ANTITUMOR AGENTS
I.
II.
Cell Cycle
Antimetabolites
III.
Alkylating Agents
IV.
Topoisomerase Inhibitors
V.
Antimitotic Agents
VI.
Endocrine Agents
VII.
A.
Adrenocorticosteroids (Glucocorticoids)
B.
Antiandrogens
C.
Antiestrogens
Biological Response Modifiers, Chemoprotectants, and Others
A.
Biological Response Modifiers
B.
Chemoprotectants
C.
Monoclonal Antibodies
D.
Cell Growth Inhibitors
E.
Antisense Drugs
F.
Gene Therapies
G.
Vaccines
VI.
Endocrine Agents
A.
Adrenocorticosteroids (Glucocorticoids)
Prednisone and Dexamethasone
B.
Antiandrogens
1.
Leuprolide (Lupron)
Goserelin (Zoladex)
Abarelix (Plenaxis)
O
HN
2.
C
CH3
C
CH3
Flutamide (Eulexin)
Bicalutamide (Casodex)
Nilutamide (Nilandrone)
H
CF3
NO2
O
HN
C
CH3
C
CH2
CH3
CF3
C
N
O
S
O
F
C.
Antiestrogens
1.
Tamoxifen Citrate
[Nolvadex]
CH3
O CH2 CH2 N
H
O
CH3
CH2 C
HO
C
C
OOH
O
CH2 C OH
C
C
O
CH2CH3
Toremifene
[Fareston]
Fulvestrant
[Faslodex]
2.
Anastrozole
[Arimidex]
Letrazole
[Femara]
N
N
N
N
N
N
CH3
CH3
CH3
CH3
C
N
C
N
N
C
C
H3C
3.
H 3C
Exemestane
[Aromasin]
O
CH2
O
N
VII.
BIOLOGICAL RESPONSE MODIFIERS, CHEMOPROTECTANTS, AND
OTHERS
A. Biological Response Modifiers
1. Cyclosporin Tacrolimus -
Cyclic peptide used as an immunosuppressive agent in bone
marrow transplant patients. It binds to immunophilin receptors
on T-lymphocytes thereby decreasing their activation.
A major dose-limiting toxicity is nephrotoxicity (and sometimes
hepatotoxicity).
Cyclosporin is metabolized by CYP3A isoforms to inactive
products and CYP3A inducers can increae its rate of metabolism
and cause organ rejection. Inhibitors of CYP3A can increase
cyclosporin drug concentrations and lead to nephrotoxicity.
2. BCG -
A live, attenuated strain (Bacillus of Calmette and Guérin) of
Mycobacterium bovis that when instilled into the bladder
(intravesical administration) causes an inflammatory response
leading to an infiltration of granulomatous cells (neutrophils,
monocytes, etc.) that kill bladder cancer cells.
Cannot be used with immunosuppressive therapy.
3. Interferons -
These are glycoproteins synthesized by lymphocytes,
macrophages and fibroblasts that bind to cellular receptors
leading to activation of RNAases that degrade RNA produced by,
e.g., oncogenes.
Major toxicities are flu-like anaphylaxis, hypotension and
tachycardia; sometimes liver failure.
They are P450 inhibitors.
Interferon--2a (Roferon-A) is used primarily for CML, nonHodgkins lymphomas, multiple myeloma and hemangiomas.
Interferon--2b (Intron-A) is used primarily for malignant
melanoma and Kaposi's sarcoma.
4. Interleukins -
Cytokines produced by a variety of cells as an inflammatory
response.
IL-1 enhances platelet recovery, e.g., after carboplatin therapy.
IL-2 is produced by altered T-lymphocytes and transforms them
to Lymphokine Activated Killer (LAK) cells. Use IL-2/LAK
therapy for renal cells carcinomas and melanoma. Can cause
life-threatening hypotension and pulmonary/peripheral edema
(decrease by giving lower doses in combo with IFN--2b).
5.
Granulocyte Colony Stimulating Factor (G-CSF) and Granulocyte Macrophage
Colony Stimulating Factor (GM-CSF)
These are recombinant hematopoietic growth factor proteins that
stimulate the bone marrow to produce granulocytes (G-CSF) or
graulocytes and monocytes (GM-CSF). They are used to
increase white blood cell production in chemotherapy regimens
that cause BMD and in patients undergoing bone marrow
transplants.
They can cause fever and severe flu-like symptoms.
6. Retinoic Acids -
CH3
CH3
CH3
All trans-retinoic acid (Tretinoin) causes normalization of an
abnormal retinoic acid nuclear receptor found in promyelocytic
leukemia.
CH3
O
C OH
CH3
13-cis-retinoic acid (Isotretinoin, Accutane)
inhibits progression of basal and squamous cell
carcinomas of the skin and cervix in combo
with IFN- 2
7. Arsenic Trioxide (Trisenox) - An old poison that in the right doses preferentially kills
promyelocytic leukemia cells by apoptotic and other
mechanisms.
B. Chemoprotectants (see previous discussion of Leucovorin and Mesna)
1. Dexrazoxane (Zinecard) -
A piperidinedione that chelates iron and
protects cardiac cells against free radical
formation. Used to protect against
cardiotoxicity caused by anthracycline
antibiotics
O
H
HN
N
CH2
C
CH3
N
O
O
N
H
O
2. Amifostine (Ethyol) O
H2N
CH2
H
CH2 CH2 N CH2
CH2 S P
OH
OH
C. Monoclonal Antibodies -
1. Trastuzumab (Herceptin) Problems:
Has caused some deaths
due to immunotoxicities
(allergic shock,
pulmonary edema) and
weakens heart muscle
 CHF
Contraindicated with anthracyclines.
A thiophosphonate prodrug that is
hydrolyzed by alkaline phosphatase in
tissues to an aminothiol that protects
some cells from toxic effects of antitumor
agents, e.g., cisplatin nephrotoxicity, and
leads to less BMD with carboplatin,
paclitaxel, cyclophosphamide, and
melphalan.
Antibodies directed against specific proteins
associated with some tumors.
MAb directed against the HER 2/neu protein
(erB2), an oncogenic protein found in some
advanced breast cancers that causes aggressive
spread of the cancer.
2. Rituximab (Rituxan) Problems:
Anaphylaxis, infusion
reaction (hypotension,
chills)
3. Ibritumomab (Zevalin) Problems: Same as Rituximab
MAb that binds to CD-20 antigens on Blymphocytes  their destruction - Use in
refractory non-Hodgkins B-cell lymphomas.
A radioimmunoconjugate with the same MAb as
Rituximab plus a chelated Yttrium-90 -emitter
 radioactive destruction of B-lymphocytes
4. Bexaar
Same as Ibritumomab but with I131 -emitter
5. Gemtuzumab (Mylotarg) -
Monoclonal Ab - Toxin conjugate in which MAb
binds to CD33 antigen on myeloblastic leukemia
cells and linker toxin (calicheamycin) kills the
cells. Used to treat AML.
Problems:
BMD and hepatotoxicity
from toxin plus severe
hypersensitivity reaction
(flu-like)
6. Denileukin Diftitox (Ontak) Problems:
Allergic reactions and
hypotension
7. Alemtuzumab (Campath) Problems:
Hematological toxicities
8. Bevacizumab (Avastin) Problems:
Bleeding, GI perforations,
stroke, cardiotoxicity with
anthracyclines
9. Cetuximab (Erbitux) Problems:
Rash and severe N/V/D
10. Panitumumab (Vectibix)
MAb - toxin conjugate that binds to CD25 anti–
gens of the IL-2 receptor expressed on lymphoma
T-cells and linker diphtheria toxin kills the cells.
Use in non-Hodgkins T-cell lymphomas.
MAb that binds to the CD52 antigen on the
surface of malignant lymphocytes  cell lysis
(use in CLL)
Monoclonal antibody binds to vascular
endothelial growth factor (VEGF) 
inhibits angiogenesis in colorectal cancer
Monoclonal antibody binds to and inhibits the
epidermal growth factor (EGF) receptor 
blocks angiogenesis and tumor invasion
A MAb similar to Cetuximab with same activity
in treating colorectal cancers
D.
Cell Growth Inhibitors 1. Imatinib Mesylate (Gleevec) Problems:
Edema, N/V/D, BMD
and hepatotoxicity;
plus inhibits and is
metabolized by
CYP3A4, + some
cardiotox
Inhibits Bcr - Abl tyrosine kinase that
phosphorylates proteins that cause cell
proliferation in myeloid cells which contain
the mutated Philadelphia chromosome found
in >90% of CML patients
2. Dasatinib (Sprycel) -
Same mechanism but binds to more and different
conformers of the enzyme
3. Gefitinib (Iressa) -
Inhibits phosphorylation of tyrosine kinases,
especially the Epidermal Growth Factor Receptor
tyrosine kinase, thereby blocking tumor invasion
and angiogenesis. Approved use in Non-Small
cell lung cancer.
Problems:
Interstitial lung disease,
rash, N/V/D; plus
metabolized by
CYP3A4
4. Erlotinib (Tarceva)
Similar to Gefitinib, but apparently more effective
in non-small-cell lung cancer and also in
pancreatic cancer.
5. Bortezomib (Velcade) -
Inhibits the 26S proteosome that normally
degrades signal transduction and cell cycle
regulatory proteins   activity of factors for cell
growth. Approved for use in multiple myeloma.
Problems:
Peripheral neuropathy,
BMD, N/V/D
6. Sunatinib (Sutent)
Sorafenib (Nevaxar)
Problems:
Skin rashes, diarrhea,
hypertension
Tyrosine kinase inhibitor that decreases activity of
vascular endothelial growth factor and plateletderived growth factor  blocks angiogenesis in
renal cells
E. Antisense Drugs -
Antisense oligonucleotides are short pieces of
DNA that are complementary to a segment of
messenger RNA (mRNA) that bind to the
oncogenic RNA of interest and block translation
of its oncogenic protein.
In development - Antisense oligos to bcl-2
mRNA overexpressed in melanoma cells and
BCR-ABL mRNA overexpressed in CML
cancer cells.
F. Gene Therapies -
Goal is to modify the cellular genome for
therapeutic benefit by:
1. Insertion of cancer fighting genes (e.g., gene for tumor necrosis factor) into cancer
cells or into a virus that only infects cancer cells.
2. Insert enzyme-activating genes into cells (GDEPT = gene-directed enzyme prodrug
therapy) or via viruses (VDEPT = virus-directed enzyme prodrug therapy) that encode
enzymes that convert prodrugs to their toxic products. Examples - trials with a
carboxypeptidase (CPG2) gene that cleaves a prodrug of doxorubicin, and a P450
gene that converts cyclophosphamide to its toxin.
G. Vaccines -
1. HPV Vaccine (Gardasil) - Active against 2 HPV
strains that cause cervical cancer, +2 strains that
cause genital warts.
2. Melacine by Corixa, a Seattle-based company.
Mixture of modified melanoma tumor cells and
an immune stimulant  production of Abs that
kill melanoma cells.
Other reports of successes with fusion of renal tumor cells with dendritic cells to treat
renal carcinoma.
Ongoing studies with vaccines to treat breast, prostate and lymphoma cancers.