From Cancer Research to Anti Apicomplexa

Members of the phylum Apicomplexa account for some of the most debilitating infections of humans and livestock. Malaria, caused by Plasmodium sp., is undoubtedly the most important infectious disease and a major cause ofdeath in developing countries. Other infections by apicomplexan parasites such as Toxoplasma gondii, Cryptosporidium parvum and Babesia sp. are usually asymptomatic in humans but become life-threatening diseases in immune-compromised patients. The latter species, as well as Theileria and Eimeria sp., are the pathogenic agents of fatal infections in livestock. Although effective treatments are available against these human and animal diseases, the problem has become serious in recent years due to the spread of drug resistance. Since Plasmodium and the other Apicomplexa are highly diverse and genetically polymorphic, they are provided with a variety of mechanisms to escape drug treatment which leads to an urgent and pressing need for new drugs that can attack the different metabolic pathways of the parasites in order to avoid cross-resistance with the commonly used drugs. Consequently, the control of apicomplexan infections in humans and animals depends greatly on the identification of novel drug targets, and on the design of their inhibitors. Collected data relating to the polyamine metabolism of the malarial parasite and other parasitic protozoa has been reviewed previously [3-5]. In this chapter, a summary is provided of polyamine metabolism in Apicomplexa, with respect to its potential for chemotherapeutic intervention.

Since polyamines are known to be essential for cell proliferation and differentiation, numerous approaches have been taken to interfere with their metabolism, not only for tumor therapy but also in a preventive role [6-9]. The inhibition of polyamine biosynthesis, with a resultant depletion of polyamines, was initially proposed as a very promising antiproliferative strategy. Unfortunately, however, attempts to target the synthesis by using enzyme inhibitors and polyamine analogs have not yet proved to be as successful in cancer treatment as anticipated. Nonetheless, the use of these compounds either as preventive agents or in combination with other drugs has provided some benefits in multiple cancer trials. For example, alpha-difluoromethyl-ornithine (DFMO), an irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), which catalyzes the initial step in polyamine biosynthesis, did not provide the expected curative effect in clinical trials, but did show promise as a chemo-preventive agent [7]. The reasons for the modest success of DFMO in anticancer therapy are based on the complex regulation of the polyamine pool, which is supplied not only by biosynthesis and exogenous polyamines but also by a sophisticated fine-tuning via interconversion. DFMO, as such, is a safe and well-tolerated drug, which is today frequently used in cosmetics for hair removal [10, 11].

As the rapid proliferation of protozoan parasites is thought to be associated with a high demand for polyamines, the blockade of polyamine metabolism by using inhibitors and analogs - both of which have been created in abundance in cancer research - was monitored against infections caused by parasites. Notably, this strategy has been applied successfully against trypanosomes, with eflornithine (i.e., DFMO) being shown as highly effective in the fight against West African human sleeping sickness [12-14]. Such pioneering studies with trypanosomal infections encouraged the use of DFMO to validate the blockade of polyamine synthesis in other protozoan parasites for drug intervention, although unfortunately the effect of DFMO was far less pronounced. Trypanosomes depend on a unique trypanothione system that consists of a spermidine-glutathione conjugate which is essential for maintenance of the intracellular thiol redox state (similar to the glutathione system in other organisms) [15,16]. Nevertheless, some curative results have been reported for DFMO in the treatment of patients suffering from Pneumocystis carinii and C. parvum infections [17, 18], and it also prevented infections by Eimeria tenella [19]. Furthermore, DFMO showed a potent therapeutic effect on experimental Leishmania donovani infections [20], and also inhibited the growth of Giardia lamblia as well as of Acanthamoeba castellani [21, 22]. The fact that the antiparasitic effects of DFMO treatment could be reversed by the addition of physiological polyamines indicated clearly that the drug functions by blocking the biosynthesis of these compounds. However, the results of experiments with Anopheles and rodent model infections with P. berghei, as well as with cultured P. falciparum erythrocytic stages, varied from promising to modest. In this case, DFMO was shown to block the development of trophozoites in the erythrocytic schizogony, an inhibition which was reversible and cytostatic rather than cytotoxic. However, when compared to the impact on sporogony and liver schizogony, the effect on the erythrocytic schizogony was less pronounced, due either to an inefficient uptake of DFMO or to a lower multiplication rate of the erythrocytic stages [3, 4]. In the other stages, the application of DFMO blocked the sporogonous cycle of P. berghei in Anopheles stephensi [23], and also protected mice against infection with sporozoites, thus providing evidence for the exoerythrocytic schizogony as a potent target [24-26]. The treatment of mice infected with blood-stage forms of P. berghei with DFMO led to controversial results, however, when the drug was seen to block the development of erythrocytic schizonts in cultured P. falciparum- and P. berghei-infected mice [27, 28], but did not show any convincing effect on their survival [24, 25, 29, 30].

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