Like Carlos, the international terrorist who escaped capture for twodecades, Plasmodium falciparum, the main malarial parasite, stillescapes capture. Like Carlos, the mosquito-borne pathogen seemsnever to sleep twice in the same safe house.Since long before biotechnology began, molecular parasitologists havebeen trying _ and failing _ to construct a vaccine against P.falciparum. They are still trying. (See BioWorld Today, June 3, 1993,p. 1.) Malaria remains the world's greatest single killer infection.Meanwhile, travelers to tropical regions take along chloroquine orpyrimethamine, chemical compounds that keep malarial parasites atbay, but can't cure the disease. Meanwhile too, strains of Plasmodium,including P. falciparum, have become resistant to chloroquine andpyrimethamine.Rescue may be at hand from an unexpected source: taxol. Thismetabolite of the Pacific yew tree, Taxus brevifolia, and its syntheticanalogs, have gained an expanding foothold in the treatment of cancer,particularly tumors of breast, lung, ovary and pancreas. (See BioWorldToday, May 17, 1994, p. 1.)What links malignancy to malaria? "Tubulin," explains cell biologistJoseph Schravel, who heads the Laboratory of Parasite Biology andChemotherapy at France's National Center of Scientific Research(CNRS). "Tubulin," he told BioWorld Today, "an essential part of thecell's structural scaffolding, has an important role in the multiplicationof the malarial parasite."So when his laboratory set about seeking a high-efficiency drug toshort-stop chloroquin, they turned to taxol, which targets tubulin.Jointly with Rhone-Poulenc Rorer, the French chemical giant, the teamdevised an analog of taxol, Taxotere, a.k.a. docetaxel, and studied itsanti-malarial effect, first in vitro, more recently in vivo.A paper by Schravel et al. appears in the current issue of theProceedings of the National Academy of Sciences (PNAS). It carriesthe title, "Interactions between docetaxel (Taxotere) and Plasmodiumfalciparum-infected erythrocytes."When a mosquito bites, it injects a culture of single-cell sporozoite-stage parasite cells into its victim's bloodstream. These make straightfor a safe house in the liver, where they multiply in hepatocytes, andturn into merozoites. These reenter the blood, invade its erythrocytes_ red blood cells (RBC) _ and proliferate still more"Our paper in PNAS," Schravel said, "reported that Taxotere proved 10times as efficacious as taxol in vitro. We have since found it to be 10times better in mice as well."He and his team incubated normal RBCs with various concentrations ofTaxotere for one hour. Then they added a culture of chloroquin-resistant parasites. At a critical concentration, the merozoites could notpenetrate the erythrocytes that had been pre-incubated with Taxotere."We know from Rhone-Poulenc Rorer " Schravel said, "that when oneinjects Taxotere _ and I think it is the same with taxol _ in the firsttwo hours, the RBCs capture a part of the analog. Also, at very lowconcentration, the Taxotere kills the parasite."Another finding of potential importance to Taxotere's eventual use intreating malaria is that a single bolus of the drug, administered as apulse for only a few hours "can also kill the parasite, or stop itsdevelopment." This short exposure to Taxotere, so far only in vitro,"Schravel pointed out, "means that in the future _ but it's a long step togo _ one might avoid the clinical side-effects that taxol has in treatingcancer."He hastened to add, "At this level, we are only in the field offundamental research."Schravel's parasitology lab performed its anti-malarial experimentsjointly with CNRS chemical laboratories. One co-author on thechemical side is Francois Frappier. He told BioWorld Today that thegroup "is relying heavily on clinical information acquired from patientswith tumors treated by Taxotere. He expects France's equivalent of theFDA to issue marketing authorization for Taxotere, specifically to treatovarian cancer, before the end of 1994.Taxotere, Frappier explained, differs from the native, plant-derivedtaxol, in substituting a butyl-oxy-carbonyl radical for a benzyl group."This original chemical mechanism," he said, "makes the moleculemore soluble, hence more effective, than the parent compound. Itenhances the analog's specificity to tubulin. For parasites in general itshould be more efficacious."On this score, Schravel noted, citing unpublished findings, "Taxoterealso works nicely, in Chagas disease." This is a Latin-Americanscourge caused by the Trypanosoma cruzi parasite, for which there isno therapeutic drug at all.Cell biologist Theodore Taraschi at the Jefferson Medical College inPhiladelphia is attacking the parasites of malaria with native taxol,extracted from the yew tree's stem bark by Hauser Chemical Research,Inc. of Boulder, Colo.In the July 1994 Journal of Clinical Investigation, Taraschi reported,"Taxol arrests the development of blood-Stage Plasmodium falciparumin vitro and Plasmodium chabaudi adami in malaria-infected mice."Adding taxol to cultured RBCs infected with P. falciparum," Taraschitold BioWorld Today, prevented establishment of new infections. Andin trials with a score of mice, taxol eliminated a different strain ofmalarial parasites from the animal's blood."The impressive antimalarial activity of taxol, at a dosage that has beentolerated in humans," his paper concluded, "establishes its potentialutility for treatment of severe, drug-resistant human malaria." He hopesto mount human trials "within a year."Unlike the French researchers, teamed with Rhone-Poulenc Rorer,Taraschi has no links with industry "at the moment." Hauser, he added,supplied taxol to Bristol-Myers Squibb, "which was not particularlyinterested in collaborating with us."Hauser and Bristol-Myers Squibb, he said, "parted company as of Aug.1, 1994.Taraschi surmised, "that Bristol-Myers Squibb has decided to make asemi-synthetic formulation, rather than the actual taxol isolated fromthe yew tree, which is what I was using." n
-- David N. Leff Science Editor
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