MALARIA has long been eradicated from most of Europe and North America.
However, with the threat of global warming due to the greenhouse effect,
there is a real danger that malaria may return to these areas. It is alarming,
therefore, that there are few safe drugs for malaria treatment and prophylaxis.
Some of the best, which include chloroquine and pyrimethamine, are almost
useless because the malaria parasite has developed a resistance to the drugs.
New insight into developing better malaria drugs may come from research
into cancer, a disease also beleaguered by drug resistance. Researchers
have noted that some of the mechanisms by which tumour cells become resistant
to drugs are the same as in the unicellular malaria parasite Plasmodium
When a cell becomes cancerous, the normal mechanism of transporting
toxins out of the cell is subverted to transport anticancer drugs out of
the cell. In healthy cells of the liver, kidney, adrenal glands and gut
of humans, such transport is achieved by a protein in the cell membranes,
known as P-glycoprotein. This protein is encoded by a complex of genes,
known as multiple drug resistance (mdr) genes.
Now, researchers in the US and Australia have discovered mdr genes in
P falciparum. Craig Wilson and Dyann Wirth at the Harvard School of Public
Health (Science, vol 244, p 1184), and Simon Foote and David Kemp at the
Walter and Eliza Hall Institute, Melbourne (Cell, vol 57, p 921), have found
that some strains of parasites, which are resistant to chloroquine, have
multiple copies of one of the mdr genes. This makes the chromosome on which
they reside bigger, which suggests that the drug-resistant parasite is synthesising
more P-glycoprotein to pump out chloroquine, in the same way that drug-resistant
tumour cells pump out anticancer agents.
Interestingly, Simon Foote noticed a similarity between the sequence
of mdr in P. falciparum and the ‘white’ gene of Drosophila. This gene encodes
for a protein involved in the transport of pigment. Recently, David Warhurst,
of the London School of Hygiene and Tropical Medicine, suggested that perhaps
this observation will form a basis for exploring the side effects of chloroquine.
The drug can affect pigmented tissue in humans, turning the skin yellow
and damaging the retina.
Although the mechanism involving the P-glycoprotein pump may not be
the only mechanism for chloroquine resistance in the malaria parasite, it
offers some hope that it may be possible to reverse resistance. Drugs such
as verapamil can inhibit the P-glycoprotein pump. Researchers have also
found that verapamil reverses drug resistance in cancer cells. However,
verapamil is not an ideal drug because it is used in correcting cardiac
arrythmia as well.
The fact that verapamil inhibits the P-glocoprotein pump prompts the
speculation that on the shelves of cancer pharmacologists there may be safe
Cancer research may also help the development of antimalaria treatments
in other ways. Many cancer drugs, for instance, block the synthesis of DNA
in the rapidly dividing cells of tumours. This tactic would be useful for
malaria parasites, which also divide rapidly.
Pyrimethamine, one of the repertoire of drugs developed by the Nobel
laureate George Hitchings when at Burroughs Wellcome in Tuckahoe, New York,
blocks the synthesis of DNA in P. falciparum, just like anticancer drugs.
It does this at an enzyme known as DHFR-TS (dihydrofolate reductase-thymidylate
Unlike resistance to other antimalarial drugs, resistance to pyrimethamine
does not develop by increasing synthesis of a protein in order to pump a
drug out of the cell. Several parasitologists have compared the gene sequence
for DHFR-TS in pyrimethamine-sensitive and resistant strains of P falciparum
(Parasitology Today, vol 5, p 252). But they have found only a few base
changes in the nucleotide sequence.
The most important change appears to be one that results in the substitution
of the amino acid asparagine for threonine in one of the alpha-helices that
border the active site of DHFR-TS. Researchers believe that this amino acid
substitution causes a profound conformational change in the active site
that prevents pyrimethamine from binding. This prediction has been derived
from molecular graphics imagery using data from the homologous enzyme extracted
from viruses and vertebrate tissues. It is yet to be verified, however,
in pure DHFR-TS from P falciparum.