INTRODUCTION ( Cancer):

The American Cancer Society defines cancer as a group of diseases characterized by

uncontrolled growth, and the spread of abnormal cells that left untreated may lead to
death. Related to this definition is the term neoplasia, which is the uncontrolled growth
of new tissue, the product of which is known as a tumor, and these tumors may be
either malignant or benign. Malignant tumors have the capability of invading
surrounding tissues and moving to distant locations in the body in a process known as
metastasis; characteristics that benign tumors do not possess. Treatment of malignant
tumors or cancer has generally involved initially surgical removal followed by radiation
and/or chemotherapy.

Chemotherapy:
The term chemotherapy, in the strictest sense, refers to drugs that are used to kill cells
and includes both antibiotics and agents used in the treatment of cancer, but it is
often used to refer exclusively to anticancer agents also known as antineoplastics.
A neoplasm, or tumour is an abnormal mass of tissue, the growth of which exceeds and
is uncoordinated with that of the normal tissue and continues in the same manner after
cessation of the stimuli which have initiated it.

A malignant tumour grows rapidly and continuously, and even when it has impoverished
its host and source of nutrition, it still retains the potentiality for further proliferation.
Besides, malignant tumours invade and destroy neighbouring tissues and possess no
effective capsule, a malignant tumour readilty ulcerate and tend sooner or later to
disseminate and form metastases.
S—DNA : replication phase = 10-20 hours ;

G2—Resting phase = 2-10 hours ;

G1—Resting phase = highly variable due to another phase ;

M—Mitosis phase = 0.5 – 1 hours ;

Go—Pool = Cell not active during cell division.

CLASSIFICATION
Antineoplastic agents are classified under the following seven categories,
namely :
(i) Alkylating Agents (ii) Antimetabolites
(iii) Antibiotics (iv) Plant products
(v) Miscellaneous compounds (vi) Hormones
(vii) Immunotherapy.
1. Alkylating Agents:
Alkylating agents are chemically reactive compounds that combine most readily with
nucleophilic centres a fully saturated carbon atom of the alkylating group becoming
attached to the nucleophile. The term ‘alkylating agents’ is applied to compounds which, in
a sense, alkylate the substance with which they react, by joining it through a covalent bond,
although a strong polar bond is not excluded from this general definition. Any
‘antineoplastic agent’ whose activity is explained by such a mechanism is called an
alkylating agent.

These are further sub-divided into four categories, namely :

(i) Mustards

(ii) Methanesulphonates

(iii) Ethylenimines

(vi) Nitrosoureas
A. Mustards
Eg Mechlorethamine hydrochloride, Mephalan, Cyclophosphamide and Chlorambucil.
a. Mechlorethamine Hydrochloride

b. Melphan
c. Cyclophosphamide

d. Chlorambucil
B) Methanesulphonates
Eg Busulfan

Busulfan

C) Ethylenimines
Eg Triethylenemelamine,
Triethylenethiophosphoramide

D) Nitrosoureas:
1)Carmustine
2. Lomustine
A) Methotreate

B.

Mercaptopurine
 C)

D)
3.
Mitomycin
Doxorubicin
(iv) Plant products
 Vincristine

E
Tamoxifen Citrate
CHLORAMBUCIL (AMBOCHLORIN, ABMOCLORIN, LEUKERAN)
Chlorambucil is available as 2-mg tablets for oral administration in the treatment of
Hodgkin’s lymphoma, and chronic lymphocytic leukemia in combination with prednisone
and as a single agent. The mechanisms of resistance are the same as those seen for other
agents of the class such as mechlorethamine. The agent is well absorbed (75%) upon oral
administration and highly protein bound. Metabolism is mediated by CYP and occurs
extensively to give several metabolites, including the active phenylacetic acid–nitrogen
mustard. The drug is eliminated via the kidneys with a terminal elimination half-life of 1.5
hours. Adverse effects include dose-limiting myelosuppression, which are seen as both
leucopenia and thrombocytopenia. Nausea and vomiting occur less often than for
mechlorethamine. Additional adverse effects include hyperuricemia, azoospermia,
amenorrhea, seizures, pulmonary fibrosis, and skin rash.
CYCLOPHOSPHAMIDE (CTX, CPM, CPA, CLAFEN, CYTOXAN, NEOSAR)
Cyclophosphamide is available in 25- and 50-mg tablets for oral administration and 100-,
200-, 500-, 1,000-, and 2,000-mg vials for IV use in the treatment of a wide variety of
cancers, including breast cancer, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia,
ovarian cancer, bone and soft tissue sarcoma, rhabdomyosarcoma, neuroblastoma,
and Wilms tumor. Coadministration of mesna is recommended. The alkylating agent is cell
cycle–nonspecific, and mechanisms of resistance are similar to those seen for other
alkylating agents including decreased uptake and activation and increased inactivation by
glutathione and oxidase enzymes (aldehyde dehydrogenase and alcohol dehydrogenase)
as well as increased DNA repair mechanisms. The agent is well absorbed when given orally.
Metabolism by CYP2B6 and 3A4/5 is required for activation of the agent, and metabolites
are formed as a result of this activation by subsequent reactions that are shown in Scheme
10.5. The major metabolite seen in plasma is the phosphoramide mustard, although there
is a small amount of material (10%) arising from the dechloroethylation, which is primarily
mediated by 3A4/5. This metabolic pathway gives rise to a small amount of
chloroacetaldehyde, which is both neurotoxic and nephrotoxic.
The parent compound and metabolites are eliminated in the urine with an elimination
half-life of 4 to 6 hours. Adverse effects include dose-limiting myelosuppression, which
normally presents as leucopenia. Bladder toxicity, which presents as hemorrhagic cystitis,
is related to the formation of electrophilic species in the kidney including acrolein and
may be treated by administration of mesna and increased water intake. Additionally,
amenorrhea may be seen and sterility may be permanent. Other effects include alopecia,
cardiotoxicity, inappropriate secretion of antidiuretic hormone, and an increased risk of
secondary cancers.
CISPLATIN (CIS-DIAMINEDICHLOROPLATINUM, DDP, PLATINOL, PLATINOL-AQ)
Cisplatin is available in 10- and 50-mg vials for IV administration in the treatment of a
wide variety of cancers including non-Hodgkin’s lymphoma, bladder cancer, ovarian
cancer, testicular cancer, and cancers of the head and neck. A liposomal form is also
available as well as an injectable collagen matrix gel containing cisplatin. Compared with
other platins, cisplatin is the most reactive and therefore the most effective in
platinating DNA. After IV administration, the agent is widely distributed, highly protein
bound (90%), and concentrates in the liver and kidney. After infusion, covalent
attachment to plasma proteins occurs such that after 4 hours, 90% of drug is protein
bound. The elimination of platinum from the blood is a slow process with a terminal
elimination halflife of 5 to 10 days. Metabolism involves aquation, which occurs
to a greater extent once distribution out of the plasma has occurred. Additional
metabolites have been seen resulting from reaction with glutathione and cysteine. The
greater reactivity of cisplatin gives rise to significant toxicities compared with other
platins. These include dose-limiting nephrotoxicity, which normally presents as elevated
blood urea nitrogen (BUN) and creatinine.
5-FLUOROURACIL (5-FU, EFUDEX, ADRUCIL, FLUOROPLEX)
The drug is available in a 500-mg or 10-mL vial for IV use and as a 1% and 5% topical
cream. 5-FU is used in the treatment of several carcinoma types including breast
cancer,
colorectal cancer, stomach cancer, pancreatic cancer, and topical use in basal cell cancer
of the skin. The mechanism of action includes inhibition of the enzyme TS by the
deoxyribose monophosphate metabolite, 5-FdUMP. The triphosphate metabolite is
incorporated into DNA and the ribose triphosphate into RNA. These incorporations into
growing chains result in inhibition of synthesis and function of DNA and RNA. Resistance
can occur as a result of increased expression of TS, decreased levels of reduced folate
substrate 5,10-methylenetetrahydrofolate, or increased levels of dihydropyrimidine
dehydrogenase. Dihydropyrimidine dehydrogenase
is the main enzyme responsible for 5-FU catabolism.
MERCAPTOPURINE (6-MP, MERCAPTOPURINUM, PURINETHOL)
The drug is available as a 50-mg tablet for oral use. The primary uses of mercaptopurine
are in the treatment of lymphoblastic leukemia, acute lymphocytic leukemia, and Crohn
disease. The mechanism of action includes incorporation of mercaptopurine into DNA
and RNA via the triphosphate metabolite. This incorporation inhibits synthesis and
function of the resulting modified DNA or RNA.
The parent drug is inactive and requires phosphorylation for activity. Resistance can
occur via decreased expression of the activating enzymes or increased expression of the
major catabolic enzymes. Oral absorption is generally incomplete (about 50%) and the
drug does not enter the CNS in therapeutic quantities. Mercaptopurine is metabolized by
methylation, and the methylated product has anticancer activity. Oxidation by xanthine
oxidase yields inactive metabolites. The concurrent use of xanthine oxidase inhibitors
such as allopurinol can enhance the potency of mercaptopurine by inhibiting its catabolic
breakdown. The toxicities for mercaptopurine include myelosuppression,
immunosuppression, nausea, vomiting, diarrhea, dry skin, urticaria, and photosensitivity.
METHOTREXATE (MTX, ABITREXATE, MEXATE, FOLEX)
The drug is available in 50-, 100-, 200-, and 1,000-mg vials for IV use. Methotrexate is used to
treat several cancer types including breast cancer, bladder cancer, colorectal cancer, and head
and neck cancer. The mechanism of action of methotrexate involves inhibition of DHFR
leading to a depletion of critical reduced folates. The reduced folates are necessary for
biosynthesis of several purines and pyrimidines. Resistance to methotrexate can occur
because of decreased carrier-mediated transport of drug into cells or increased expression of
the target enzyme DHFR. Oral bioavailability varies with dose because of saturable uptake
processes, and high doses are required to reach therapeutic levels in the CNS. The majority of
drug dosage is excreted unchanged in the urine. The renal excretion of methotrexate
is inhibited by several carboxylic acid drugs such as penicillins, probenecid, nonsteroidal anti-
inflammatory agents, and aspirin. Methotrexate enhances 5-FU antitumor effects
when given 24 hours prior to the fluoropyrimidine. Methotrexate toxicity includes
myelosuppression, mucositis, nausea, vomiting, severe headaches, renal toxicity, acute
cerebral dysfunction, skin rash, and hyperpigmentation.