Anticancer agents

Antineoplastics

Introduction
The antineoplastic drugs are designed to either inhibit abnormal cell proliferation or to
cause death of abnormal cells. Given the complex biochemical pathways and the specific
phases of cellular life cycles, there are numerous opportunities for these drugs to exert a
beneficial effect.

Summarising the biochemical requirements for successful cell life and division, bases
(purines and pyrimidines) that ultimately form RNA and DNA must first be synthesised
(antimetabolites may inhibit this step). Upon synthesis, these bases are used to form
ribonucleotides, which are then reduced to form deoxyribonucleotides (this step may be
inhibited by hydroxyurea) and used to form DNA (many of the steps from ribonucleotide
reduction through DNA synthesis may be inhibited by antimetabolites or folate
antagonists). (DNA structure and function may be inhibited at any point during the life of a
cell by agents such as the alkylators and the anthracycline antibiotics.) The DNA is then
used as a template to form RNA, which is used to synthesis proteins (DNA function may be
inhibited here OR protein synthesis may be inhibited by L-asparaginase) that may be
required for cell life or division (such as microtubules, whose function may be inhibited by
the antimitotic antineoplastics). Additionally, at cell division, the DNA is replicated for
daughter cells (this may be inhibited as well). The entire scheme is illustrated below:

One aspect of neoplastic cells is a high proclivity to replication. Considering the cell cycle,
recall that there are four distinct phases in the life of a cell. The G1 phase is a pre-DNA
synthesis phase during which purines are synthesised and ribonucleotides are formed. As
the necessary components for DNA synthesis are accumulated, the cell enters the S phase,
during which DNA synthesis occurs. Following DNA synthesis, the cell prepares to divide
during the pre-mitotic G2 phase. Once the cell has prepared itself, it enters the M or mitotic
phase, in which the four stages of mitosis (prophase, metaphase, anaphase, and telophase)
occur. Some cells also exhibit a G0 or resting phase that may proceed the G1 phase.
Depending upon their mechanism of action, antineoplastics may exert their effect
specifically during one of these phases -- these are called cell-cycle specific antineoplastics
and are illustrated below. Conversely, other drugs may act during any phase of the cell
cycle to cause cell death -- these are termed non-cell cycle specific antineoplastics. As
damage occurs to the cell one of two actions may take place. Damage to DNA may prevent
replication by altering DNA, RNA or their function. Agents which work by this mechanism
inhibit the proliferation of the neoplastic cell (it cannot divide). Other drugs may cause
damage to the DNA that results in cell death. This action has been correlated to the
presence of a specific gene, the p53 gene. If DNA damage occurs and the p53 gene is
present, then as the cell proceeds from the G1 phase to the S phase, the damage is detected
and results in cell death by apoptosis. Apoptosis has been referred to as programmed cell
death and may represent the natural "life limit" of the cell. Absence of the p53 gene will
prevent cell death or allow the cell to survive (this is one mechanism of resistance that may
develop to anti-neoplastics). The ability of most antineoplastics to damage DNA will cause
cell death by this mechanism, accounting for their cytotoxic effects.

Antineoplastic Agents
The primary goal of these drugs, as stated above, is to kill or inhibit proliferation of
abnormal cells. This is best accomplished by administering the highest dose possible (one
that does not endanger the life of the patient). Since these agents may present with severe
toxicity, there are several agents whose dose may be limited by their toxicity. Since many
of these agents act by different mechanisms, combination therapy is common. Additionally,
since these drugs act by inhibiting cell division, the most common side effects are those that
occur in areas of the body where cell replication occurs, such as the GI mucosa (nausea,
vomiting, diarrhœa), the bone marrow (myelosuppression causing leukopænia and other
blood dyscrasias), and hair follicles (alopecia). Most antineoplastics have less effects on
those cells that are non-dividing (kidney, heart) and effects on these organs are often the
result of damage to portions of the cell other that DNA. These side effects (except alopecia)
may represent the dose limiting toxicity (DLT) or some other toxic effect may limit the dose
of a particular anti-neoplastic.
Antineoplastics, while sharing many of the same mechanisms of action, may exhibit varying
degrees of efficacy in different neoplasias. This may represent differences in the growth
cycle of the specific neoplasia or it can result from different uptake mechanisms, that may
limit the amount of drug that reaches the nucleus of the neoplastic cell. Antineoplastic
drugs enter the cell by different mechanisms including active transport (often at sites for
amino acids or other cell constituents such as choline) and passive diffusion. Changes in
the uptake of the drug represent one form of resistance that may develop to antineoplastic
therapy. Other forms of resistance include increases in glutathione production, which may
serve as the site of drug action, reducing its effect on DNA, increased efficiency in DNA
repair, increased metabolism of the drug, and failure to express the p53 gene as previously
described.

A E cont. P cont.

 Aclarubicin  Erlotinib  Pelretin

 Actinomycin  Estramustine  Pemetrexed
 Alemtuzumab  Etoglucid  Pentostatin
 Alitretinoin  Etoposide  User:Pepe.king.prawn/Diazonamide
 Altretamine  Everolimus A
 Aminolevulinic acid F  Personalized medicine
 Amsacrine  Picoplatin
 Ferruginol  Pipobroman
 Anagrelide
 Fludarabine  Pirarubicin
 Antiestrogen
 Fluorouracil  Pixantrone
 Antineoplastic
 Fotemustine  Plicamycin
 Arsenic trioxide
 Fulvestrant  Porfimer sodium
 Asparaginase
 Azacitidine
G  Prednimustine
 8-Azaguanine  Procarbazine
 Gefitinib
B  Gemcitabine
 Psc833
R
 Gemtuzumab
 Bevacizumab
ozogamicin
 Bexarotene  Raltitrexed
 Bleomycin  Glembatumumab  Reditux
 Bortezomib vedotin  Rituximab
 Bropirimine H  Romidepsin
 Busulfan S
 Hydroxycarbamide
C
I  Satraplatin
 Cabazitaxel  Semustine
 Idarubicin
 Capecitabine  Sorafenib
 Ifosfamide
 Carboplatin  Sparsomycin
 Imatinib
 Carboquone  Streptozotocin
 Irinotecan
 Carmofur  Sunitinib
 Ixabepilone
 Carmustine T
 Catumaxomab
L
 Talampanel
 Celecoxib  Lapatinib
 Tamibarotene
 Cetuximab  Lipoplatin
 Taxane
 Chemically linked  Lomustine
Fab  Tegafur
 Lonidamine
 Chlorambucil  Temoporfin
M  Temozolomide
 Cisplatin
 Cladribine  Temsirolimus
 Mafosfamide
 Clofarabine  Teniposide
 Mannosulfan
 Crizotinib  Tesetaxel
 Masoprocol
 Cyclophosphamide  ThioTEPA
 Mechlorethamine
 Cytarabine  Tiazofurin
 Melphalan
D  Tioguanine
 Mercaptopurine
 Toceranib
 Methotrexate
 DHA-paclitaxel
Methyl aminolevulinate  Topotecan

 Dacarbazine  Trabectedin
 Miltefosine
 Dasatinib  Trastuzumab
 Mithramycin
 Daunorubicin  Treosulfan
 Mitobronitol
 Decitabine  Tretinoin
 Mitoguazone
 Demecolcine  Triaziquone
 Mitomycin
 Denileukin diftitox  Trofosfamide
 Mitotane
 Dichloroacetic acid
 Docetaxel  Mitoxantrone V
 Doxorubicin  Monomethyl auristatin
 Valrubicin
E E
 Mubritinib  Vinblastine
 Edrecolomab N  Vincristine
 Efaproxiral  Vindesine
 Epirubicin  Nafoxidine  Vinorelbine
 Epoxomicin  Nelarabine  Vorinostat
 Nilotinib Z
 Nimustine
 Nitrilosides  Zorubicin
O

 Oblimersen
 Ortataxel
 Oxaliplatin
P

 Paclitaxel
 Panitumumab
 Pazopanib
 Pegaspargase

Alkylating Agents

Basic Mechanism of Action -- The alkylating agents, by chemical interactions, form

covalent links with DNA. This causes "mistakes" in the DNA that may result in
mispairing, substitutions, or excision. The cellular response of these mistakes may
inhibit DNA synthesis and proliferation or they may result in apoptosis as described
above. Alkylating agents may be broadly categorised as monofunctional (those that
result in one covalent link) or bifunctional (cause two covalent links with DNA,
either on one strand or by cross-linking the two strands). Monofunctional agents are
typically mutagenic or carcinogenic while bifunctional agents exhibit greater
cytotoxic activity. Alkylating agents are non-cell-cycle specific, but they are more
active in the G1/S phases of the cell life.
 Typically, non-proliferating cells repair DNA damage readily. Rapidly proliferating
cells are much less efficient in repair. Additionally, the higher the dose, the more
damage to DNA, and therefore the higher the chance of cellular death. (This is why
the highest dose possible is administered.) Given the decreased efficiency of DNA
repair in rapidly proliferating cells, such as neoplastic cells, the higher dose accounts
for greater activity.

General Toxicity -- The most common side effects of alkylating agents are GI upset
and bone marrow suppression. The profile of myelosuppression differs among the
different classes of alkylating agents, with nitrogen mustards producing a rapid
suppression (nadir within 6-10 days) and recovery (2-3 weeks) and nitrosoureas
producing a suppression of slower onset (nadir at 4-6 weeks) and recovery. Less
common but potentially lethal and irreversible effects include pulmonary fibrosis,
veno-occlusive disease of the liver, renal failure (nitrosoureas), and neurotoxicity.
They may also produce menstrual irregularities and oligospermia. The side effect
profiles for individual drugs may differ, as do their efficacy in specific neoplasias.

Meclorethamine IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., 2-chloro-N-(2-
Int. P., N.F., Ind. P chloroethyl)-N-
methyl-ethanamine

Class of drug and specific uses:

In combination with vincristine (Oncovin®), procarbazine, and prednisone (MOPP) for

Hodgkin's disease.
MOA:

Synthesis:

Metabolism: Toxic reactions:

GI upset, lacrimation, local damage (irritation, sloughing,

necrosis) if extravasation occurs (this may be diminished by
the administration of sodium thiosulphate, which binds to
 the drug, limiting its interaction with local tissue). DLT is
myelosuppression (bone marrow suppression, BMS).
Assay method: Reagents /Conditions Used:

Cyclophosphamide IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., N,N-bis(2-
Int. P., N.F., Ind. P chloroethyl)-1,3,2-
oxazaphosphinan-
2-amine 2-oxide

Class of drug and specific uses:

Lymphoma, chronic leukæmia, numerous carcinomas, non-Hodkin's lymphoma, breast

cancer, multiple myeloma, neuroblastoma and retinoblastoma in children, and lung,
cervical, ovarian, and testicular cancers.
MOA:

Synthesis:

Metabolism: Toxic reactions:

Alopecia (high incidence), GI upset, pulmonary fibrosis.

DLT is cardiotoxicity. Other toxicities include a syndrome
of inappropriate ADH (SIADH), ridging of nails, and
hæmorrhagic cystitis. The hæmorrhagic cystitis may be
diminished by the administration of 2-mercaptoethane
sulphonate or MESNA, which donates sulphydryl groups to
inactive the drug.
Assay method: Reagents /Conditions Used:
Ifosfamide IUPAC Name Structure Formulation
and dose:
B.P., U.S.P., Eur. P., N-3-bis(2-
Int. P., N.F., Ind. P chloroethyl)-1,3,2-
oxazaphosphinan-
2-amide-2-oxide

Class of drug and specific uses:

Germ cell testicular cancer, sarcomas, and also effective in most cancers that respond to
cyclophosphamide.
MOA:

Synthesis:

Metabolism: Toxic reactions:

DLT is nephrotoxicity. Others include neurotoxicity

(coma, death), GI upset, and myelosuppression.
Nephrotoxicity may be diminished by 2-MESNA.
Assay method: Reagents /Conditions Used:

Melphalan IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. 4-
P., Int. P., N.F., [bis(chloroethyl)amino]phe
Ind. P nylalanine
Class of drug and specific uses:

Multiple myeloma, breast and ovarian cancers

MOA:

Synthesis:

Metabolism: Toxic reactions:

DLT = BMS, GI upset (but less than others of the class)

Assay method: Reagents /Conditions Used:

IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P.,
4-[bis(2- and dose:
Int. P., N.F., Ind. P
chlorethyl)amino]
benzenebutanoic
acid
Class of drug and specific uses:

Chronic lymphocytic leukemia, Hodkin's and non-Hodkin's lymphoma,

macroglobulinæmia
MOA:

Synthesis:

Metabolism: Toxic reactions: Slow acting

Relatively (to other antineoplastics) side effect free,

Pulmonary toxicity is rare, low incidence of GI side effects.
Assay method: Reagents /Conditions Used:
Ethylenimines/Methylmelamines

Thiotepa IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., 1,1',1''-
Int. P., N.F., Ind. P phosphorothioyltriaziridine

Class of drug and specific uses:

Bladder, breast, and ovarian cancers

MOA:

Synthesis:

Metabolism: Toxic reactions:

bone marrow depression,
causing leucopenia, thrombocytopenia, and anemia
Assay method: Reagents /Conditions Used:

Altretamine IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., N2,N2,N4,N4,N6,N6-
Int. P., N.F., Ind. P hexamethyl-1,3,5-
triazine-2,4,6-
triamine
Class of drug and specific uses:

Ovarian cancer
MOA:

Synthesis:

Metabolism: Toxic reactions:

DLT = Neurotoxicity, also GI upset, leukæmia

Assay method: Reagents /Conditions Used:

Busulfan IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., butane-1,4-diyl
Int. P., N.F., Ind. P dimethanesulfonate
Class of drug and specific uses:

Chronic granulocytic leukæmia

MOA:

Synthesis:

Metabolism: Toxic reactions:

Low dose, relatively toxicity free except for BMS; High dose,
DLT = GI Upset, also pulmonary fibrosis, Addison-like syndrome
(with sufficient levels of glucocorticoids).

Assay method: Reagents /Conditions Used:

Nitrosoureas -- These agents are bifunctional alkylating agents and are also highly
lipophilic

Carmustine IUPAC Name Structure Formulation

(BCNU) N,N'-bis(2- and dose:
B.P., U.S.P., Eur. P., chloroethyl)-N-
Int. P., N.F., Ind. P nitroso-urea

Class of drug and specific uses:

Hodkin's and non-Hodkin lymphoma, brain tumours, multiple myeloma, malignant

melanoma
MOA:

Synthesis:
Metabolism: Toxic reactions:

DLT = Pulmonary fibrosis, Liver and Renal Failure. Also,

GI upset, flushing, and delayed BMS
Assay method: Reagents /Conditions Used:

Lomustine IUPAC Name Structure Formulation

(CCNU) N-(2-chloroethyl)- and dose:
B.P., U.S.P., Eur. P., N'-cyclohexyl-N-
Int. P., N.F., Ind. P nitrosourea

Class of drug and specific uses:

Hodkin's and non-Hodkin lymphoma, brain tumours, multiple myeloma, malignant

melanoma, and small cell lung cancer
MOA:

Synthesis:
Metabolism: Toxic reactions:

DLT = Pulmonary fibrosis, Liver and Renal Failure. Also,

GI upset, flushing, and delayed BMS
Assay method: Reagents /Conditions Used:

Semustine IUPAC Name Structure Formulation

(methyl- or Me- N-(2-Chloroethyl)- and dose:
CCNU) N'-(4-
methylcyclohexyl)-
B.P., U.S.P., Eur. P., N-nitrosourea
Int. P., N.F., Ind. P

Class of drug and specific uses:

Primarily brain tumour, stomach and colon cancer. Also effective in the cancers treated
by CCNU.
MOA:

Synthesis:

Metabolism: Toxic reactions:

DLT = Pulmonary fibrosis, Liver and Renal Failure. Also,

GI upset, flushing, and delayed BMS
Assay method: Reagents /Conditions Used:

Anticancer agents

Streptozotocin IUPAC Name Structure Formulation

(streptozocin) and dose:
B.P., U.S.P., Eur. 2-deoxy-2-
P., Int. P., N.F., ({[methyl(nitroso)amino]carbonyl}amino)-
Ind. P β-D-glucopyranose
Class of drug and specific uses:

Pancreatic islet cell tumour (streptozotocin has a high specificity of action, compleatly
and irreversibly killing beta cells of the islets of Langerhans -- therefore it is effective in
treating insulin-secreting cancers of these cells -- it is also used experimentally to
produce DM in laboratory animals), malignant carcinoid, and Hodgkin's lymphoma

MOA:

Synthesis:

Metabolism: Toxic reactions:

DLT = Nephrotoxicity. Also, GI upset, hepatotoxicity

and BMS.
Assay method: Reagents /Conditions
Used:

Chlorozotocin IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., 1-(2-Chloroethyl)-1- and dose:
Int. P., N.F., Ind. P nitroso-3-
[(2R,3R,4S,5R)-
3,4,5,6-
tetrahydroxy-1-
oxohexan-2-yl]urea

Class of drug and MOA:

specific uses: Exhibits relatively low incidence of BMS.
Rarely used, it has
no effect on beta
cells of the
pancreas

Synthesis:
Metabolism: Toxic reactions:

Assay method: Reagents /Conditions Used:

Triazene
Dacarbazine IUPAC Name Structure Formulation
5-(3,3-Dimethyl-1- and dose:
B.P., U.S.P., Eur. P., triazenyl)imidazole-
Int. P., N.F., Ind. P 4-carboxamide

Class of drug and MOA:

specific uses: Malignant melanoma, Hodkin's lymphoma, soft tissue cancers, and
sarcomas

Synthesis:

Metabolism: Toxic reactions:

GI upset, mild to moderate BMS, flu-like syndrome

Assay method: Reagents /Conditions Used:

Antimetabolites
 Folate Antagonists --

Methotrexate IUPAC Name Structure Formulation

B.P., U.S.P., Eur. (2S)-2-[(4-{[(2,4-diaminopteridin-6- and dose:
P., Int. P., N.F., yl)methyl](methyl)amino}phenyl)formamido]
Ind. P pentanedioic acid

Class of drug and specific uses:

Acute lymphocytic leukæmia (children typically respond better than adults in this use of
methotrexate), choriocarcinoma, mycosis fungoides, osteogenic sarcoma, and breast, head,
and neck cancers.
MOA:
Methotrexate inhibits dihydrofolate reductase to
1) decrease the synthesis of thymidylate, a necessary component of DNA,
2) increase the intracellular levels of dihydrofolate polyglutamates, that decrease de
novo synthesis of purines (see previous notes on the significance of this action), and
3) the standard action of DHF reductase inhibition as previously described. Methotrexate is
primarily active during the S phase of the cell cycle. If the effects of methotrexate become
body wide, serious toxicity may endanger the life of the patient. (RECALL that in the
synthesis of DNA, THF serves as methyl donor/recipients and is interconverted to DHF in
the process. It must be reduced to regenerate THF for re-use.) The toxic effects of
methotrexate may be reversed by the administration of leucovorin, which is a fully reduced
folate co-factor. Leucovorin "rescue" is used (either prophylactically as part of the standard
antineoplastic regimen or therapeutically, if toxicity has occurred) when methotrexate
toxicity has "escaped" to systemic circulation.

Synthesis:
Metabolism: Toxic reactions:

BMS (nadir at 5-10 days) and GI upset. Also, alopecia and

pneumonitis. Chronic side effects (seen with methotrexate
as a immunosuppressant in rheumatoid arthritis or psoriasis)
include hepatic fibrosis and cirrhosis.
Assay method: Reagents /Conditions
Used:

Pyrimidine Antagonists

5-Fluorouracil IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., 5-fluoro-1H- and dose:
Int. P., N.F., Ind. P pyrimidine-2,4-
dione

Class of drug and specific uses:

Breast, GI, ovarian, cervical, bladder, prostate, and pancreatic cancers and hepatoma.
MOA:

these drugs are analogues of uridine

Mechanism of Action -- Both of these agents are metabolised in vivo to F-UTP and F-dUTP
which inhibit RNA and DNA synthesis respectively (refer to the mechanism of action of the
antifungal flucytosine). The pharmacodynamic effects of RNA and DNA inhibition have been
covered previously in this course (see Anti-viral section). NOTE that there are numerous
biochemical pathways that produce these metabolites. One of these pathways is folate
dependent. Therefore, the administration of leucovorin will enhance the formation of the
metabolites and increase the efficacy of the drugs.
Synthesis:

Metabolism: Toxic reactions:

GI upset and delayed BMS. NOTE that the BMS is delayed

7-14 days. If the drug is continued to that point, serious
toxicity could result. Therefore, administration should stop
when stomatitis and diarrhœa occur (earlier GI effects
include anorexia and nausea), to avoid excessive BMS.
May also see cardiotoxicity that is ischæmic in nature.
Assay method: Reagents /Conditions Used:

Floxuridine IUPAC Name Structure Formulation

B.P., U.S.P., 5-Fluoro-1-[4-hydroxy-5- and dose:
Eur. P., Int. P., (hydroxymethyl)tetrahydrofuran-
N.F., Ind. P 2-yl]-1H-pyrimidine-2,4-dione

Class of drug and specific uses : Colon cancer

MOA: same as 5FU
Synthesis:
Metabolism: Toxic reactions:
Same as 5FU

Assay method: Reagents /Conditions Used:

Cytarabine IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., 4-amino-1- and dose:
Int. P., N.F., Ind. P [(2R,3S,4R,5R)-3,4-
dihydroxy-5-
(hydroxymethyl)oxolan-
2-yl] pyrimidin-2-one

Class of drug and specific uses:

Acute granulocytic and lymphocytic leukæmias.

MOA:

activated to the nucleotide form to substitute for CTP, inhibiting DNA chain elongation,
as previously described.

Synthesis:
Metabolism: Toxic reactions:

DLT = Neurotoxicity (especially in older adults). Also,

BMS, GI upset.
Assay method: Reagents /Conditions Used:
 Purine Antagonists
Mechanism of Action -- The MOA of purine antagonists is complex and does
not appear to be totally dependent upon incorporation into DNA. Similar to
other nucleotide analogues, they must first be phosphorylated. After this step,
purine antagonists appear to substitute for guanine or adenosine to
decrease/inhibit metabolic reactions that are necessary to form the guanine or
adenine that will be incorporated into DNA. At least three different enzymes
have been identified that may be inhibited by these drugs. These actions
ultimately inhibit DNA synthesis. Thioguanine may also inhibit glycoprotein
synthesis, thus decreasing the membrane integrity of the cell.

6-Mercaptopurine IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., 3,7-dihydropurine-
Int. P., N.F., Ind. P 6-thione

Class of drug and specific uses:

Leukæmias
MOA:

Synthesis:

Metabolism: Toxic reactions:

BMS (slow onset), GI upset (25% of patients), jaundice
(33%), and hyperuricæmia and hyperuricosuria. The latter
two effects could increase the incidence of gouty attacks in
patients so predisposed. NOTE that allopurinol will
INCREASE the plasma urate levels if co-administered
(indeed, it was originally designed as an adjunct to 6-MP
therapy, to increase its effectiveness -- only later was the
therapeutic benefit in gout realised). Therefore, it should
 not be used in gouty patients who are also receiving 6-MP
chemotherapy.
Assay method: Reagents /Conditions Used:

Azathioprine IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., 6-[(1-methyl-4- and dose:
Int. P., N.F., Ind. P nitro-1H-imidazol-5-
yl)sulfanyl]-7H-
purine

Class of drug and MOA:

specific uses: 6-MP derivative and works in a similar manner
Immunosuppressive

Synthesis:

Metabolism: Toxic reactions:

Assay method: Reagents /Conditions Used:

Thioguanine IUPAC Name Structure Formulation
B.P., U.S.P., Eur. P., and dose:
Int. P., N.F., Ind. P 2-amino-7H-purine-
6-thiol

Class of drug and MOA:

specific uses:

Leukæmias

Synthesis:

Metabolism: Toxic reactions:

BMS, GI upset

Assay method: Reagents /Conditions Used:

Anticancer agents

Fludaribine IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., [(2R,3R,4S,5R)-5-(6- and dose:
Int. P., N.F., Ind. P amino-2-fluoro-purin-
9-yl)- 3,4-dihydroxy-
oxolan-2-
yl]methoxyphosphonic
acid
Class of drug and specific uses:

Chronic lymphocytic leukæmia

MOA:

Fludaribine inhibits DNA polymerase, DNA primase, ribonucleotide reductase, and is

incorporated into DNA/RNA. All of these actions will result in damage to DNA, leading to
decreased proliferation and/or cell death.

Synthesis:

Metabolism: Toxic reactions:

BMS, GI upset, chills, fever, neurotoxicity, and pulmonary

toxicity (increased with co-administration of pentostatin)
Assay method: Reagents /Conditions Used:
Cladribine IUPAC Name Structure Formulation
B.P., U.S.P., Eur. P., and dose:
Int. P., N.F., Ind. P 5-(6-amino-2-chloro-
purin-9-yl)-2-
(hydroxymethyl)oxolan-
3-ol

Class of drug and specific uses:

Cladribine is the drug of choice of hairy cell leukæmia (due to its high efficacy and low
incidence of side effects)
MOA:

Similar to fludaribine, incorporation may cause strand breaks in DNA and it may also
decrease NAD/ATP mediated reactions.

Synthesis:

Metabolism: Toxic reactions:

DLT = BMS, nausea

Assay method: Reagents /Conditions Used:

Pentostatin IUPAC Name Structure Formulation
(8R)-3-(2-deoxy-β-D- and dose:
B.P., U.S.P., Eur. P., erythro-
Int. P., N.F., Ind. P pentofuranosyl)-
3,4,7,8-
tetrahydroimidazo[4,5-
d][1,3]diazepin-8-ol

Class of drug and specific uses:

hairy cell leukæmia and chronic lymphocytic leukæmia

MOA:

Pentostatin inhibits adenosine deaminase to increase intracellular levels of adenosine

and deoxyadenosine nucleotides. This, in turn, causes decreased DNA synthesis by
decreasing ribonucleotide reductase activity and by decreasing S-adenosyl homocysteine
hydrolase activity (this is inhibited specifically by deoxyadenosine nucleotides).
Inhibition of SAH hydrolase activity will increase intracellular levels of S-adenosyl
homocysteine, which is directly cytotoxic. Pentostatin also inhibits RNA synthesis and
is incorporated into DNA.

Synthesis:
Obtained via fermentation of Streptomyces antibioticus

Metabolism: Toxic reactions:

DLT = neurotoxicity, nephrotoxicity. Also, BMS, GI upset,

rash, and hepatotoxicity.
Assay method: Reagents /Conditions Used:
Natural Products
Anti-Mitotic Agents

Vinblastine IUPAC Name Structure Formulation

dimethyl and dose:
B.P., U.S.P., (2β,3β,4β,5α,12β,19α)- 15-
Eur. P., Int. P.,
[(5S,9S)- 5-ethyl- 5-hydroxy- 9-
N.F., Ind. P (methoxycarbonyl)-
1,4,5,6,7,8,9,10-octahydro-
2H- 3,7-
methanoazacycloundecino[5,4-
b]indol- 9-yl]- 3-hydroxy- 16-
methoxy- 1-methyl- 6,7-
didehydroaspidospermidine-
3,4-dicarboxylate
Class of drug and specific uses:

metastatic testicular cancer (often in combination with bleomycin and cisplatin) and
lymphoma
MOA:

The vinca alkaloids block cellular mitosis by directly binding to and inhibiting tubulin
formation, specifically during metaphase. Therefore, these agents inhibit cell
replication.

Synthesis:

Metabolism: Toxic reactions:

BMS (nadir - 7 days, recovery - 14 days), SIADH (rare),

alopecia, and sloughing/necrosis with extravasation
Assay method: Reagents /Conditions Used:

IUPAC Name
Vincristine Structure Formulation
methyl (1R,9R,10S,11R,12R,19R)- 11- and dose:
B.P., (acetyloxy)- 12-ethyl- 4-[(13S,15S,17S)- 17-
U.S.P., ethyl- 17-hydroxy- 13-(methoxycarbonyl)- 1,11-
Eur. P., diazatetracyclo[13.3.1.04,12.05,10]nonadeca-
Int. P., 4(12),5,7,9-tetraen- 13-yl]- 8-formyl- 10-
N.F., hydroxy- 5-methoxy- 8,16-
Ind. P diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-
2,4,6,13-tetraene- 10-carboxylate

Class of drug and specific uses:

Hodkin's and non-Hodkin lymphoma, pediatric leukæmias, numerous solid tumours

MOA:
Same as vinblastine

Synthesis:

Metabolism: Toxic reactions:

Neurotoxicity (including paralysis of vocal cords and eye

muscles, and seizures), sloughing, alopecia, and at high doses,
constipation (probably due to neurotoxicity). Vincristine
produces minimal BMS.
Assay method: Reagents /Conditions
Used:

IUPAC Name
Vinorelbine Structure Formulation

4-(acetyloxy)- 6,7-didehydro- 15- and dose:

B.P.,
U.S.P., ((2R,6R,8S)-4-ethyl- 1,3,6,7,8,9-
Eur. P., hexahydro- 8-(methoxycarbonyl)- 2,6-
Int. P., methano- 2H-azecino(4,3-b)indol-8-yl)-
N.F.,
Ind. P 3-hydroxy- 16-methoxy- 1-methyl- methyl
ester,

(2beta,3beta,4beta,5alpha,12R,19alpha)-
aspidospermidine- 3-carboxylic acid
Class of drug and specific uses:

Non-small cell lung cancer

MOA:

Synthesis:

Metabolism: Toxic reactions:

Less BMS suppression that vinblastine and less neurotoxicity

than vincristine, venorelbine has moderate adverse effects,
 including sloughing and alopecia.
Assay method: Reagents /Conditions Used:

Yew Derivatives -- Paclitaxel (Taxol) and Docetaxel -- These agents are derived from the
Western or Pacific yew, Taxus brevifolia.

Paclitaxel IUPAC Name Structure Formulation

B.P., U.S.P., Eur. (2α,4α,5β,7β,10β,13α)- and dose:
P., Int. P., N.F., Ind. 4,10-bis(acetyloxy)-13-
P {[(2R,3S)- 3-
(benzoylamino)-2-
hydroxy-3-
phenylpropanoyl]oxy}-
1,7-dihydroxy-9-oxo-
5,20-epoxytax-11-en-
2-yl benzoate

Class of drug and specific uses:

Ovarian and breast cancers, but also may be effective in head, neck, lung, œsophageal,
and bladder cancers.
MOA:

These drugs bind to and inhibit the beta-tubulin subunit, causing tubulin disassembly.
Rather that inhibiting tubulin synthesis, the yew derivatives cause the formation of
bunches or bundles of tubulin (preventing the linear tubulin formation that is required
for mitosis), thus inhibiting mitosis.

Synthesis:
Metabolism: Toxic reactions:

BMS (nadir - 8-11 days; recovery, 15-21 days). If G-CSF

(filgrastim) is co-administered, then the DLT is
neurotoxicity. These agents may also cause bradycardia
(early) and silent ventricular tachycardia (late). This is
generally not a problem unless the patient has pre-existing
arrhythmias.
Assay method: Reagents /Conditions Used:

Clinical Note -- In combination therapy, the other antineoplastic chosen is important.

Cisplatin administered prior to taxol will result in increased efficacy of taxol. However,
doxorubicin prior to taxol will result in decreased efficacy and increased toxicity.
Resistance may develop to taxol. Curiously, if this does occur, then the tumour will then
exhibit increased sensitivity to the vinca alkaloids.

Epipodophyllotoxins -- These compounds are derived from the mandrake (or

mayapple), Podophyllum peltatum.

Etoposide IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., and dose:
Int. P., N.F., Ind. P 4'-demethyl-
epipodophyllotoxin
9-[4,6-O-(R)-
ethylidene-beta-D-
glucopyranoside],
4' -(dihydrogen
phosphate)

Class of drug and specific uses:

Testicular, breast and small-cell lung cancers, non-Hodkin lymphoma, leukæmia, and
Kaposi's sarcoma.
MOA: The epipodophyllotoxins form a ternary complex with DNA and topoisomerase
II, causing double-strand breakage (mediated by the topoisomerase) that cannot be
repaired (this is usually due to the drug binding to the "broken" end of the DNA chain).
This in turn, causes an accumulation of DNA breaks and subsequent cell death via
apoptosis.
Synthesis:
Metabolism: Toxic reactions:

BMS (nadir - 10-14 days; recovery - 21 days), GI upset,

alopecia
Assay method: Reagents /Conditions Used:

Teniposide IUPAC Name Structure Formulation

(5R,5aR,8aR,9S)-5,8,8a,9- and dose:
B.P., U.S.P., Eur. P., Tetrahydro-5-(4-hydroxy-3,5-
Int. P., N.F., Ind. P dimethoxyphenyl)-9-({4,6-O-
[(R)-2-thienylmethylene]-β-D-
glucopyranosyl}oxy)furo[3',4':6,7
]naphtho[2,3-d]-1,3-dioxol-
6(5aH)-one
Class of drug and specific uses:

Primarily used for refractory acute lymphocytic leukæmia in children

MOA:

Synthesis:

Metabolism: Toxic reactions:

BMS, GI upset

Assay method: Reagents /Conditions Used:

Etopophos IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., [5R-[5a,5a~,8aa,9~(R*)]]-5-[3,5-
Int. P., N.F., Ind. P
dimethoxy-4-
(phosphonooxy)phenyl]-9-[(4,6-
 O-ethylidene βD

glucopyranosyl)oxy]-5,8,8a,9-
tetrahydrofuro[3',4':6,7]naphtho[
2,3-d]- 1,3-dioxol-6(5aH)-one
disodium

sallt

Class of drug and specific uses:

Refractory testicular cancers, small cell lung carcinoma

MOA:
DNA Topoisomerase II inhibition and G2 phase arrest

Synthesis:

Metabolism: Toxic reactions:

BMS, GI upset, renal falure

Assay method: Reagents /Conditions Used:

Actinomycin D IUPAC Name Structure Formulation
(Dactinomycin) and dose:
2-amino-N,N'-
B.P., U.S.P., Eur. bis[(6S,9R,10S,13R,18aS)-
P., Int. P., N.F., 6,13-diisopropyl- 2,5,9-
Ind. P
trimethyl- 1,4,7,11,14-
pentaoxohexadecahydro-
1H-pyrrolo[2,1-i]
[1,4,7,10,13]
oxatetraazacyclohexadecin-
10-yl]- 4,6-dimethyl- 3-oxo-
3H-phenoxazine- 1,9-
dicarboxamide
Class of drug and specific uses:

Rhabdomyosarcoma, Wilm's tumour, Choriocarcinoma, testicular cancer, and Kaposi's

sarcoma
MOA:

Dactinomycin intercalates with DNA (situates itself within the groove or trough formed
by the double helix) to prevent DNA transcription by RNA polymerase. This inhibits
RNA synthesis and subsequent protein synthesis as well as cell replication. Additionally,
Dactinomycin causes strand breaks by decreasing topoisomerase II activity.

Synthesis:
From cultures of Actinomyes antibioticus and chromatographic purification on A120,

Metabolism: Toxic reactions:

GI upset, alopecia, inflammation with extravasation

Assay method: Reagents /Conditions Used:

Anthracycline Antibiotics
Daunorubicin IUPAC Name Structure Formulation
(daunomycin, (8S,10S)-8-acetyl- and dose:
rubidomycin) 10-[(2S,4S,5S,6S)-
4-amino-5-hydroxy-
B.P., U.S.P., Eur. P., 6-methyl-oxan-
Int. P., N.F., Ind. P 2-yl]oxy-6,8,11-
trihydroxy-1-
methoxy-
9,10-dihydro-7H-
tetracene-5,12-
dione

Class of drug and specific uses:

Primarily used for leukæmias

MOA:

DNA intercalation, preventing DNA and RNA synthesis, single and double stranded
breaks (via topoisomerase II). Additionally, the anthracycline antibiotics form free
radicals (ferrous ion and oxygen are necessary catalysts for their formation) which may
directly damage DNA, RNA, or cellular components, accounting at least in part for the
cytotoxic effects of the drugs. This free radical formation is probably responsible for the
cardiotoxicity associated with these drugs, through damage to the contractile structures
of the myocardium. Free radical formation may be minimised (with concurrent
reduction in free radical toxicity and free radical cytotoxicity) by the administration of
an anti-oxidant (alpha-tocopherol or amifostine, formerly known as ethiofos) or an iron
chelating agent (dexrazoxane).

Synthesis:
Fermentation of Streptomyces peucefius.

Metabolism: Toxic reactions:

DLT = cardiotoxicity (manifest early as arrhythmia, late as

congestive failure that does not respond to digoxin). Also --
pain, irritation, and sloughing with extravasation; BMS, GI
upset, and alopecia.
Assay method: Reagents /Conditions Used:
Doxorubicin IUPAC Name Structure Formulation
(doxomycin) and dose:
(8S-cis)-l0-[(3-
B.P., U.S.P., Eur. P., amino-2,3,6-
Int. P., N.F., Ind. P trideoxy-a-L-lyxo-
hexopyanosyl)oxy]-
7,8,9,l0-tetrahydro-
6,8,11-

trihydroxy-8-
(hydroxyacety1)- I-
methoxy-5,12-
naphthacenedion

Class of drug and specific uses:

Broader spectrum of activity, used in several solid tumours

MOA:
Same as daunorubicin

Synthesis:
From culture of mutant F. 1. 106 of Streptomyces peucetius va,: caesius
Metabolism: Toxic reactions:

DLT = cardiotoxicity (manifest early as arrhythmia, late as

congestive failure that does not respond to digoxin). Also --
pain, irritation, and sloughing with extravasation; BMS, GI
upset, and alopecia. Doxorubicin also produces a benign
allergic reaction referred to as the "doxorubicin flare".

Assay method: Reagents /Conditions Used:

Idarubicin IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., (7S-cis)-9-acetyl-7-
Int. P., N.F., Ind. P [(3-amino-2,3,6-
trideoxy--~-lyxo-
hexopyranosyl)oxy]-
7,8,9,IO-tetrahydro-
 6,9,11-

trihydroxy-5,12-
naphthacenedione

Class of drug and specific uses:

Most often used in combination with cytarabine for leukæmias

MOA:

Synthesis:
Metabolism: Toxic reactions:

Similar to others in the class, but less incidence

Assay method: Reagents /Conditions Used:

Valrubicin IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., 2-oxo-2-[(2S,4S)-
Int. P., N.F., Ind. P
2,5,12-trihydroxy-7-
methoxy-6,11-dioxo-
4-({2,3,6-trideoxy-3-
[(trifluoroacetyl)amino]
hexopyranosyl}oxy)-
1,2,3,4,6,11-
hexahydrotetracen-
2-yl]ethyl pentanoate
Class of drug and specific uses:

Used primarily in the treatment of refractory bladder cancer that is unresponsive to BCG
MOA:
It’s a semisynthetic analogue of doxorubicin and possess same MOA

Synthesis:
Metabolism: Toxic reactions:

Blood in urine, incontinence and painful urination

Assay method: Reagents /Conditions Used:

Mitoxantrone IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., and dose:
Int. P., N.F., Ind. P 1,4-dihydroxy-5,8-
bis[2-(2-
hydroxyethylamino)
ethylamino]-
anthracene-9,10-
dione

Class of drug and specific uses:

Mitoxantrone has limited activity in leukæmias and breast cancer

MOA: derivatives of the anthracycline antibiotics
The anti-neoplastic effects of mitoxantrone are due to DNA intercalation. It does not
exhibit the degree of free radical formation and therefore essentially lacks the
cardiotoxic effects of others in the class.

Synthesis:

Metabolism: Toxic reactions:

BMS and less GI upset and alopecia than others in the class
Assay method: Reagents /Conditions Used:

Epirubicin IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., and dose:
Int. P., N.F., Ind. P 10-(4-amino-5-
hydroxy-6-
methyl-oxan-2-yl)
oxy-6,8,11-
trihydroxy-8-(2-
hydroxyacetyl)-
1-methoxy-9,10-
dihydro-7H-
tetracene-5,12-
dione
Class of drug and specific uses:

MOA:
DNA intercalation, free radical generation and Topoisomerase II activity m,odulation leading to DNA strand
scission and cell death

Synthesis:
Metabolism: Toxic reactions:

Assay method: Reagents /Conditions Used:

Bleomycin IUPAC Name Structure Formulation

(Blenoxane) and dose:

B.P., U.S.P., Eur. P.,

Int. P., N.F., Ind. P
Class of drug and specific uses:

-- Squamous cell carcinoma, œsophageal cancer, testicular and ovarian cancer, and both
Hodgkin's and non-Hodgkin lymphoma.
MOA: DNA cleavage by bleomycin depends on oxygen and metal ions, at
least in vitro. It is believed that bleomycin chelates metal ions (primarily iron)
producing a pseudoenzyme that reacts with oxygen to produce superoxide
and hydroxide free radicals that cleave DNA
Bleomycin binds to DNA and is bioactivated through the catalysts ferrous iron and
oxygen to generate free radicals. These free radicals then cause DNA scission. The
effects are primarily dominant during the G2 phase, appearing as changes in the
chromosomes, chromatid breaks, and DNA gaps, fragments, and misrepair

Synthesis:

From culture of Streptornyces verticillus by ion-exchange adsorption and column chromatographic

purification

(on alumina) via the copper complex

Metabolism: Toxic reactions:

DLT = Pulmonary fibrosis, often preceded by dry cough

and rales. Others include cutaneous toxicity
(hyperpigmentation, hyperkeratosis, erythema, ulceration).
Bleomycin produces minimal BMS.
Assay method: Reagents /Conditions Used:

Plicamycin IUPAC Name Structure Formulation

(Mithramycin) and dose:

B.P., U.S.P., Eur. P.,

Int. P., N.F., Ind. P
Class of drug and specific uses:

Testicular cancer and, at low doses, Paget's disease of bone

MOA:

DNA intercalation, similar to others of the antibiotic class, to decrease RNA synthesis.
Additionally, plicamycin directly interacts with osteoclasts to reduce bone resorption.
The exact mechanism of this action is not know.

Synthesis:
Antibiotic obtained from Streptomyces plicatus

Metabolism: Toxic reactions:

Antineoplastic doses cause severe BMS, nephrotoxicity and

hepatotoxicity (which includes a reduction of liver-
mediated synthesis of clotting factors). Other side effects
include epistaxis (from the reduction of clotting factors).
Side effects at lower doses (for Paget's disease) are
relatively rare
Assay method: Reagents /Conditions Used:

Mitomycin IUPAC Name Structure Formulation

and dose:
B.P., U.S.P.,
Eur. P., Int. P., [I aR-(laa,8~,8aa,8ba)]-6-amino-8-
N.F., Ind. P [[(aminocarbonyl)oxy]methy1]-1 ,I
 a,2,8,8a,8b-hexahydro-8a-

methoxy-5-
methylazirino[2',3':3,4]pyrrolo~1,2-
a]indole-4,7-d

Class of drug and specific uses:

Mitomycin is used primarily in combination with 5-FU, cisplatin, or doxorubicin for the
treatment of cervical, colorectal, breast, bladder, and lung cancers
MOA:

Mitomycin is converted in vivo to an active metabolite by either reduction of the

quinone portion of the structure or loss of the methoxy group. The resulting compound
acts as an alkylating agent to decrease DNA synthesis, increase cross-linking of DNA,
and to cause single-strand breakage

Synthesis:

From culture of Streptomyces caespitosus; column chromatographic purification

Metabolism: Toxic reactions:

DLT = Hæmolytic/uremic syndrome (due to endothelial

damage of the red cells and renal epithelium). Other
toxicities include pulmonary fibrosis, cardiotoxicity, GI
upset, and slow onset BMS (nadir, 6-8 weeks).

Assay method: Reagents /Conditions

Used:

Enzymes
L-Asparaginase IUPAC Name Structure Formulation
and dose:
B.P., U.S.P., Eur. P.,
Int. P., N.F., Ind. P

Class of drug and specific uses:

Used primarily in combination with other anti-neoplastics for the treatment of

leukæmias
MOA:

Most normal cells can synthesis the amino acid asparagine. However, many neoplastic
cells lack this capability and require exogenous sources of the amino acid. L-
Asparaginase catalyses the destruction of asparagine to the metabolic products aspartic
acid and ammonia, thereby depriving the neoplastic cell of asparagine and thus
inhibiting protein synthesis, which leads to cell death by apoptosis

Synthesis:

Metabolism: Toxic reactions:

Hypersensitivity, very few "typical" antineoplastic effects.

However decreases in protein synthesis may lead to insulin
deficiency and clotting factor deficiency
Assay method: Reagents /Conditions Used:

Clinical Note -- The order of combination therapy is important with L-Asparaginase.

For example, methotrexate prior to L-asparaginase increases the cytotoxic activity and
side effect incidence. However, L-asparaginase prior to methotrexate reduces the
overall cytotoxic efficacy.

Miscellaneous Antineoplastics
Platinum Complexes
Cisplatin IUPAC Name Structure Formulation
and dose:
B.P., U.S.P., Eur. (SP-4-2)-
P., Int. P., N.F.,
Ind. P
diamminedichloridoplatinum

Class of drug and specific uses:

Ovarian, testicular, bladder, head, neck, and endometrial cancers

MOA:

These agents are bioactivated through substitution of chloride ions for hydroxyl groups.
The active moiety then interacts with DNA, forming both inter- and intra-strand links
(especially to the DNA base guanine), resulting in decreased DNA
replication/transcription, breaks, and miscodings. NOTE that hypochloræmic states will
increase the activity of these compounds while hyperchloræmia will reduce their
efficacy.

Synthesis:

Metabolism: Toxic reactions:

DLT = Ototoxicity and Neurotoxicity (note that

neurotoxicity may actually worsen after the drug is
discontinued). Other toxicities include nephrotoxicity (this
may be attenuated by hydration and diuresis), GI upset,
BMS, and electrolyte disturbances (probably mediated by
the liberated chloride ions).
Assay method: Reagents /Conditions Used:
Carboplatin IUPAC Name Structure Formulation
cis- and dose:
B.P., U.S.P., Eur. P.,
Int. P., N.F., Ind. P
diammine(cyclobutane-
1,1-dicarboxylate-
O,O')platinum(II)

Class of drug and specific uses:

The same as cisplatin

MOA:

Synthesis:

Metabolism: Toxic reactions:

Fewer toxicities that cisplatin, with the DLT = BMS

Assay method: Reagents /Conditions Used:

Clinical Note -- Platinum complexes should not be administered with or come in

contact with aluminium-containing needles or vials, since the platinum may interact
with the aluminium, inactivating the drug.
Hydroxyurea IUPAC Name Structure Formulation
and dose:
B.P., U.S.P., Eur. P., hydroxyurea
Int. P., N.F., Ind. P

Class of drug and specific uses:

Leukæmias, polycythemia vera (overproduction of erythrocytes), malignant melanoma.

Hydroxyurea is also used in the treatment of sickle cell anæmia to decrease hæmolysis.
This effect is mediated by an increase in the synthesis of hæmoglobin F (probably by a
separate mechanism, possibly increased expression of the Hgb F gene).
MOA:

Hydroxyurea inhibits the enzyme ribonucleotide reductase, thereby inhibiting the

conversion of ribonucleotide to deoxyribonucleotides. This inhibits DNA synthesis. Its
actions are specific for the G1 to S phase of the cell cycle, with the majority of effects
observed during the S phase. The action of hydroxyurea will greatly increase the
efficacy of radiation therapy.

Synthesis:

Metabolism: Toxic reactions:

Typical types of toxicity for antineoplastics

Assay method: Reagents /Conditions Used:

Procarbazine IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., N-isopropyl-4-[(2-
Eur. P., Int. P.,
N.F., Ind. P
methylhydrazino)methyl]benzamide
Class of drug and specific uses:

Hodkin's lymphoma
MOA:

Procarbazine methylates DNA, essentially acting in a manner similar to the alkylating

agents. Additionally, free radical formation may contribute to the action of
procarbazine. Both of these actions will decrease DNA, RNA, and protein synthesis

Synthesis:

Metabolism: Toxic reactions:

BMS, GI upset, neurotoxicity (including behavioural

changes), and a disulfiram-like reaction.
Assay method: Reagents /Conditions
Used:

Dacarbazine IUPAC Name Structure Formulation

and dose:
B.P., U.S.P., Eur. P., 5-(3,3-Dimethyl-1-
Int. P., N.F., Ind. P triazenyl)imidazole-
4-carboxamide
Class of drug and specific uses:

Metastatic melanoma, Hodgkin’s disease (ABVD regimen)

MOA:

Dacarbazine methylates DNA, essentially acting in a manner similar to the alkylating

agents. Additionally, free radical formation may contribute to the action of
procarbazine. Both of these actions will decrease DNA, RNA, and protein synthesis

Synthesis:

Metabolism: Toxic reactions:

BMS, GI upset, neurotoxicity (including behavioural

changes), and a disulfiram-like reaction.
Assay method: Reagents /Conditions Used:

Mitotane IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., and dose:
Int. P., N.F., Ind. P 1-chloro-2-[2,2-dichloro-
1-(4-
chlorophenyl)e~hyl]benze

Class of drug and specific uses:

Mitotane is used only for the treatment of adrenal gland tumour or ectopic tumours with
adrenal-like activity. It completely obliterates adrenal production of glucocorticoids,
mineralocorticoids, and adrenal gland-produced sex hormones
MOA:
A DDT derivative
The MOA of mitotane is not known

Synthesis:

Metabolism: Toxic reactions:

GI upset, CNS depression, dermatitis

Assay method: Reagents /Conditions Used:

Hormonal drugs are successfully used for complex treatment of malignant tumors. Tumors
can be both hormone-dependent, as well as hormone-sensitive.
Hormone-dependent tumors regress in the absence of hormonal activity. Consequently, it
is possible to both hinder and even prevent the development of hormone-dependent tumors
using drugs. In particular, the antiestrogen drug tamoxifen prevents stimulation of cancerous
breast tumor cells by estrogens. This also applies to aminoglutethimide, an inhibitor of
corticosteroid synthesis by the adrenal glands.
Hormone-sensitive tumors may regress, and frequently stop growth upon introduction of
certain hormones. The main hormone-sensitive forms of cancer are breast and prostate carcinoma,
lymphoma, and a few other forms of carcinomas.
Hormonal drugs that inhibit growth of certain human tumors are steroids, including androgens,
estrogens, progestins, and corticosteroids, although only glucocorticoids are used.
Moreover, neither cortisol nor cortisone are used to treat malignant tumors, but instead prednisone,
prednisolone, methylprednisolone, and dexametasone are used.
Hormonal drugs do not cure cancer, although they do exhibit pronounced palliative action,
with the exception of the cytotoxic action of glucocorticoids on lymphoid cells. In particular,
this concerns predinsone, which is used to treat lymphomas and certain leukemias in
combination therapy.
The exact mechanism of action of steroids is not fully known.

Androgens
Androgens are derivatives of testosterone (29.1.5), methyltestosterone (29.1.7), fluoxymesterone
(29.3.5), and testolactone (30.5.1), and are frequently used for palliative
treatment of breast cancer in post-menopausal women, for which hormone therapy is used.
The exact mechanism of the anticancer effect of androgens is not known. However, it is
presumed that androgens block cell growth by inhibiting transport of natural hormone into
the cell. Moreover, androgens can inhibit estrogen synthesis, thus depleting estrogen
reserves.

Estrogens
Estrogens, estrone (28.1.9), estradiol (28.1.17), ethynylestradiol (28.1.26), diethylstilbestrol
(28.1.33), and chlorotrianisene (30.5.2), are used for palliative treatment of postmenopausal
breast cancer, prostate cancer, and breast cancer in men. It is highly probable
that the mechanism of action is similar to the mechanism of action of androgens.

Progestins
Progestins, steroid compounds similar to progesterone, such as hydroxyprogesterone caproate
(28.3.6), medroxyprogesterone acetate (28.3.7), and megestrol acetate (28.3.7), are used for
palliative treatment of breast carcinomas and renal tumors. Progestins can have a direct local
effect on cells, and can simultaneously lower the quantity of leutenizing hormone.

Corticosteroids
Corticosteroids, synthetic steroid drugs made from the natural hormone hydrocortisone, and
particularly prednisone, are frequently used for combination therapy for treating severe and
chronic lymphocyte leukemia, Hodgkin’s and non-Hodgkin’s lymphomas, multiple
myeloma, and breast cancer. Corticosteroids exhibit an antitumor effect by binding with corticosteroid
receptors that exist in many cancerous lymphoma cells, which leads to inhibition
of both glucose transport and phosphorylation, which reduces the amount of energy necessary
for mitosis and protein synthesis, which, accordingly, leads to cell lysis.

Nonhormonal drugs
In addition to hormonal drugs, five other nonsteroids that have a direct relationship to this
section are also used in cancer chemotherapy. They are aminoglutethimide, flutamide,
mitotan, tamoxifen, and leuprolide.

Hormones and anti-hormones

Aminoglutethimide IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., (+/-)3-(4-aminophenyl)- and dose:
Int. P., N.F., Ind. P 3-ethyl-piperidine-2,6-
dione

Class of drug and specific uses:

palliative treatment of prostate carcinomas and
post-menopausal breast carcinomas
MOA:
1. It blocks aromatase in the generation of estrogens from androstenedione and
testosterone.
2. It blocks the conversion of cholesterol to pregnenolone by inhibiting the enzyme P450scc
and consequently decreases synthesis of all hormonally active steroids.
Synthesis:
Metabolism: Toxic reactions:

Assay method: Reagents /Conditions Used:

Flutamide IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P., 2-methyl-N-[4-nitro-3- and dose:
Int. P., N.F., Ind. P (trifluoromethyl)phenyl]-
propanamide

Class of drug and specific uses:

It facilitates a
reduction in size and density of the prostate gland, and it reduces the amount of metastases
in such cancer, for which it is used in palliative treatment of prostate gland cancer.
MOA:
Flutamide is a nonsteroid drug that possesses antiandrogenic action. It blocks androgens
from binding with target tissues, thus preventing androgen action. The mechanism of
action is possibly also linked with a halt in dihydrotestosterone transport.

Synthesis:

Metabolism: Toxic reactions:

Assay method: Reagents /Conditions Used:

Tamoxifen IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P.,
(Z)-2-[p-(1,2- and dose:
Int. P., N.F., Ind. P
diphenyl-1-
butenyl)phenoxy]N,N-
dimethylethylamine

Class of drug and specific uses:

Tamoxifen is used for palliative treatment of breast cancer in pre- and post-menopausal women.
MOA:
Tamoxifen is a competitive inhibitor of estradiol. It is used for palliative treatment of estrogen-
receptor positive breast cancer

Synthesis:
Metabolism: Toxic reactions:

Assay method: Reagents /Conditions Used:

Leuprolide IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P.,
5-oxo-L-prolyl-L- and dose:
Int. P., N.F., Ind. P
histadyl-L-tryptophyl-
L-seryl-L-tyrosyl- D-
leucil-
L-leucil-L-arginyl-N-
ethyl-L-prolinamide

Class of drug and specific uses:

prostate cancer or breast cancer, estrogen-dependent conditions (such asendometriosis[1] or uterine
[2]
fibroids), to treat precocious puberty, and to control ovarian stimulation in In Vitro Fertilization (IVF). It is
considered a possible treatment for paraphilias
MOA:
Leuprolide acts at pituitary GnRH receptors. It down regulates the secretion of gonadotropinsluteinizing
hormone (LH) and follicle-stimulating hormone (FSH) leading to a dramatic reduction in estradiol levels
Synthesis:

Metabolism: Toxic reactions:

Assay method: Reagents /Conditions Used:

IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P.,
and dose:
Int. P., N.F., Ind. P

Class of drug and MOA:

specific uses:

Synthesis:

Metabolism: Toxic reactions:

Assay method: Reagents /Conditions Used:

IUPAC Name Structure Formulation

B.P., U.S.P., Eur. P.,
and dose:
Int. P., N.F., Ind. P
Class of drug and MOA:
specific uses:

Synthesis:

Metabolism: Toxic reactions:

Assay method: Reagents /Conditions Used: