Download Growth Factor Receptor inhibitors

Just Drugs – Pharm 18-19
Want to know which drugs work on what part of the cycle.
Cytotoxic Drug Toxicity
 Bone marrow suppression (doxorubicin, methotrexate,
fluorouracil, docetaxel)
 Nausea/vomiting (cisplatin, doxorubicin)
 Hair loss (doxorubicin, paclitaxel)
 Cardiac toxicity (doxorubicin)
 Hemorrhagic cystitis (cyclophosphamide)
 Renal toxicity (cisplatin)
 Pulmonary toxicity (bleomycin)
 Neurotoxicity/neuropathy (vincristine, paclitaxel,
ixabepilone)
Alkylating Agents – cross-links DNA - not specific to cell cycle


Transfer of alkyl group to DNA on N7 position of guanine in addition to other lesser sites; this leads to miscoding and strand breakage; crosslinks with DNA occurs with nitrosoureas after biotransformation
Nitrogen mustard and the platinums create cross-links with DNA to inhibit DNA synthesis
Antimetabolites
Nitrogen Mustard
Mechlorethamine
*rarely used*
Cyclophosphamide
(most widely used),
Ifosfamide
MOA
First chemotherapy
agent
Use
PK
AE
Hodgkin’s lymphoma
Additional Info
chemical warfare.
Effect rapid growing
lymphoid cells



Leukemia
Non-Hodgkin’s
lymphoma
Breast, Lung, Ovarian
Prodrugs converted
to active agent by
hepatic CYP 450
Immunosuppressant:
 RA
 Autoimmune nephritis
 Pre-transplantation




Alopecia
Nausea, Vomiting
Bone marrow
suppression
Hemorrhagic
cystitis: acrolein, a
toxic metabolite,
causes cystitis
Mesna = antidote
for cystitis –
administered w/
chemo
Ifosfamide  2nd line
for: testicular & sarcoma
Melphalan
Bendamustine(newest
agent, low toxicity
profile)
Dacarbazine
Procarbazine



Melphalan - Multiple Procarbazine –
weak monoamine
myeloma
oxidase inhibitor
Bendamustine –
non-Hodgkin’s
lymphoma
Dacarbazine –
replace
procarbazine for
non-Hodgkin’s
lymphoma,
melanoma
 bone marrow
suppression
 sterility
 secondary leukemia,
 nausea and vomiting

Procarbazine:
multiple drug
interactions
and alcohol
Nitrosourea:
Carmustine, Lomustine,
Streptozocin
Carmustine/lomustine: Crosses BBB
 Brain tumors
M: extensively
 Lymphoma
Carmustine:
 Melanoma
 Multiple myeloma
Streptozocin:
 Carcinoid tumor
 Pancreatic islet tumor
Temozolamide
(Temodar)
Platinum
Compounds:
Cisplatin, Carboplatin,
Oxaliplatin
brain tumors
(astrocytoma,
glioblastoma) in
conjunction with
radiation
1st line for:
 Testicular, Ovarian,
Cervical, Bladder, Lung
Melanoma
Carboplatin:
 Lung, Ovarian
Oxaliplatin:
 Colorectal, pancreatic
E: renally
Carmustine/lomustine Can also affect IQ
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
 nausea and vomiting
(cisplatin most
toxic), renal toxicity
(cisplatin),
myelosuppression,
peripheral
neuropathy
(oxaliplatin)
peripheral
neuropathy – hands
go to sleep
Antimetabolites –Most are analogs of purine or pyrimidine bases found in DNA or of folic acid

Mechanism of action (MOA) – this class of drugs target the synthesis of DNA in the cancer cells
Antimetabolites
Methotrexate
(prototype)
MOA
Structure similar to
folic acid  inhibit
dihydrofolate
reductase (required
for T & purine
synthesis) thereby
interfering with RNA,
DNA and cellular
proteins
Use
PK
Childhood leukemia
A: variable, oral
*Osteosarcoma
D: variable in body
water
RA
Lupus erythematosus
Doesn’t cross BBB –
can be administered
intrathecally
E: primarily as parent
cmpnd in urine
Premetrexed
Antifolate  Inhibits
tetrahydrofolatedependent enzymes
specifically
thymidylate synthase
Lung
Pancreatic
Colorectal
Degraded in intestine
& liver
M: rapidly
metabolized to active
polyglutamate form
AE
Bone marrow
suppression
GI mucosa – mouth
ulcers
Additional Info
*Leucovorin –used
for rescue in high
dose treatment
before toxicity
occurs
Long term 
hepatotoxicity
May crystallize in urine
Bone marrow
suppression - not as
severe as alkylating
agents
 toxicity by giving
folic acid & B12
Can be used as a
maintenance drug
5-FU/
Capecitabine
(converted to5FU)
Similar to
Metorexate
Binds to thymidylate
synthase
Purine analogs:
Converted to
nucleotide by catalyst
 impairs DNA
synthesis
6-thioguanine &
Mercaptopurine
Blocks DNA synthesis
and function
Purine nucleoside
analogues:
Fludarabine,
Cladribine,
Metabolites
incorporated into
developing DNA
Pyrimidine analogs:
S phase specific,
incorporated into
DNA to stop
replication and
repair
Cytarabine,
Gemcitabine
Chain termination
Gemcitabine:
several mechanisms
of action






Colorectal, anus
breast
stomac
pancreas, esophagus
Liver
head and neck
Leukemias (mostly in
adults)




Oral admin  by food
myelosuppression
mucositis
diarrhea
skin toxicity (handfoot syndrome)
 neurotoxicity
Bone marrow
suppression
Hepatotoxicity
Leukemias
Low-grade nonHodgkin’s lymphoma
Cytarabine:
Leukemia
Gemcitabine:
Pancreatic
Non-small-cell lung
Biliary tract gallbladder
Breast
Ovarian
Carcinogenic
 myelosuppression
 immunosuppressive
– take PCP
prophylaxis during
treatment and for 1
year after
Bone marrow
suppression
Diarrhea
Hand and foot
syndrome –
reddening of palms
and feet
DI – allopurinol
Tumor cell can
develop resistance
by deleting this
enzyme
Mitotic Inhibitors
MOA
Binds to tubulin &
Vinca alkaloids:
Vincristine,
Vinblastine,
Vinorelbine
blocks polymerization
Use
PK
Vincristine:
 Hodgkin’s lymphoma
 Non-Hodgkin’s
lymphoma
 Leukemia
 Multiple myeloma
 Small-cell lung
 Neuroblastoma
 Sarcoma
AE
Peripheral
neuropathies
Additional Info
Vincristine/vinblastine
 Natural alkaloids
from periwinkle
plant,
Vinorelbine –
semisynthetic
derivative of
vinblastine
Vinblastine:
 Lymphomas
 Bladder
 Breast, Ovarian
 Testicular
Taxanes:
Paclitaxel, Docetaxel
Ixibepilone
Binds to tubulin &
prevents
depolymerization
in addition to taxane
MOA, inhibits
angiogenesis
Vinorelbine:
Non-small-cell
carcinoma
Paclitaxel
*1st line:
 Metastatic ovarian
 Non-small-cell lung
*2nd line:
 Metastatic breast
Docetaxel:
 Breast
 Non-small-cell lung
Breast resistance to
taxanes, vinca
alkaloids, &
anthracyclines
Eliminated by
metabolism &
biliary excretion
metabolized and
eliminated by fecal
and renal excretion
Myelosuppression
Alopecia
Paclitaxel derived
from Pacific yew tree
bark
Neurotoxicity
docetaxel – from
needles of European
yew
fatigue, joint/muscle
pain, alopecia,
neurotoxicity,
peripheral sensory
neuropathy,
myelosuppression
Have to find the right
pt for this!
Pt can get very sick
Antibiotics
Anthracycline
Drugs:
Doxorubicin,
Daunorubicin,
Idarubicin
epirubicin,
mitoxantrone(less AE’s
than others)
MOA
Use
PK
Intercalation of DNA
 inhibit
topoisomerase
Dauno & Ida:
 Myeloid leukemia
D: rapidly to all body Myelosuppression
tissues except CNS
Cardiac damage
M: extensively in
liver – some
Nausea & vomiting
metabolites are
active
Alopecia
Undergo reducation
rxn  form highly
destructive hydroxyl
radicals  DNA
damage
Doxorubicin – very
broad:
 Hodgkin’s
 Bladder
 Ovarian
 Gastric
 Some hematologic
Long t1/2
AE
Additional Info
Mucosal ulceration
Extravasation  severe
tissue
ulceration/necrosis
epirubicin – breast
mitoxantrone – breast,
non-Hodgkin’s
lymphoma, acute
myeloid leukemia
Bleomycin
(antibiotic)
Active at G2 phase of
cell cycle
Hodgkin’s lymphoma
D: widely
Non-Hodgkin’s
lymphoma
Inactivated in cells
by aminohydrolase
– in skin & lung 
location of some
toxicities
Testicular
E: renal
Dactinomycin
Antibiotic – prevents
DNA transcription &
mRNA synthesis
Choriocarcinoma
Pediatric tumors
-Wilms’ tumor
-Ewing’s sarcoma





Pulmonary toxicity
Mucocutaneous
Skin
hyperpigmentation
Erythema
Edema
Potent, very good
drug
Stop immediately if
drug is causing
heart problems
Chemistry – doxoand daunoantibiotics from
Streptomyces
peucetius,
idarubicin,
epirubicin,
mitoxantrone are
synthetic
derivatives
all have bright red
color
mixture of 2
peptides from
Streptomyces
verticillus;
Topoisomerase Inhibitors  permanent breaks in DNA – cell death!
 2 groups Podopyllotoxins –inhibit type II(dsDNA), Camptothecin – inhibit type I(ssDNA)
Topoisomerase
Inhibitors
Podopyllotoxins:
MOA
Inhibits type II
Etoposide, Teniposide topoisomerase
Use
Etoposide:
 Testicular – 1st line
 Lung
 Non-Hodgkin’s
lymphoma
 Bone marrow
transplantation
 Synergistic w/
Cisplatin
PK
AE
Etoposide:
E: renal
Additional Info
Extracted from
mandrake or
mayapple plant; 2
semisynthetic
derivatives
Teniposide:
M: hepatic
Teniposide:
 Leukemias
Camptothecin:
inhibits type I
Irinotecan, Topotecan topoisomerase
Irinotecan:
 Colorectal
 Lymphomas
 Breast
 Cervical
 Gastric
 Lung
Topotecan:
 Glioma
 Sarcoma
 Lung
 Ovarian
Irinotecan:
Rapidly metabolized
to active metabolite
Eliminated by bile
Topotecan:
Elimination by renal
excretion
Irinotecan:
 Myelosuppression
 Diarrhea
 Alopecia
 Mild nausea &
vomiting
Topotecan:
 Myelosuppression
 Alopecia
 Mild nausea &
vomiting
Camptotheca
acuminata;
synthetic
derivatives are
clinically useful –
irinotecan and
topotecan
Protein Kinase Inhibitors – inhibits kinases involved w/ regulatory proteins


 blocks pathways promoting malignant transformation & proliferation
VEGF: vascular endothelial growth factor
o Wound healing
Protein Kinase
Inhibitors
Imatinib,
Dasatinib,
Nilotinib
Erlotinib
Lapatinib
Bortezomib
MOA
Use
Inhibit BCR-ABL
tyrosine kinase
expressed by
Philadelphia chrom.
Renal cell carcinoma
Imatinab: + inhibits ckit
Highly specific for
tyrosine kinase
associated w/
epidermal growth
factor receptor
Kinase associated w/
HER2/neu receptor
Inhibits proteasome
& targets apoptosis
inhibitors
Imatinab:
+ GI stromal tumors
*2nd line:
Non-small-cell lung
cancer
PK
Chronic Myeloid
Leukemia
Breast cancer
Multiple myeloma
M: CYP 450 3A4
AE
Additional Info
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
Bevacizumab
recombinant
humanized
antibody to vascular
endothelial growth
factor (VEGF)
Rituximab:
Chimeric
human/murine to treat
tumors
First approved
monoclonal ab to tx
cancer
Alemtuzumab
Trastuzumab
MOA
Prevents binding of
VEGF on endothelial
cells  inhibits blood
vessel formation
Use
Colon cancer
NSC lung cancer
PK




Bind to CD20 ag on
surface of 90% of nonHodgkin’s lymphoma
cells
AE
Additional Info
GI bleeding
Perforation
Pulmonary
hemorrhage
Thromboembolic
events
First drug to target
VEGF – doesn’t
seem to make a
different on survival
Non-Hodgkin’s
lymphoma
Attached to
radioactive isotopes to
kill cancer cells
Binds CD52 – found on Chronic lymphocytic
all B & T lymphocytes
leukemia
& other leukocytes
Extracellular
Breast cancer
HER2/neu receptor
* 90Y-ibitumomab
and 131-Itositumomab
Chills, Fever
NauseaVomiting
Chest pain, Dyspnea
Combind for Brest
cancer “AC followed
by T”
Sorafenib,
Sunitinib,
Pazopanib
small molecule
inhibitors of tryosine
kinases including
some of the VEGF
receptors and plateletderived growth factors
Growth Factor
Receptor
inhibitors:
Cetuximab,
Panitumumab
epidermal growth
Cetuximab:
factor receptor (EGFR)  Colorectal
inhibitors;
 Head
overexpressed in solid  Neck
tumors (colorectal,
head and neck, NSCLC, Panitumumab:
pancreatic
Colorectal
Hormones &
Antagonists
Estrogen
antagonists:
Tamoxifen,
Anastrozole,
Letrozole, Leuprolide
Androgen
antagonists:
Leuprolide,
Flutamide,
Nilutamide,
Bicalutamide
Corticosteroids
MOA
 renal cell carcinoma
 hepatocellular
carcinoma
(sorafenib)
 gastrointestinal
stromal tumors
(sunitinib)
Use
Cancers that are
hormone dependent
may respond to
antagonist
Breast cancer
Cancers that are
hormone dependent
may respond to
antagonist
Prostate cancer
Lymphocytic leukemias
Lymphomas
M: All 3 are oral
therapies liver
CYP3A4 and have
potential for multiple
drug interactions
 hypertension,
bleeding
complications,
fatigue
 sorafenib – skin
rash and hand/foot
syndrome
 sunitinib – cardiac
dysfunction
Infusion-related
reactions
Acne-like skin rash
Currently used only
with patients who
have wild-type
KRAS
Hypertension
Renal damage
PK
AE
Additional Info