Abstract
The development of resistance to MTX (methotrexate) during the treatment of malignant neoplasia has been reported in a number of papers. Three mechanisms for this resistance have been also described:(1) An increase in DHFR (dehydrofolate reductase) which is the target enzyme of MTX and is essential for glycine, purine and thymidylate synthesis. Thus the increase of DHFR give resistance against MTX. (2) Alteration in the structure of DHFR such that the high affffinity for MTX is lost. Therefore DHFR is no longer effectively inhibited by MTX, (3) Alteration in transport of MTX into cell or acceration in export of MTX out of cell such that the intracellular concentration of MTX decreases.
Molecular mechanisms as to the increase in resistant cells have been studied using DNA recombint techniques. They found that the number of copies of the gene coding for this enzyme was increased through gene amplification, which was stable in the absence of MTX. Furthermore, the prolonged chromosome coding for DHFR was observed on HSR (homogeneously staining region) of chromosome number 2 with in situ hybridization. In addition, DNA sequence analysis for DHFR gene provides the fact that there is intronless gene presumably originated from functional mRNA molecules.
The other feature of MTX resistance is unstable in the absence of MTX. The amplified genes for this feature are located in extra-chromosonal DNA elements called DM (double minutes), which are not equally separated during cell division and thus are not stable.
Alteration in transportational systems was also discussed in detail.
The point is that all of physician who manipulate anticancer drug should know the outline of molecular mechanism for the development of resistance to perform effective admiaistartion of the anti cancer drug.
