Wednesday, 13 September 2017

Insights into Dermatological Applications and Cutaneous Toxicities of Bleomycin

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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