Anticancer agents against malaria: time to revisit?

Abstract

The emergence of artemisinin resistance could adversely impact the current strategy for malaria treatment; thus, new drugs are urgently needed. A possible approach to developing new antimalarials is to find new uses for old drugs. Some anticancer agents such as methotrexate and trimetrexate are active against malaria. However, they are commonly perceived to be toxic and thus not suitable for malaria treatment. In this opinion article, we examine how the toxicity of anticancer agents is just a matter of dose or 'only dose makes the poison', as coined in Paracelsus' law. Thus, the opportunity exists to discover new antimalarials using the anticancer pharmacopoeia.

Figure 1

Dose–response effect of drugs in humans, as per Paracelsus’ law, using methotrexate (MTX) as an example. For any drug, there is a dose range (concentration) that is without any effect, one with a pharmacological effect but with minimal toxicity (or acceptable safety profile) and another with pharmacological and toxic effects. Most drugs used in the treatment of human diseases fall within the middle group. In the case of MTX, experience in multiple sclerosis indicates that a dose of 7.5 mg per week for up to 2 years is not associated with toxicity . The use of 7–30 mg per week LD–MTX in the treatment of rheumatoid and juvenile arthritis and psoriasis is associated with an acceptable toxicity profile . Higher doses (<100 mg) are associated with toxicity, as shown in the treatment of cancer .