Anticancer drugs

Cancer is a disease characterised by uncontrolled

multiplication and spread of abnormal forms of the body's
own cells.

The terms cancer, malignant neoplasm (neoplasm simply

means 'new growth') and malignant tumour are synonymous.
Both benign and malignant tumours manifest uncontrolled
proliferation, but the latter are distinguished by their capacity
for dedifferentiation, their invasiveness and their ability
to metastasise (spread to other parts of the body).

The appearance of these abnormal characteristics reflects

altered patterns of gene expression in the cancer cells,
resulting from genetic mutations.
 There are three main approaches to treating
established cancer-
surgical excision,
irradiation
Chemotherapy

The relative value of each of these approaches depends on the

type of tumour and the stage of its development.

Chemotherapy may be used on its own or as an adjunct to other

forms of therapy.
THE PATHOGENESIS OF CANCER
Cancer cells manifest, to varying degrees,
four characteristics that distinguish them
from normal cells.
These are
uncontrolled proliferation
dedifferentiation and loss of function
invasiveness
metastasis.
THE GENESIS OF A CANCER CELL
Normal cell turns into a cancer cell because of one or more
mutations in its DNA, which can be acquired or inherited.

A good example is breast cancer; women who inherit a

single defective copy of either of the tumour suppressor
genes BRCA1 and BRCA2 have a significantly increased
risk of developing breast cancer.

However, carcinogenesis is a complex multistage process,

usually involving more than one genetic change as well as
other, epigenetic factors (hormonal, cocarcinogen and
tumour promoter effects, etc.) that do not themselves
produce cancer but which increase the likelihood that the
genetic mutation(s) will result eventually result in cancer.
 There are two main categories of genetic change
that are important.
The activation of proto-oncogenes to
oncogenes.
Proto-oncogenes are genes that normally control cell division,
apoptosis and differentiation, but which can be converted to
oncogenes that induce malignant change by viral or
carcinogen action.
The inactivation of tumour suppressor
genes.
Normal cells contain genes that have the ability to suppress
malignant change-termed tumour suppressor genes
(antioncogenes)-and there is now good evidence that
mutations of these genes are involved in many different
cancers. The loss of function of tumour suppressor genes can
be the critical event in carcinogenesis.
 Alkylating agents and related compounds,
Nitrogen mustards (Mechlorethamine , Cyclophosphamide, Ifosfamide,Melphalan
(L-sarcolysin), Chlorambucil)
Ethyleneimines and methylmelamines (Altretamine, Thiotepa)
Methylhydrazine derivative(Procarbazine)
Alkyl sulfonate(Busulfan)
Nitrosoureas(Carmustine, Streptozocin (streptozotocin))
Triazenes (Dacarbazine )
Platinum coordination complexes (Cisplatin, carboplatin,oxaliplatin)
antimetabolites,
Folic acid analogs Methotrexate (amethopterin)
Pyrimidine analogs( Fluorouracil, capecitabine, Cytarabine, Gemcitabine.
Purine analogs and related inhibitors (6-mercaptopurinePentostatin)
Cytotoxic antibiotics (bleomycin, Doxorubucin, Daunorubucin, idarubicin,
Dactinomycin)
plant derivatives (vinca alkaloids, taxanes, campothecins)
Hormones (Adrenocortical suppressants, Adrenocorticosteroids,
Progestins, Estrogens, Anti-estrogens, Aromatase inhibitors,
Androgens, Anti-androgen, Gonadotropin-releasing hormone analog
Miscellaneous agents (Tretinoin, arsenic trioxide, Imatinib,
Gefitinib, erlotinib)
 undergoes intramolecular
cyclisation, forming an
unstable ethylene
immonium cation (2) and
releasing Cl-, the tertiary
amine being transformed to
a quaternary ammonium
compound. The strained
ring of the ethylene
immonium intermediate
opens to form a reactive
carbonium ion (in yellow
box) (3), which reacts
immediately with N7 of
guanine (in green circle) to
give 7-alkylguanine (bond
shown in blue), the N7
being converted to a
quaternary ammonium
nitrogen. These reactions
can then be repeated with
thea other
Alkylation and cross-linking of DNA by -CH2mustard
nitrogen CH2Cl to give
a cross-link.
 The metabolism of
cyclophosphamide.
Cyclophosphamide is
inactive until
metabolised in the
liver by P450 mixed
function oxidases to
4-
hydroxycyclophospha
mide, which
(reversibly) forms
aldophosphamide.
Aldophosphamide is
conveyed to other
tissues, where it is
converted to
phosphoramide
mustard, the actual
cytotoxic molecule,
and acrolein, which is
responsible for
unwanted effects.
The part of the
cyclophosphamide
molecule that gives
rise to the active
metabolites is shown
in the blue box.