ovarian
 Testicular
Taxanes:
Paclitaxel, Docetaxel
Binds to tubulin &
prevents
depolymerization
Vinorelbine:
Non-small-cell
carcinoma
Paclitaxel
*1st line:
 Metastatic ovarian
 Non-small-cell lung
*2nd line:
 Metastatic breast
Eliminated by
metabolism &
biliary excretion
Myelosuppression
Alopecia
Neurotoxicity
Additional Info
Ixibepilone
Semisynthetic
analogue of
epothilone B  binds
beta-tubulin subunits
Suppress microtubule
actions
Also inhibits
angiogenesis
Docetaxel:
 Breast
 Non-small-cell lung
Breast resistance to
taxanes, vinca
alkaloids, &
anthracyclines
M: fecal & renal
excretion
Neurotoxicity –
microtubules involved
w/ nerve conduction
Alopecia
Unique toxicities:
 Fatigue
 Joint/muscle pain
 Hand-foot syndrom
Topoisomerase Inhibitors  permanent breaks in DNA
Topoisomerase
Inhibitors
Podopyllotoxins:
MOA
Inhibits type II
Etoposide, Teniposide topoisomerase
Camptothecin:
Use
Etoposide:
 Testicular
 Lung
 Non-Hodgkin’s
lymphoma
 Bone marrow
transplantation
 Synergistic w/
Cisplatin
Teniposide:
 Leukemias
Irinotecan:
PK
AE
Etoposide:
E: renal
Teniposide:
M: hepatic
Irinotecan:
Irinotecan:
Additional Info
Irinotecan, Topotecan
 Colorectal
 Lymphomas
 Breast
 Cervical
 Gastric
 Lung
Topotecan:
 Glioma
 Sarcoma
 Lung
 Ovarian
Rapidly metabolized
to active metabolite
Eliminated by bile
Topotecan:
Elimination by renal
excretion
 Myelosuppression
 Diarrhea
 Alopecia
 Mild nausea &
vomiting
Topotecan:
 Myelosuppression
 Alopecia
 Mild nausea &
vomiting
Protein Kinase Inhibitors – inhibits kinases involved w/ regulatory proteins

 blocks pathways promoting malignant transformation & proliferation
Protein Kinase
Inhibitors
Imatinib,
Dasatinib,
Nilotinib
Erlotinib
Sunitinib,
Sorafenib
MOA
Inhibit BCR-ABL
tyrosine kinase
expressed by
Philadelphia chrom.
Imatinab: + inhibits ckit
Highly specific for
tyrosine kinase
associated w/
epidermal growth
factor receptor
Inhibit multiple
kinases:
VEGFR
Use
PK
Chronic Myeloid
Leukemia
Imatinab:
+ GI stromal tumors
*2nd line:
Non-small-cell lung
cancer
Renal cell carcinoma
Sunitinib:
M: CYP 450 3A4
AE
Additional Info
c-kit
Gefitinib
Lapatinib
Bortezomib
GI stromal tumor
Epidermal growth
factor receptor
Kinase associated w/
HER2/neu receptor
Inhibits proteasome
& targets apoptosis
inhibitors
Sorafenib:
Hepatocellular
carcinoma
NSC lung
Breast cancer
Multiple myeloma
Monoclonal Antibodies




Different mechanisms
o Target growth factors or their receptors
o Release cytotoxic drug or isotope
o Enhance host immunity
Must be given IV
All expensive!
Nomenclature
o Letter before mab:
 o – mouse
 u – human
 xi – chimeric
o Internal letter – therapeutic use
 tu – tumor
 vi – virus
 c or ci – circulation
Monoclonal
Antibodies
Rituximab:
MOA
Chimeric
human/murine to treat
tumors
Bind to CD20 ag on
surface of 90% of nonHodgkin’s lymphoma
cells
First approved
monoclonal ab to tx
cancer
Attached to
radioactive isotopes to
kill cancer cells
Use
Non-Hodgkin’s
lymphoma
PK
AE
Additional Info
Alemtuzumab
Gentozumab
ozogamicin
Trastuzumab
Binds CD52 – found on Chronic lymphocytic
all B & T lymphocytes
leukemia
& other leukocytes
Conjugated to a
Acute myeloid leukemia
cytotoxic antibiotic
Binds CD33 on
hematopoietic cells 
complex internalized
in lysosomes 
antibiotic release
Extracellular
HER2/neu receptor
Breast cancer
Chills
Fever
Nausea
Vomiting
Chest pain
Cetuximab,
Bevacizumab,
Panitumumab
Cetuximab:
 Colorectal
 Head
 Neck
Bevacizumab:
 Colorectal
 Lung
 Brain
Bevacizumab
Prevents binding of
VEGF on endothelial
cells  inhibits blood
vessel formation
Dyspnea
Infusion-related
reactions
Acne-like skin rash
Hypertension
Renal damage
Panitumumab:
Colorectal
Colon cancer
GI bleeding
NSC lung cancer
Perforation
Pulmonary
hemorrhage
First drug to target
VEGF – doesn’t
seem to make a
different on survival
Thromboembolic
events
Cytokine & Interferons:

Interferons – endogenous proteins that increase activity of cytotoxic cells in immune system
Cytokines &
Interferons
Interferon alpha2b
Aldesleukin
MOA
Use
Inhibits expression of
oncogenes 
suppresses cell growth
 reduces cell
proliferation
Kaposi’s sarcoma
Activates IL-2
receptors
Renal cell carcinoma
Hairy cell leukemia
Melanoma
Melanoma
PK
AE
 Leukopenia
 Thrombocytopenia
 Flu-like syndrome
 Nausea
 Vomiting
 Tiredness
 Altered taste
 Diarrhea
 Depression
 Hypotension
 Fluid retention
 Renal dysfunction
Additional Info
Start patients on
anti-depressants to
avoid depression
Promotes B- & T-cell
proliferation &
differentiation 
destroy tumor cells
Hormones &
Antagonists
Estrogen
antagonists:
MOA
Use
Breast cancer
Tamoxifen,
Anastrozole,
Letrozole, Leuprolide
Androgen
antagonists:
Prostate cancer
Leuprolide,
Flutamide,
Nilutamide,
Bicalutamide
Corticosteroids
 Hematologic
deficiencies
 Skin lesions
 Neuropsychiatric
changes
 Reverse/prevent
toxicity w/
corticosteroids
before therapy
Colorectal cancer
Lymphocytic leukemias
Lymphomas
PK
AE
Additional Info