Hypothesis: The potential application of doxorubicin against cutaneous leishmaniasis.

Sir,

DNA topoisomerases (TOP) have been used as chemotherapeutic targets for antibacterial and antiprotozoal diseases. They are ubiquitous enzymes that play an important role in many essential processes (such as DNA replication, transcription, and recombination). They are classified as TOP type I, type II that cleavage single stranded and double stranded DNA, respectively.[1]

Topoisomerases I (EC 5.99.1.2) have been characterized from Leishmania donovani and Trypanosoma cruzi. The enzyme was found to be independent of ATP.[2] Inhibitors of TOP I include anti-Leishmania compounds such as sodium stibogluconate (glucantime). TOP II (EC 5.99.1.3) has been identified from Trypanosoma brucei,[3] T. cruzi[4] and L. donovani.[5] TOP II inhibitor, 9-anilinoacridine; antitumor agent, and other acridine derivatives inhibited Leishmania and Trypanosoma effectively.[6]

The structure of L. donovani topoisomerase I, bound to nicked DNA captured as a vandate complex has been elucidated.[7] The structural analysis of these enzymes will give us an insight into their catalytic mechanisms and will also enable us to design specific inhibitors against Leishmania parasites. Doxorubicin is available in liposome-encapsulated forms as Doxil. Also known as hydroxyl daunorubicin that is commonly used in the treatment of a wide range of cancers. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines. The Food and Drug Administration approved a generic version of Doxil in February 2013. The drug is administered intravenously, as the hydrochloride salt. Recently has been demonstrated that acute inflammation induced by doxorubicin is associated with apoptosis of macrophages in the mouse model and that it is specific for doxorubicin, an imuunogenic chemotherapeutic target.[8] Doxorubicin interacts with DNA by inhibition of macromolecular biosynthesis. This inhibits the progression of the enzyme TOP II, which relaxes supercoils in DNA for transcription. Doxorubicin stabilizes the TOP II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thus stopping the process of replication.[910] Accordingly, Doxorubicin could be effective against Leishmania parasite. Hence, combination of the Doxil, as a liposomal formulation of doxorubicin, preferable as a topical formulation with glucantime (as a drug of choice) could integrate for treatment and also decrease the resistance of Leishmania against current available drugs. It would be desirable because liposome-encapsulated doxorubicin is fewer side-effects than unencapsulated doxorubicin in the same treatment regimen. Moreover, since liposome labor to deliver the drug by diffusion rather than by direct cell fusion, this form allowing doxorubicin to pass freely through the membrane and gave an effective drug delivery. Our remark favorable utility of it for clinical trials and also in vitro and or in vivo experiments in the future.