Date Published: June 11, 2008
Publisher: Public Library of Science
Author(s): Danilo C. Miguel, Jenicer K. U. Yokoyama-Yasunaka, Silvia R. B. Uliana, Charles Jaffe
Abstract: BackgroundChemotherapy is still a critical issue in the management of leishmaniasis. Until recently, pentavalent antimonials, amphotericin B or pentamidine compounded the classical arsenal of treatment. All these drugs are toxic and have to be administered by the parenteral route. Tamoxifen has been used as an antiestrogen in the treatment and prevention of breast cancer for many years. Its safety and pharmacological profiles are well established in humans. We have shown that tamoxifen is active as an antileishmanial compound in vitro, and in this paper we analyzed the efficacy of tamoxifen for the treatment of mice infected with Leishmania amazonensis, an etiological agent of localized cutaneous leishmaniasis and the main cause of diffuse cutaneous leishmaniasis in South America.Methodology/Principal FindingsBALB/c mice were infected with L. amazonensis promastigotes. Five weeks post-infection, treatment with 15 daily intraperitoneal injections of 20 mg/kg tamoxifen was administered. Lesion and ulcer sizes were recorded and parasite burden quantified by limiting dilution. A significant decrease in lesion size and ulcer development was noted in mice treated with tamoxifen as compared to control untreated animals. Parasite burden in the inoculation site at the end of treatment was reduced from 108.5±0.7 in control untreated animals to 105.0±0.0 in tamoxifen-treated mice. Parasite load was also reduced in the draining lymph nodes. The reduction in parasite number was sustained: 6 weeks after the end of treatment, 1015.5±0.5 parasites were quantified from untreated animals, as opposed to 105.1±0.1 parasites detected in treated mice.Conclusions/SignificanceTreatment of BALB/c mice infected with L. amazonensis for 15 days with tamoxifen resulted in significant decrease in lesion size and parasite burden. BALB/c mice infected with L. amazonensis represents a model of extreme susceptibility, and the striking and sustained reduction in the number of parasites in treated animals supports the proposal of further testing of this drug in other models of leishmaniasis.
Partial Text: Protozoan parasites of Leishmania genus are the etiological agents of leishmaniasis, a disease distributed worldwide with a broad spectrum of clinical manifestations according to the causative species and immunological status of the host. Leishmaniasis current therapy is mainly based on the systemic administration of toxic pentavalent antimonials or amphotericin B, drugs with several side effects, such as arrhythmia, nephro- and hepatotoxicity. Additionally, emergence of Leishmania strains resistant to antimonials has been reported ,. Recently, miltefosine has been approved in India for the therapy of visceral leishmaniasis , but its efficacy on the treatment of American cutaneous leishmaniasis has been shown to be variable depending on the causative species ,,,. Therefore, new alternatives for the treatment of leishmaniasis are greatly needed.
The Ethics Committee that has approved this study is the Ethics Committee for Animal Experimentation of the Instituto de Ciências Biomédicas, University of São Paulo.
The treatment of L. amazonensis-infected BALB/c mice was initiated 5 weeks post-infection, time when lesions were already established and apparent. Mice were treated with 20 mg/kg/day tamoxifen intraperitoneally for 15 days. No toxic effects were detected during or after drug treatment. At the end of treatment, the average body weight in animals treated with tamoxifen was equivalent to values for the control group (untreated mice: 26.2±1.1 g; treated mice: 25.4±1.8 g) and the average weight of uteri indicated no significant alteration between tamoxifen-treated (0.18±0.4 g) and untreated mice (0.21±0.6 g). Figure 1A shows the progression of lesion size in untreated versus tamoxifen-treated mice. During and after tamoxifen administration we observed that treated animals presented less swelling at the infection site when compared to control animals. A statistically significant difference between the average thickness of lesions of untreated and tamoxifen-treated mice was evident on completion of treatment, at week 7 post-infection (P<0.001) and remained clear until the end of the experiment (week 13, P<0.01), when control mice had to be euthanized. Macroscopical aspects of the lesions are displayed in Figure 1B for untreated (left column) and tamoxifen-treated animals (right column). Our data reveal a significant effect of tamoxifen in the reduction of skin lesions caused by L. amazonensis in BALB/c mice. Effectiveness was apparent not only as reduced swelling and ulceration in treated animals but also as an important reduction in parasite burden. Source: http://doi.org/10.1371/journal.pntd.0000249