Bleomycin is a chemotherapeutic agent used for treatment of many types of tumors including lymphomas, testicular cancer
and breast cancer. Its cytotoxic effect may be attributed to its interaction with O2
and Fe2+ leading to scission of DNA. Its
systemic application may be associated with serious pulmonary fibrosis. It may be used by intralesional injection for management
of keloids, hypertrophic scars, cutaneous warts, hemangiomas, cutaneous malignancies, cutaneous leishmaniasis
and condyloma accuminata. However, its use may lead to significant dermatologic toxicities including scratch dermatitis,
Raynaud’s phenomenon, hyperpigmentation, fibrosis, gangrene, neutrophilic eccrine hidradenitis, alopecia areata, oedema
and nail changes.
The bleomycins are DNA-cleaving antibiotics that were discovered
as fermentation products of Streptococcus verticillus.
The drug currently employed clinically is a mixture of the two
copper-chelating peptides, bleomycins A2
and B2. Bleomycins
have attracted interest because of their significant antitumor
activity against squamous carcinoma of the cervix, lymphomas
and testicular tumors. They are minimally myelo- and
immunosuppressive but cause unusual cutaneous side effects
and pulmonary fibrosis. Because their toxicities do not
overlap with those of other drugs and because of their unique
mechanism of action, bleomycins maintain an important role
in combination chemotherapy.
Although bleomycin has a number of interesting biochemical
properties, its cytotoxic action results from their ability
to cause oxidative damage to the deoxyribose of thymidylate
and other nucleotides leading to single- and double-stranded
breaks in DNA. Studies in vitro indicate that bleomycin
causes accumulation of cells in the G2
phase of the cell cycle
and many of these cells display chromosomal aberrations
including chromatid breaks, gaps and fragments, as well as
translocations.
Bleomycin causes scission of DNA by interacting with O2
and
Fe2+ (Figure 1). In the presence of O2
and a reducing agent,
such as dithiothreitol, the metal-drug complex becomes activated
and functions as a ferrous oxidase, transferring electrons
from Fe2+ to molecular oxygen to produce activated species of
oxygen. Metallobleomycin complexes can be activated by
reaction with the flavin enzyme, NADPH-cytochrome P450 reductase.
Bleomycin binds to DNA through its amino-terminal
peptide and the activated complex generates free radicals
that are responsible for scission of the deoxyribose backbone
of the DNA chain. Bleomycin is degraded by a specific hydrolase
found in various normal tissues. However, hydrolase
activity is low in skin and lung, perhaps contributing to the
toxicity at these sites.
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