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Chemotherapy

By
Dr Dambo
Introduction
• Chemotherapy:- the treatment of disease
or infection with chemicals or drugs
• Effective chemotherapy for gynaecological
cancers exploits xteristic differences b/w
tumour cells and normal cells to
selectively kill malignant cells without
producing serious, irreversible harm to
vital organs and tissues.
• Research in molecular biology and cell kinetics,
has improved knowledge on the scientific basis
of cancer chemotherapy, which is serving in the
development of new drugs, establishment of
more rational protocol basic for the design of
protocols, the optimal use of the presently
available drugs.
• Long-lasting remissions and occasional cures
for several types of cancer have been achieved
with antitumour drugs. E.g up to 90% of patients
with metastatic choriocarcinoma achieve a
normal life expectancy, and almost 100% of
those without metastases are cured now.
• The effect of the drugs may be monitored
by the level of Beta-hCG which provide a
reliable index of tumour growth.
• The use of cytotoxic drugs for Ca of the
Cx vagina and vulva is still on clinical trial
basis, since this tumours usually grow
more slowly, and cytotoxic drug treatment
has been palliative but not curative;. these
types of cancer are better controlled by
surgery and radiation therapy, and
chemotherapy should be considered only
when these standard methods have
proved ineffective
• Among the uncommon gynaecological Ca
that may require chemotherapy are germ
cell tumours of the ovary, uterine, vaginal
or vulvar sarcomas. Because these
tumours are rare, little is known about
there sensitivity to antitumour drugs.
Normal cell cycle
• Go: resting phase (cell not committed to division)
• G1 enzyme produced necessary for DNA production (18 hours)
• S: DNA synthesis (20hours)
• G2: specialized protein and RNA synthesis (3hours)
• M: mitosis (1hour)
Cell Kinetics
• Cell kinetics is helpful in understanding the
dynamics of tumour cells, in which some
cells divide more slowly than others some
cells enter or leave a nondividing state,
and some are lost from the tumour
population entirely.
• The MITOTIC INDEX (MI) is the fraction of
cells in mitosis in a steady-state.
• GROWTH FRACTION (GF) is the overall
proportion of proliferating cells in a given
tumour
• CELL CYCLE TIME denotes the amount
of time needed by a proliferating cell to
progress through the cell cycle and
produce a new daughter cell.
• DOUBLING TIME is the time required for
the tumour cell population to double.
Effects on chemotherapy on the
cell cycle
• The effects of various classes of anticancer
agents on tumours depend on the basic events
occurring in the 4 main phases of the cell cycle
and the pharmacologic mechanisms of the drug
action, and these cytotoxic effects influence the
design of rational drug regimens.
• Two basic classes of antineoplastic drugs are
recognised:
-Cell cycle(phase) specific agents
-Cell cycle(phase) non-specific agents.
• CELL CYCLE SPECIFIC drugs: lethal to cells
only during a reproductive phase.
• More effective in tumours in which a large
proportion of cells are actively dividing , as
occurs when the cell mass is low.
• They produce a greater kill, if given in multiple,
repeated fractions rather than as a large single
dose.
• Drugs include:
-methotrexate/fluorouracil: s phase
-corticosteroids/asparaginase: G1 phase
-bleomycin: G2 phase
-vinca alkaloids: M phase
• CELL CYCLE NON SPECIFIC drugs:- are able
to sabotage the cells no matter what
phase they are in.
• Are effective in large tumours in which the
growth fraction LI and MI are low.
• Drugs in this group are dose dependent, since a
single bolus injection generally kills the same
number of cells as do repeated doses totaling
the same amount ie, the degree of cell kill is
directly proportional to the absolute dose given
• Drugs include:
-Alkylating agents
-Nitrosoureas
-Antibiotics
Nitrosoureas
Cellular differentiation Carmustine
Of clones Go Resting
Stem cell

(Recruitment)
1. Vinca alkalloids
(vincristine, vinblastine)
2.Taxanes (paclitaxel) 1. steroids?
3. Podophyllotoxins 2. Asparaginase Cell cycle(phase)-non specific agents
(etoposides) 3. diglycoaldehyde
18hrs
G1
• Alkylating agents
1 hr
(cyclophosphamide, busulfan,
chlorambucil)
Stem • Anthracycline antibiotics
cell
3 hrs G2 (doxorubicin, dactinomycin)
• Miscellaneous (cisplatin,
S carboplatin)

Bleomycin • Nitrosoureas (also Go)

20 hours

G1 – Enzymes produced necessary for DNAProduction.


Antimetabolites S – DNA synthesis
2. Methotrexate M – Mitosis
3. 5-fluorouracil Go – Resting phase (cells not committed to division)
4. Mercaptopurine
5. Hydroxyurea
6. Cisplatin, carboplatin
Cancer chemotherapy agents
• Classified into six general categories on
the basis of their mechanism of action:
-Alkylating agents
-Antimetabolites
-Plant alkaloids
-Hormonal agents
-immunotherapeutic agents
-Miscellaneous
• Can also be classified based on their
biochemistry into:-
-Alkylating agents
-Antimetabolites
-Vinca Alkaloids
-Antibiotics
-Miscellaneous
Alkylating agents
• They bind to DNA therefore interferes with
correct base pairing and produce single and
double stranded breaks. DNA replication in
S phase is consequently inhibited.
• They also inhibit cellular glycolysis, respiration
and synthesis of various enzymes, proteins and
nucleic acids.
• Eg Cyclophosphamide
-Chlorambucil
-Ifosfamide
.
• Side effects of alkylating agents include:-
-Nausea
-Vomiting
-Myelosuppression
-Nephrotoxicity
-Ototoxicity
-Haemorrhagic cystitis
(Cyclophosphamide)
-Alopecia
-Decreased sperm production
-Cessation of menstruation
-Infertility
-Can cause secondary cancers although not all agents
are equal in their carcinogenic potential. The most common
secondary cancer is a leukemia (Acute Myeloid Leukemia)
that can occur years after therapy.
Antimetabolites
• They interfere with normal synthesis of
nucleic acids by substituting different
compounds for the normal purines and
pyrimidines in metabolic pathways
• Exert their major activity during the S
phase
• Eg Methotrexate (folate antagonist)
-Mercaptopurine (purine antagonist)
-Fluorouracil (pyrimidine antagonist)
• Methotrexate is a folic acid antagonist.
• It inhibits the enzyme dihydrofolate
reductase, which reduces dihydrofolate to
tetrahydrofolate, the precursor of
coenzymes essential for the formation of
purines and pyrimidines.
• Side effects of Antimetabolites:-
-Nausea
-Vomiting
-Mucositis
-Stomatitis
-Hepatitis
-Myelosuppression
-Nephrotoxicity
-Alopecia
-Dermatitis
-Hepatocellular damage
Plant alkaloids
• They cause the arrest of metaphase of mitosis
by crystallization (through toxicity) of the
microtubules of the mitotic spindle.
• Eg -Vinca alkaloids:-
-Vincristine
-Vinblastine
-Podophyllotoxins:-
Etoposide
-Taxanes;-
Paclitaxel
• Side effects of plant alkaloids:-
-Nausea
-Vomiting
-Constipation
-Alopesia
-Myelosuppression
-Paralytic ileus
-Neurotoxicity (convulsions)
-Peripheral neuropathy
-Bladder atony
N. B. Vincristine is one of the very few
chemotherapeutic drugs that is not myelotoxic.
Antibiotics
• They interfere with nucleic acid synthesis
and block DNA-directed RNA and DNA
transcription.
• Eg Doxorubicin (Adriamycin)
Bleomycin
Actinomycin D
• Side effects of Antibiotics :-
-Nausea
-Vomiting
-Alopecia
-Diarrhoea
-Mucositis
-Cardiomyopathy
-Myelosuppression
-Pulmunary fibrosis (Bleomycin)
.Bleomycin is also not myelotoxic.
Miscellaneous
• Platinum Agents:-
-They act in a similar way like the alkylating agents
but are given intraveinously.
-Eg Cisplatin
Carboplatin
Side effects include :-
-Severe nausea and vomiting
-myelosuppression
-ototoxicity (high tone deafness)
-nephrotoxicity
-neurotoxicity (dose-dependent peripheral
neuropathy)
Miscellaneous contd
• Hormones:-
Do not possess cytotoxic action but can cause
tumour regression by altering the hormonal millieu.
They are primarily effective against tumours that
arise from hormone responsive tissues e.g endometrial
and breast cancer.
This treatment are not curative but may provide
excellent palliation of symptoms in selected patients.
They include MEDROXYPROGESTERONE,
PREDNISOLONE and TAMOXIFEN
Side effects: - Fluid retension
CVD due to prolonged use.
Route of administration
• Oral
-Alkylating agents
-May be given on daily basis but usually intermittent
• Intravenous
-Drugs are normally given at intervals of 1-4 weeks.
-This allows bone marrow to recover.
• Intramuscular
• Intrapleural
Bleomycin given for recurrent pleural effussions but
forms adhesions.
• Intraperitoneal
-Cisplatin
-Given high concentration of drug into the peritoneal
which acts as a reservoir.
• Drugs can be used alone or in combination.
• Combination is more effective than single
chemotherapy.
• Advantages of combination chemotherapy
theoretically:-
-Drugs combine to give synergistic effect
-Reduced resistance to the drugs
-The cumulative toxic effects of each
individual drug is avoided by combination.
• Sequential therapy:- this is an alternative
mechanism in preventing the development of drug
resistance by giving different drugs in turn. This
also allows for a shorter treatment time. Effective
for germ cell tumours and GTD but not epithelial
tumours.
Ovarian cancer
• Chemotherapy is the standard in most ovarian
cancers after initial surgery.
• Of all gynaecological malignancies, ovarian
cancer responds best to chemotherapy
regimens
• Drugs used include:
-Cisplatin
-Carboplatin
-Cyclophosphamide
-Paclitaxel
Endometrial Cancer

• Mainly confine to patients with recurrent


metastatic or advanced disease
• Agents -Doxorubicin
-Paclitaxel
-Medoxyprogesteron
Cervical carcinoma
• As in endometrial carcinoma
• Agents -Platinum compounds
- Cisplatin
-Carboplatin
Conclusion
• The role of chemotherapy in gynaecological
cancer is limited. Only the rare trophoblastic and
germ cell tumours are cured by drugs. Its use in
solid tumours is adjunctive to surgery and
radiotherapy, and will remain so unless new
drugs with greater activity and tolerable toxicity
become available.
• Probably the most important contribution from
chemotherapy is improved quality and duration
of survival.

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