The genetic toxicology of 5-fluoropyrimidines and 5-chlorouracil.
The halogenated pyrimidines were synthesized in the 1950s as potential anti-tumor agents after the discovery that certain tumors preferentially incorporated uracil rather than thymine into the DNA. The fluorinated derivatives are widely recognized today as effective treatment modalities, especially with tumors of the head, neck and breast. Mechanistically, efficacy of the fluorinated pyrimidines results from the ability of these compounds to incorporate into RNA and inhibit its maturation to those forms necessary for cellular metabolism and from the inhibition of the enzyme, thymidylate synthetase, which controls the biosynthesis of thymine and DNA synthesis. The 5-fluoropyrimidines can incorporate into DNA, but the contribution of this phenomenon to the overall efficacy of this class of chemotherapeutic agents is not totally resolved. Evidence exists that this class of compounds possesses the properties to induce genotoxic effects, both in bacterial and eukaryotic cells. Most notably, these effects include the induction of cellular toxicity and the induction of chromosome aberrations. The biology and chemistry of the chlorinated pyrimidines were first explored as a possible means of sensitizing the DNA to ionizing radiation in a manner similar to the sensitization observed when DNA incorporates bromodeoxyuridine. This approach was not utilized clinically. The genetic toxicology of this compound became important with the discovery of the ribonucleoside in the effluents of sewage treatment plants. Evidence is now available that the chlorinated pyrimidines, upon conversion to deoxyribonucleosides, are effective mutagens, clastogens and toxicants, as well as extremely effective inducers of sister-chromatid exchanges.
Morris
S M
SM
Division of Genetic Toxicology, Food and Drug Administration, Jefferson, AR 72079.
D000818:Animals; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D014498:Uracil / Q000031:analogs & derivatives* / Q000633:toxicity
D009153:Mutagens; D011743:Pyrimidines; D014498:Uracil; C029269:5-fluoropyrimidine; C010889:5-chlorouracil