General rules of

chemotherapy

Aggressive high-dose chemotherapy

Cyclic regimens - repeated administrations with

appropriate intervals for regeneration of normal
cells (e.g., bone marrow cells)
Supportive therapy - to reduce toxicity
hematotoxicity bone marrow transplantation,
hematopoietic growth factors
Specific antagonists: antifolate (methotrexate)
folate (leucovorin)
MESNA (Mercapto Ethane Sulfonate sodium)
donor of SH groups, decreased urotoxicity of
cyclophosphamide. Detoxifying agent.
dexrazoxane: chelates iron, reduced
anthracycline cardiotoxicity
amifostine: reduces hematotoxicity, ototoxicity
and neurotoxicity of alkylating agents

 MESNA is an adjuvant used in cancer chemotherapy involving

cyclophosphamide and ifosfamide. It is marketed by Baxter as
Uromitexan and Mesnex. MESNA is an acronym for 2MercaptoEthane Sulfonate sodium. It is a detoxifying agent.
Amifostine is a cytoprotective adjuvant used in cancer
chemotherapy involving DNA-binding chemotherapeutic agents.
Also commonly known as WR-1065 in its active form. It is
marketed by MedImmune under the trade name Ethyol.
Dexrazoxane is used to protect the heart against the cardiotoxic
side effects of anthracyclines, such as doxorubicin.
Amifostine is used therapeutically to reduce the incidence of
neutropenia-related fever and infection induced by DNA-binding
chemotherapeutic agents including alkylating agents (e.g.
cyclophosphamide) and platinum-containing agents (e.g.
cisplatin). It is also used to decrease the cumulative
nephrotoxicity associated with platinum-containing agents.
Amifostine is also indicated to reduce the incidence of xerostomia
in patients undergoing radiotherapy for head and neck cancer.

General rules of
chemotherapy
Combination of several drugs with different mechanisms of
action, different resistance mechanisms, different doselimiting toxicities.
Adjuvant therapy: Additional cancer treatment given
after the primary treatment to lower the risk that the cancer
will come back. Adjuvant therapy may include
chemotherapy, radiation therapy, hormone therapy,
targeted therapy, or biological therapy.

General rules of
chemotherapy
Supportive therapy of chemotherapy:
-Antiemetics (5-HT3 -antagonists)
-Antibiotic prophylaxis and therapy
-Prophylaxis of urate nephropathy (allopurinol)
-Enteral and parenteral nutrition
-Pain analgesic drugs
-Psychological support

Antineoplastic Agents
Alkylating agents

Topoisomerase
inhibitors

Antimetabolites

Molecularly
targeted

busulfan

dactinomycin

cytarabine

erlotinib

carboplatin

daunomycin

clofarabine

imatinib

carmustine

doxorubicin

fludarabine

sorafenib

cisplatin

etoposide

gemcitabine

sunitinib

cyclophosphamide

etoposide phosphate mercaptopurine

tretinoin

dacarbazine

idarubicin

methotrexate

Herceptin

ifosfamide

irinotecan

nelarabine

Miscellaneous

lomustine

liposomal daunomycin

thioguanine

arsenic trioxide

mechlorethamine

liposomal doxorubicin

melphalan

mitoxantrone

docetaxel

bleomycin

oxaliplatin

teniposide

ixabepilone

dexamethasone

procarbazine

topotecan

vinblastine

hydroxyurea

temozolomide

vincristine

mitotane

thiotepa

vinorelbine

PEG-asparaginase

paclitaxel

prednisone

Tubulin binders

asparaginase

Classical alkylating agents

They destroy proliferating cancer cells by adding an alkyl

group to DNA molecule and preventing its replication.
The following three groups are almost always considered
"classical".
Nitrogen mustards
Cyclophosphamide
Mechlorethamine
ormustine (HN2)(trade
nameMustargen
Uramustineoruracil
mustard
Melphalan
Chlorambucil
Ifosfamide
Bendamustine

Nitrosoureas
Carmustine
Lomustine
Streptozocin
Alkyl sulfonates
Busulfan

Alkylating-like
Platinum-based chemotherapeutic drugs (termed
platinum analogues) act in a similar manner.
These agents do not have analkyl group, but
nevertheless damage DNA. They permanently
coordinate to DNA to interfere with DNA repair, so
they are sometimes described as "alkylating-like".
Cisplatin
Carboplatin
Nedaplatin
Oxaliplatin
Satraplatin
Triplatin tetranitrate
These agents also bind at N7 of guanine.

Chemotherapy: Mechanisms of Action

Topoisomerase Inh.

DNA

Alkylating agents

Purines and
Pyrimidines

RNA
Antimetabolites

Asparaginase

Protein
tubulin

Tubulin binders

Alkylating Agents
Largest class of antineoplastics
General Properties/Mechanism:
All are electrophilic molecules that covalently modify nucleophilic
molecules in cells
DNA most important target (N7 and O6 of Guanine) for
anticancer properties
General Types of Alkylating Agents:
Monofunctional
Cause single strand DNA breaks

Bifunctional

Inhibit DNA replication and transcription by crosslinking DNA

Subtypes:
Nitrogen mustards
Nitrosoureas
Platinum Compounds

An Example of DNA Crosslinking

R

O
HN
H2N

HO

O
O

NH
N

NH2
OH

O
P
O

Crosslinking: Joining two or more molecules by a covalent bond. This

can either occur in the same strand (intrastrand crosslink) or in the
opposite strands of the DNA (interstrand crosslink). Crosslinks also
occur between DNA and protein. DNA replication is blocked by
crosslinks, which causes replication arrest and cell death.

Nitrogen Mustards

Work of DeVita and others

showed that drug
Compound
combinations can have
synergistic activity. Most
MOPP (Mechlorethamine, Vincristinecancer treatment regimens
(Oncovin), Procarbazine, Prednisone)are polymodal and involve
drug combinations.
Chlorambucil (Leukeran)
MOPP remission for ~80%
Chronic lymphocytic leukemia,
of patients where single
malignant lymphomas
agents were generally
Less alopecia and nausea
Cumulative bone marrow toxicity ~20% effective
Mechlorethamine (Mustargen)
Hodgkins/other lymphomas
and chronic leukemias.
MOPP regimen

Mechlorethamine (Mustargan)
Mustargan serves as a prototype for the mustards (and
other alkylating agents) because of its spectrum of
activity, its toxicities and its mechanism of action. It is
highly unstable and reactive still in use in combination
therapy, MOPP, 80% response, >50% cure
Toxicity: Nausea and vomiting (N&V). Dose limiting
toxicity (DLT) is bone marrow suppression, white blood
cells, esp. granulocytes. Max suppression at 10-12 days,
recovery around 42 days.
ADME: t1/2 less than 30 min., admin in free flowing
catheter
Analogs: Chlorambucil (Leukeran), Chronic Lymphocytic
Leukemia; Melphalan (Alkeran), Multiple Myeloma (longer
half-lives, p.o.);

Most Common Nitrogen Mustards

Cyclophosphamide (Cytoxan)
Malingnant lymphomas, various carcinomas.
Activated by P450 enzymes
Most versatile nitrogen mustard
Better bone marrow recovery than
Mustargen
Ifosphamide (Isophosphamide, Ifex)
Lung, breast, ovarian, lymphomas

Cyclophosphamide is a nitrogen
mustard that requires
bioactivation. The circulating form,
aldophosphamide, degenerates into
the active phosphoramide mustard
and the toxic acrolein. Aldehyde
oxidase protects the liver and other
tissues from aldophosphamide that
doesnt diffuse out.

Cyclophosphamide (Cytoxan)

Use: Most widely used alkylating agent. NonHodgkin's lymphomas , Breast (increases 7 yr
survival form 31% to 49 %)

Toxicity: N&V, anaphylactic shock. bone marrow

suppression, max 10-12 days, recovery by 21
days (relatively platelet sparing); alopecia,
hemorrhagic cystitis (minimized by diuresis), etc.
ADME: May be administered parenterally, in a
large range of doses. Resistant cells may have
aldehyde oxidase (like the liver)
Analog: Isofosfamide (Ifex)

Nitrosoureas
Compound
Bischloronitrosourea
(Carmustine, BCNU)

Chloroethylcyclohexyl
nitrosourea
(Lomustine, CCNU)

BCNU and CCNUs: Brain tumors, Hodgkins disease,

melanoma.
Lipid soluble: (CNS active)
O6 of Guanine preferred alkylation site
Prolonged cummulative myelosuppression
Teratogenic

BCNU (Carmustin)
Use: Primary glioblastoma (with surgery and
radiation can increase live span from 20 weeks to 50
weeks)
Toxicity: N&V. bone marrow suppression, max 28
days; recovery by 42 days.
ADME: Administered by injection. Unique among
antineoplastics for its high oil-to-water partition
coefficient (very lipophillic) and low ionization at
physiological pH risk of hematological toxicity persist
due to storage in the liver & adipose tissue
Analog: CCNU (lomustine), may be administered
orally. Temozolomide (Temodar) is a new non-

Platinum compounds
Cisplatin (Platinol)
testicular, ovarian, head and neck, lung,
bladder cancer
Curative in combination for metastatic testicular cancer

Carboplatin (Paraplatin)
ovarian, non-small cell and small cell lung cancers
less toxic (~45) than cisplatin but is generally less active

Oxaliplatin (Eloxatin)
broad anticancer activity: colorectal, ovarian, pancreatic, nonHodgkins lym, breast, lung, prostate, etc
Lacks cross-resistance with other platinum compounds
Generally less toxic than other platinum compounds

Oxaliplatin: Third generation platinum analog. Its

activity and toxicity profiles differ from both cisplatin
and carboplatin, and thus, it lacks cross-resistance with
these compounds. Oxaliplatin contains a bulky carrier
ligand, 1,2-diaminocyclohexane (DACH), not present in
either cisplatin or carboplatin. Unlike cisplatin or
carboplatin, oxaliplatin is not associated with significant
renal or auditory toxicity, and hematological toxicity is
usually mild. Oxaliplatin has a large spectrum of
antineoplastic activity, including colorectal cancer,
ovarian cancer, pancreatic cancer, non-Hodgkin's
lymphoma, breast cancer, lung cancer, prostate cancer,
germ-cell carcinomas, and malignant mesothelioma.
Changes in mismatch repair and enhanced replicative
bypass do not appear to contribute to oxaliplatin
resistance as compared to cisplatin or carboplatin.

Cisplatin (Platinol)
Use: Most used in combination therapy - testicular
tumors (85% curative)
Toxicity: nephrotoxicity, can be treated with Amifostine (a
thiophosphate) Major N&V, hearing loss at high end.
ADME: Administered i.v. after 1-2 liters saline and
mannitol (chloride diuresis)
Analog: Carboplatin (Paraplatin), Oxaliplatin (Eloxatin) is
now a first line drug for combination therapy of colon
cancer

Cisplatin-induced has been largely abrogated by adequate

pretreatment hydration and diuresis. Amifostine (ETHYOL) is a
thiophosphate cytoprotective agent that is labeled for the
reduction of renal toxicity associated with repeated administration
of cisplatin. Amifostine is dephosphorylated by alkaline
phosphatase to a pharmacologically active free thiol metabolite.

Ototoxicity caused by cisplatin is unaffected by diuresis and is

manifested by tinnitus and high-frequency hearing loss. The
ototoxicity can be unilateral or bilateral, tends to be more frequent
and severe with repeated doses, and may be more pronounced in
children. Marked nausea and vomiting occur in almost all patients
and usually can be controlled with 5-hydroxytryptamine (5-HT3)
antagonists, neurokinin-1 (NK1) receptor antagonists, and highdose corticosteroids (see Chapter 37). At higher doses or after
multiple cycles of treatment, cisplatin causes a progressive
peripheral motor and sensory neuropathy, which may worsen after
discontinuation of the drug and may be aggravated by subsequent
or simultaneous treatment with taxanes or other neurotoxic drugs.
Cisplatin causes mild-to-moderate myelosuppression, with
transient leukopenia and thrombocytopenia. Anemia may become
prominent after multiple cycles of treatment

Other Alkylators
Streptozocin (Zanosar), a nitrosourea
Use: Malignant pancreatic insulinoma, pancreatic carcinoid,
doubles 1 yr survival rates (Nausea and vomiting notable,
renal toxicity in 2/3 cases bone marrow suppression in ~
20%)

Procarbazine (Mutalane)
Use: Hodgkins Disease (MOPP protocol)
Few reports of cross resistance, minor toxicities (bone
marrow suppression), psychic disturbances, nausea,
vomiting, Weak MAO inhibitor - available orally

Dacarbazine (DTIC)
Temozolomide & DTIC are metabolized to same active
compound: 5-amino-imidizole-4 carboxamide - thought to be
the active alkylating species
DTIC Use: Melanoma, Hodgkins disease , dose i.v.
Temozolomide Use: malignant gliomas

 Streptococci is used in the management of pancreatic islet cell

carcinoma, carcinoid tumor, colorectal cancer, and pancreatic
adenocarcinoma. It seems to have specific activity only in pancreatic
cancers and some gastrointestinal tumors. Due to the presence of a
sugar moiety, streptozocin has a marked specificity for beta- and
exocrine cells of the pancreas, and its uptake by these cells is
enhanced.
Procarbazine is an oral, cell cycle-phase specific antineoplastic agent
used in the treatment of Hodgkin's disease, non-Hodgkin's lymphomas,
brain tumors, and lung cancers. It has been described as a nonclassic
alkylating agent and is not cross-resistant with the other alkylating
agents. Procarbazine must be activated by chemical decomposition or
by microsomal oxidation via the hepatic cytochrome P-450 enzyme
system to exert its cytotoxic effects. Several active metabolites can
form including species capable of binding to DNA and free radicals.
Resistance to procarbazine develops rapidly after exposure to the drug.
Dacarbazine is a cell cycle-phase nonspecific antineoplastic drug that is
believed to be an alkylating agent. Dacarbazine is unlike conventional
alkylating agents such as cyclophosphamide or chlorambucil. It is used
in the treatment of metastatic malignant melanoma, osteogenic
sarcoma, soft-tissue sarcoma, and Hodgkin's disease. It requires
activation by the cytochrome P-450 system to its alkylating form.

1. Mechanism
of Action

2. Clinical
application

3. Route

4. Side effects

A.
Mechlorethamine

DNA crosslinks, resulting

in inhibition of
DNA synthesis
and function

Hodgkins and nonHodgkins lymphoma

Must be
given Orally

Nausea and vomiting,

decrease in
PBL count, BM
depression, bleeding,
alopecia, skin
pigmentation,
pulmonary fibrosis

B.
Cyclophosphamid
e

Same as above

Breast, ovarian, CLL,

soft tissue sarcoma, ,
neuroblastoma

Orally and
I.V.

Same as above

C. Chlorambucil

Same as above

Chronic lymphocytic
leukemia

Orally
effective

Same as above

D. Melphalan

Same as above

Multiple myeloma,
breast, ovarian

Orally
effective

Same as above

E. Ifosfamide

Same as above

Germ cell cancer,

cervical carcinoma,
lung, Hodgkins and
non-Hodgkins
lymphoma, sarcomas

Orally
effective

Same as above

a. Nitrogen
Mustards

1. Mechanism of
Action

2. Clinical
application

3. Route

4. Side effects

A. Busulfan

Atypical alkylating
agent.

Chronic granulocytic
leukemia

Orally effective

Bone marrow
depression,
pulmonary fibrosis,
and hyperuricemia

c. Nitrosoureas

1. Mechanism of
Action

2. Clinical
application

3. Route

4. Side effects

A. Carmustine

DNA damage, it can

cross blood-brain
barrier

Hodgkins and nonHodgkins lymphoma,

brain tumors, G.I.
carcinoma

Given I.V. must

be given
slowly.

Bone marrow
depression,
CNS depression, renal
toxicity

B. Lomustine

Lomustine alkylates
and crosslinks DNA,
thereby inhibiting
DNA and RNA
synthesis. Also
carbamoylates DNA
and proteins, resulting
in inhibition of DNA
and RNA synthesis
and disruption of RNA
processing. Lomustine
is lipophilic and
crosses the bloodbrain barrier

Hodgkins and nonHodgkins lymphoma,

malignant melanoma
and epidermoid
carcinoma of lung

Orally effective

Nausea and vomiting,

Nephrotoxicity, nerve
dysfunction

C. Streptozotocin

DNA damage

pancreatic cancer

Given I.V.

Nausea and vomiting,

nephrotoxicity, liver
toxicity

b. Alkyl
Sulfonates

Alkylating Agents - Summary

Largest class of antineoplastic drugs
Nitrogen Mustards
Nitrosoureas
Platinum Compounds

All are electrophilic compounds that react with DNA

Bifunctional: Nitrogen mustards & platinum compounds
Monofuctional: Nitrosoureas

Toxicities vary depending on the particular compound

Many have severe bone marrow suppression
Platinum compounds tend to show more renal toxicities

Metabolites and their

Antimetabolites
General Properties/Mechanism:
Antimetabolites resemble cellular metabolites and act to
interfere with DNA synthesis or the synthesis of DNA
precursors.
These are classical cell cycle specific anti-cancer agents
Most are prodrugs that must be activated through
incorporation into the normal biosynthetic pathways

Toxicities: only partially selective to tumor cell

toxic to all rapidly dividing normal cells

Bone marrow and intestinal epithelium are particularly

sensitive

General Drug classes:

Antifolates
Antinucleotide analogs

 Antimetabolites resemble cellular

metabolites and act to interfere with DNA
synthesis or the synthesis of DNA
precursors.
As with most antimetabolites,
methotrexate is only partially selective for
tumor cells and is toxic to all rapidly
dividing normal cells, such as those of the
intestinal epithelium and bone marrow.
Folate antagonists kill cells during the S
phase of the cell cycle and are most
effective when cells are proliferating
rapidly.

Folate Antimetabolites
Methotrexate, Amethopterin
Trophoblastic choriocarcinoma, lymphoblastic leukemia,
Burkitts
lymphoma
Class: Folate antagonist
Mechanism: Dihydrofolate Reductase inhibitor: inhibits
dTMP synthesis. Kills in S-phase (G1 and S RNA and
protein synthesis)
Toxicity: bone marrow, GI, renal, alopecia, teratogen
Resistance: increased/altered DHFR, decreased
uptake

Nucleotide Analogs
5-Fluorouracil; 5-FU (Efudex)
Colorectal, breast, gastric, pancreatic colon cancers (35% decrease in
recurrence). Used topically for premalignant skin lesions.
Class: Pyrimidine analog
Mechanism: irreversible inhibition of thymidylate synthase (TS).
Incorporation into DNA/RNA. Kills in G1 and S-phases. Penetrates CNS.
Toxicity: N&V, GI toxicity. DLT bone marrow suppression
Resistance: increased/altered TS
Inhibits Thymidylate Synthase

ADME: Administered i.v., half-life in the blood of ~1020 min

Analog: Floxuridine (FUDR), often infused into the
hepatic artery for liver cancer

 5 FU is a prodrug that needs to be

transported into the cell and activated
(metabolized) into the nucleotide pool.
There are several parallel pathways to
achieve this, but ultimately 5 FU is
metabolized to FdUMP. FdUMP is a substrate
for thymidylate synthase, an enzyme
essential for the synthesis of thymidine (a
DNA precursor). FdUMP inhibits thymidylate
synthase and starves the cell for thymine,
the so-called thymine less death.

More nucleotide
analogs

6-Mercaptopurine; 6-MP (Purinethol)

Acute leukemias (40% remission in children)

Class: Purine analog
Mechanism: HPRTase: Hypoxanthine-guanine
phosphoribosyltransferase makes the nucleoside
phosphate from the free base - inhibition of purine
synthesis; incorporation into RNA/DNA unclear. Kills in
S-phase.
Toxicity: bone marrow, nausea, vomiting
Resistance: decreased HPRTase activity (needed to
incorporate 6-MP into RNA/DNA)
6-Thioguanine (Thioguanine)
Same as 6-MP
Used against granulocytic Leukemia
with cytarabine

 6 Mercaptopurine is a purine prodrug that,

once metabolized to the monophosphate, is
an excellent feedback inhibitor of
phosphoribosyl amidotransferase, the first
enzyme in the purine de novo synthesis
pathway. While having antineoplastic activity
of its own, probably its most important use is
for maintenance of remissions in ALL.
In addition to inhibition of PRPPase, the
purine antimetabolites also are incorporated
into DNA and RNA and inhibit other enzymes.
It is likely that their clinical use is actually
due to a sum of their activities in susceptible
tissues.

Antimetabolites - Summary
Classical cell-cycle dependent agents
Require bioactivation
Classes
Antifolates
Antinucleotide analogs

Inhibit enzymes required for DNA

synthesis
Toxicities extend to tissues with higher
rates of cellular turnover