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ANTICANCER DRUGS III

PHARMACOLOGY IV
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Definition
 Myeloma: A malignant tumor of the bone marrow
 Myeloid leukemia : A type of leukemia affecting myeloid tissue
 Myeloid tissue: The soft, fatty, vascular tissue that fills most bone
cavities and is the source of red blood cells and many white blood
cells
 Adult acute myeloid leukemia (AML): A type of cancer in which the
bone marrow makes abnormal myeloblasts (a type of white blood
cell), red blood cells, or platelets.
 Hodgkin lymphoma: A cancer originating from white blood cells
called lymphocytes
 Non-Hodgkin lymphoma: Group of blood cancers that include any
kind of lymphoma except Hodgkin's lymphomas
 Lukemia: A type of cancer of the blood or bone marrow
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Alkylating Agents
• The alkylating agents include nitrogen mustards (chlorambucil,
cyclophosphamide, mechlorethamine), nitrosoureas (lomustine,
carmustine), and alkyl sulfonates (busulfan).
• Other drugs that act in part as alkylating agents include
cisplatin, dacarbazine, and procarbazine.
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Mechanism of action and resistance

• The alkylating agents are CCNS drugs.
• They form reactive molecular species that alkylate nucleophilic
groups on DNA bases, particularly the N-7 position of guanine.
• This leads to cross-linking of bases, abnormal base-pairing,
and DNA strand breakage.

• Tumor cell resistance to the drugs occurs through

increased DNA repair
decreased drug permeability
production of trapping agents such as thiols
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Cyclophosphamide
Pharmacokinetics
Unlike most of the alkylating agents, cyclophosphamide and
isophosphamide are administered by oral route.
• Hepatic cytochrome P450-mediated biotransformation of
cyclophosphamide is needed for antitumor activity.
• One of the breakdown products is acrolein.
• Minimal amount of drug are excreted into the feces or into the
urine .
Clinical Use
• Uses of cyclophosphamide include leukemia, non-Hodgkin's
lymphoma, breast and ovarian cancers, and neuroblastoma.
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Cyclophosphamide
Toxicity
• Gastrointestinal distress, myelosuppression, and alopecia
are expected adverse effects of cyclophosphamide.
• Hemorrhagic cystitis resulting from the formation of acrolein
may be decreased by hydration and by use of
mercaptoethanesulfonate ( mesna ).
• Cyclophosphamide may also cause cardiac dysfunction,
pulmonary toxicity, and a syndrome of inappropriate
antidiuretic hormone (ADH) secretion.
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Mechlorethamine
Pharmacokinetics
• Mechlorethamine converts in the body to a reactive cytotoxic
product.
• It is a powerful vesicant (blistering agent).
Clinical Use
• Mechlorethamine is best known for use in regimens for Hodgkin's
and non-Hodgkin's lymphoma.
Toxicity
• Gastrointestinal distress, alopecia are common.
• Sever bone marrow suppression limits extensive use.
• The adverse effects caused by mechlorethamine include severe
nausea and vomiting (centrally mediated).
• These effects can be diminished by pretreatment with
ondansetron,granisetron, or palonosetron with dexamethasone.
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Platinum Analogs
(Cisplatin, Carboplatin, Oxaliplatin)
Pharmacokinetics
• Cisplatin is used intravenously.
• The drug distributes to most tissues and is cleared in
unchanged form by the kidney.
Clinical Use
• Cisplatin is commonly used as a component of regimens for
testicular carcinoma and for cancers of the bladder, lung,
and ovary.
• Carboplatin has similar uses.
• Oxaliplatin is used in advanced colon cancer.
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Platinum Analogs
(Cisplatin, Carboplatin, Oxaliplatin)
Toxicity
• Cisplatin causes gastrointestinal distress and mild
hematotoxicity and is neurotoxic (peripheral neuritis and
acoustic nerve damage) and nephrotoxic. Renal damage may
be reduced by the use of mannitol with forced hydration.

• Carboplatin is less nephrotoxic than cisplatin and is less likely

to cause tinnitus and hearing loss, but it has greater
myelosuppressant actions.

• Oxaliplatin causes dose-limiting neurotoxicity.

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Procarbazine
Mechanism of action
• Procarbazine is a reactive agent that forms hydrogen
peroxide, which generates free radicals that cause DNA strand
scission.
Pharmacokinetics
• Procarbazine is orally active and penetrates into most tissues,
including the cerebrospinal fluid.
• It is eliminated via hepatic metabolism.
Clinical Use
• The primary use of the drug is as a component of regimens for
Hodgkin's and non-Hodgkin's lymphoma, and brain
tumors.
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Procarbazine
Toxicity
• Procarbazine is a myelosuppressant and causes
gastrointestinal irritation, CNS dysfunction, peripheral
neuropathy, and skin reactions.
• Procarbazine inhibits many enzymes, including monoamine
oxidase and those involved in hepatic drug metabolism.
• Disulfiram-like reactions have occurred with ethanol.
• The drug is leukemogenic (induction or production of leukemia).
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Other Alkylating Agents

Busulfan is sometimes used in chronic myelogenous
leukemia.
• It causes adrenal insufficiency, pulmonary fibrosis, and skin
pigmentation.
 Myeloid leukemia is a type of leukemia affecting myeloid tissue.

Carmustine and lomustine are highly lipid-soluble drugs used

as adjuncts in the management of brain tumors.

Dacarbazine is used in regimens for Hodgkin's lymphoma.

• Itcauses alopecia, skin rash, gastrointestinal distress,
myelosuppression, phototoxicity, and a flu-like syndrome.
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Antimetabolites
• The antimetabolites are structurally similar to endogenous
compounds and are antagonists of folic acid (methotrexate),
purines (mercaptopurine, thioguanine), or pyrimidines
(fluorouracil, cytarabine, gemcitabine ).
• Antimetabolites are CCS drugs acting primarily in the S phase
of the cell cycle.
• In addition to their cytotoxic effects on neoplastic cells, the
antimetabolites also have immunosuppressant actions.
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Methotrexate
Mechanisms of Action and Resistance
• Methotrexate is an inhibitor of dihydrofolate reductase. This
action leads to a decrease in the synthesis of thymidylate,
purine nucleotides, and amino acids and thus interferes with
nucleic acid and protein metabolism.
• The formation of polyglutamate derivatives of methotrexate
appears to be important for cytotoxic actions.
• Tumor cell resistance mechanisms include
1. decreased drug accumulation
2. changes in the drug sensitivity or activity of dihydrofolate
reductase
3. decreased formation of polyglutamates
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Methotrexate
Pharmacokinetics
• Oral and intravenous administration of methotrexate affords good
tissue distribution except to the CNS.
• Methotrexate is not metabolized, and its clearance is dependent on
renal function.
• Adequate hydration is needed to prevent crystallization in renal
tubules.
Clinical Use
• Methotrexate is effective in acute leukemias, non-Hodgkin's and
primary central nervous system lymphomas, and a number of solid
tumors, including breast cancer, head and neck cancer, and bladder
cancer.
• Methotrexate is used also in rheumatoid arthritis psoriasis and
ectopic pregnancy (A pregnancy in which the fetus develops outside the
uterus).
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Methotrexate
Toxicity

• Common adverse effects of methotrexate include bone

marrow suppression and toxic effects on the skin and
gastrointestinal mucosa (mucositis).

• The toxic effects of methotrexate on normal cells may be

reduced by administration of folinic acid (leucovorin); This

strategy is called leucovorin rescue.

• High MTX levels in the blood require additional leucoverin

rescue.
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Methotrexate

• Nephrotoxicity can be a problem with high doses of MTX, but

it is less likely to occur than myelosuppression especially if

patient is well hydrated and the urine is alkalinized.

• MTX is a weak acid and is more water soluble at alkaline pH;

it is thus eliminated more rapidly in alkaline urine.

• Long-term use of methotrexate has led to hepatotoxicity and

to pulmonary infiltrates and fibrosis.

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Mercaptopurine (6-MP) &

Thioguanine (6-TG)
Mechanisms of Action and Resistance
• Mercaptopurine and thioguanine are purine antimetabolites.
• Both drugs are activated by hypoxanthine-guanine
phosphoribosyl transferases (HGPRTases) to toxic
nucleotides that inhibit several enzymes involved in purine
metabolism.
• Resistant tumor cells have a
1. decreased activity of HGPRTase
2. increased their production of alkaline phosphatases that
inactivate the toxic nucleotides
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Mercaptopurine (6-MP) &

Thioguanine (6-TG)
Pharmacokinetics
• Mercaptopurine and thioguanine have low oral bioavailability
because of first-pass metabolism by hepatic enzymes.
• The metabolism of 6-MP by xanthine oxidase is inhibited by the
xanthine oxidase inhibitors allopurinol and febuxostat.
Clinical Use
• Purine antimetabolites are used mainly in the acute leukemias
and chronic myelocytic leukemia.
Toxicity
• Bone marrow suppression is dose limiting, but hepatic
dysfunction (cholestasis, jaundice, necrosis) also occurs.
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Fluorouracil (5-FU)
• Mechanism of action and Resistance
• Fluorouracil is converted in cells to 5-fluoro-2'-deoxyuridine-5'-
monophosphate (5-FdUMP), which inhibits thymidylate
synthase and leads to "thymine less death" of cells.
• Incorporation of FdUMP into DNA inhibits DNA synthesis and
function while incorporation of 5-fluorouridine-5'-triphosphate
(FUTP), another 5-FU metabolite, into RNA interferes with RNA
processing and function.
• Tumor cell resistance mechanisms include
1. decreased activation of 5-FU
2. increased thymidylate synthase activity
3. reduced drug sensitivity of this enzyme
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Fluorouracil (5-FU)
Pharmacokinetics
• When given intravenously, fluorouracil is widely distributed,
including into the cerebrospinal fluid.
• Elimination is mainly by metabolism.
Clinical Use
• Fluorouracil is used in bladder, breast, colon, anal, head and
neck, liver, and ovarian cancers.
• The drug can be used topically for keratoses (a growth of keratin
on the skin or on mucous membranes) and superficial basal cell
carcinoma.
Toxicity
• Gastrointestinal distress, myelosuppression, and alopecia are
common.
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Cytarabine (ARA-C)
Mechanisms of Action and Resistance
• Cytarabine (cytosine arabinoside) is a pyrimidine
antimetabolite.
• The drug is activated by kinases to AraCTP, an inhibitor of DNA
polymerases.
• Of all the antimetabolites, cytarabine is the most specific for the
S phase of the cell cycle.
• Resistance to cytarabine can occur as a result of its decreased
uptake or its decreased conversion to AraCTP.
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Gemcitabine
Mechanism of action
• Gemcitabine is a deoxycytidine analog that is converted into the
active diphosphate and triphosphate nucleotide form.
• Gemcitabine diphosphate appears to inhibit ribonucleotide
reductase and thereby diminish the pool of
deoxyribonucleoside triphosphates required for DNA synthesis.
• Gemcitabine triphosphate can be incorporated into DNA, where
it causes chain termination.
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Gemcitabine
Pharmacokinetics
• It is infused IV.
• It is delaminated to difluorodeoxy, which is not cytotoxic and is
excreted in the urine.
Clinical Use
• Gemcitabine was initially approved for pancreatic cancer and
now is used widely in the treatment of non-small cell lung
cancer, bladder cancer, and non-Hodgkin's lymphoma.
Toxicity
• Myelosuppression is dose limiting toxicity, mainly as
neutropenia.
• It may cause pulmonary toxicity, nausea, rash, vomiting
alopecia, and flu like syndrome .
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