Majority of the cytotoxic drugs have more profound effect on rapidly multiplying cells, because the most important target of action are the nucleic acids and their precursors; rapid nucleic acid synthesis occurs during cell division.
GENERAL TOXICITY OF CYTOTOXIC
DRUGS
Majority of the
cytotoxic drugs have more profound effect on rapidly multiplying cells, because
the most important target of action are the nucleic acids and their precursors;
rapid nucleic acid synthesis occurs during cell division. Many cancers
(especially large solid tumours) have a lower growth fraction (lower percentage
of cells are in division) than normal bone marrow, epithelial linings,
reticuloendothelial (RE) system and gonads. These tissues are particularly
affected in a dose-dependent manner by majority of drugs; though, there are
differences in susceptibility to individual members.
Bone Marrow: Depression of bone marrow results in granulo-cytopenia, agranulocytosis,
thrombocytopenia, aplastic anaemia. This is the most serious toxicity; often
limits the dose that can be employed. Infections and bleeding are the usual complications.
Lymphoreticular
Tissue: Lymphocytopenia and inhibition of lymphocyte function results
in suppression of cell mediated as well as humoral immunity.
Because of action (1)
and (2) + damage to epithelial surfaces, the host defence mechanisms (specific
as well as nonspecific) are broken down → susceptibility to all
infections is increased. Of particular importance are the opportunistic
infections due to low pathogenicity organisms. Infections by fungi (Candida and others causing deep
mycosis), viruses (Herpes zoster,
cytomegalo virus), Pneumocystis jiroveci
(a fungus) and Toxoplasma are seen
primarily in patients treated with
anticancer drugs.
Oral Cavity: The oral mucosa is particularly susceptible to cytotoxic drugs because of high
epithelial cell turnover. Many chemotherapeutic drugs produce stomatitis as an
early manifestation of toxicity. The gums and oral mucosa are regularly
subjected to minor trauma, and breaches are common during chewing. Oral
microflora is large and can be the source of infection. Neutropenia and depression
of immunity caused by the drug indirectly increase the chances of oral
infections. Thrombocytopenia may cause bleeding gums. Xerostomia due to the
drug may cause rapid progression of dental caries.
GIT: Diarrhoea, shedding of
mucosa, haemorrhages occur due
to decrease in the rate of renewal of the mucous lining. Drugs that frequently
cause mucositis are—bleomycin, actinomycin D, daunorubicin, doxorubicin,
fluorouracil and methotrexate.
Nausea and vomiting are prominent with many cytotoxic drugs. This
is due to direct stimulation of CTZ by the drug as well as generation of emetic
impulses/mediators from the upper g.i.t. and other areas (see Ch. No. 47).
Skin: Alopecia occurs due to
damage to the cells in hair follicles.
Dermatitis is another complication.
Gonads: Inhibition of gonadal cells causes oligozoospermia and impotence in males; inhibition
of ovulation and amenorrhoea are common in females.
Damage to the germinal
cells may result in mutagenesis.
Foetus: Practically all cytotoxic
drugs given to pregnant women
profoundly damage the developing foetus → abortion, foetal
death, teratogenesis.
Carcinogenicity: Secondary
cancers, especially leukaemias, lymphomas
and histocytic tumours appear with greater frequency many years after the use
of cytotoxic drugs. This may be due to depression of cell mediated and humoral blocking factors against neoplasia.
Hyperuricaemia: This is secondary to
massive cell destruction (uric
acid is a product of purine metabolism). Gout and urate stones in the urinary
tract may develop. Allopurinol is protective by decreasing uric acid synthesis.
In addition to these
general toxicities, individual drugs may produce specific adverse effects, e.g.
neuropathy by vincristine, cardiomyopathy by doxorubicin, cystitis and alopecia
by cyclophosphamide.
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