General principles in chemotherapy of cancer

GENERAL PRINCIPLES IN
CHEMOTHERAPY OF CANCER
BY
DR SOWMYA SPOORTHI.M
ASSISTANT PROFESSOR
KLE COP KAHER ,
BELAGAVI.

CANCER
 Tumour or Neoplasm
‘‘A mass of tissue formed as a result of
abnormal,excessive,uncoordinated ,autonomous and
purposeless proliferation of cells even after cessation
of stimulus for growth which caused it’’.
The common term used for all malignant tumours is
cancer.
The word ‘cancer’ means crab,thus reflecting the true
character of cancer since ‘it sticks to the part
stubbornly like a crab.

CHEMOTHERAPY
 The Term comes from two words that means
“Chemical ’’ and “treatment’’.
 The treatment of cancer using specific chemical
agents or drugs that are destructive to malignant cells
and tissues.
Ex : Alkylating agents –Cyclophosphamide
Platinum co-ordination complexes- Cisplatin
Antimetabolites -Methotrexate

1. In cancer chemotherapy, analogy is drawn
with bacterial chemotherapy; the malignant cell
being viewed as an invader. However, there are
two main differences-

( a) Bacterial metabolism differs markedly from
that of the host, while malignant cells are
in fact host cells with deranged regulation
of growth and differentiation and only minor other
differences.
 Therefore, selectivity of drugs is limited.
 A number of measures which enhance selectivity of
drugs for the tumour need to be exploited.
 However, lately some unique tumour antigens and
oncogenes have been identified, which provide
specific targets for drug therapy.

(b) Infecting microorganisms are amenable to
immunological and other host defence mechanisms.
 This is absent or minimal against cancer cells.

2. A single clonogenic malignant cell is capable
of producing progeny that can kill the host.
 To effect cure, all malignant cells must be killed or
removed.
 Survival time is related to the number of cells that
escape chemotherapeutic attack.

3. In any cancer, subpopulations of cells differ in their rate
of proliferation and susceptibility to cytotoxic drugs.
 These drugs kill cancer cells by first order kinetics, i.e.
a certain fraction of cells present are killed by one
treatment

4. Drug regimens or number of cycles of
combined chemotherapy which can effectively
palliate large tumour burdens may be curative
when applied to minute residual tumour cell
population after surgery and/ or irradiation.
 This is the basis of the combined modality approach

5. Whenever possible, complete remission should be the
goal of cancer chemotherapy: drugs are often used in
maximum tolerated doses. Intensive regimens used at
an early stage in disease yield better results.

6. Formerly cancers were treated with one drug at a time.
 Now a combination of 2-5 drugs is given
in intermittent pulses to achieve total tumour cell kill,
giving time in between for normal cells to recover .

Synergistic combinations and rational
sequences are devised by utilizing
(a) Drugs which are effective when used alone.
(b) Drugs with different mechanisms of action.
(c) Drugs with differing toxicities.
(d) Empirically by trial and error; optimal schedules are mostly
developed by this procedure.
(e) Drugs with different mechanisms of resistance.
(f) Drugs with known synergistic biochemical interactions.

(g) Kinetic scheduling: On the basis of cell cycle
specificity /nonspecificity of the drugs and
the phase of cell cycle at which the
drug exerts its toxicity.

Cytotoxic drugs are either cell cycle specific (CCS)
or cell cycle nonspecific (CCNS).
(a) Cell cycle nonspecific Kill resting as well as
dividing cells.
Example :- nitrogen mustard,
cyclophosphamide,
carmustine,
dacarbazine,
busulfan,
L-asparaginase,
cisplatin,
procarbazine,
actinomycin D.

(b) Cell cycle specific Kill only actively dividing cells. Their
toxicity is generally expressed in S phase. However,
these drugs may show considerablephase selectivity,
e.g.-
 G1: Vinblastine.
 S : cytarabine
hydroxyurea, doxorubicin.
 G2: bleomycin.
 M: Vincristine, vinblastine.

 It is logical to use cell cycle specific drugs in short
courses (pulses) of treatment.
 This allows noncycling cells (which are generally less
susceptible to drugs) to re-enter the cycle between
drug courses.
 The CCS drugs are generally scheduled after a
course of CCNS drug(s) to improve the cell kill.
 The CCS drugs are more effective in haematological
malignancies and in solid tumours with a large growth
fraction, while the CCNS drugs are effective in these
as well as in solid cancers with a small growth fraction.

 Many regimens have been devised by taking
into consideration the above factors and by
observing patient response.
 When cyclic treatment is given ,6-11 cycles may be
needed for optimum respose.
 It has been found that maintenance therapy thereafter
does not produce additional benefit.

 Similarly many other regimens have been devised
for different tumours.
 VAMP: Vincristine + Amethopterine (Mtx) + 6-MP
+Prednisolone: used in acute leukaemia.
 COAP: Cyclophosphamide + Oncovin (Vincristine)+
Ara-C (Cytarabine) + Prednisolone

7. Tumours often become resistant to any drug that is used
repeatedly due to selection of less responsive cells. Such
selection is favoured if low dose of a single drug is used .
 Several mechanisms of tumour resistance have been
recognized.
 Mutations altering the target biomolecule confer specific
(to single drug)resistance.
 An important mechanism of multidrug resistance is over
expression of MDR 1 gene which increases the
concentration of P-glycoprotein (an efflux transporter) on
the surface of cancer cells,resulting in pumping out of the
chemotherapeutic agents, especially natural products like
vinca alkaloids, anthracycline antibiotics, taxanes, etc.

General principles in chemotherapy of cancer

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General principles in chemotherapy of cancer