General Toxicity of Cytotoxic Drugs

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.