VOL. 3, No. 3/4, October 2006

J. G. Affleck and V. K. Walker [2006] Med Hypotheses Res 3: 813-825.

A Drosophila Model for Methotrexate Developmental
Toxicity and Teratogenicity

Joslynn G. Affleck* and Virginia K. Walker

Department of Biology, Biosciences, room 2522, Queen’s University, Kingston, Ontario,
Canada K7L 3N6

Abstract. More than 50 years have elapsed since the discovery of antifolate therapies
for the treatment of childhood leukemia, with the result that they have become one of the
most useful family of pharmaceuticals in the physician’s arsenal. Methotrexate (MTX), one
member of this family, has become a commonly-prescribed chemotherapeutic agent, and
used for a host of other diseases such as ectopic pregnancy, rheumatoid arthritis and
asthma.  However, caution must be exercised in MTX treatments since it is a potent
teratogen. It is well known that MTX inhibits dihydrofolate reductase (DHFR), and is crucial
for the synthesis of purines, thymidylate and certain amino acids, but it is less certain that
birth defects can be attributed solely to DHFR inhibition. Clearly, more research is needed,
but mammalian cell lines may not be ideal, and using substantial numbers of mammalian
embryos for toxicity testing is not always held in high regard by the public. Recently, the
fruit fly, Drosophila melanogaster, has been used to model human illnesses including cardiac
disease, neurodegeneration, ageing and cancer. We have shown that MTX exposure of female
Drosophila results in dose-dependent developmental abnormalities in progeny as well as
changes in a number of ovarian transcripts, suggesting secondary drug targets. Since
Drosophila DHFR has similar kinetic properties to the human enzyme, but the encoding gene
is more compact, investigations to understand the molecular mechanisms that result in birth
defects should include this model. In the future, such studies may also generate useful tools
for mammalian antifolate “rescue” therapies.

*Address all correspondence to: Dr. Joslynn Affleck, Department of Biology,
Biosciences, room 2521, Queen’s University, Kingston, Ontario, Canada K7L 3N6.
Telephone: 613 533 6000 (ext 77397). Fax: 613 533 6617.

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