Antifolate resistance and its circumvention by new analogues.
We have established human leukemia cell lines made resistant to various antifolate drugs and analyzed resistance mechanisms developed in these cells at the cellular and molecular levels. The cells acquired resistance to antifolate drug(s) through: (1) impaired drug uptake via the reduced folate carrier, (2) increased activity of the target enzymes[dihydrofolate reductase(DHFR) or thymidylate synthase(TS)] resulted from a concomitant amplification and overexpression of their gene, (3) induction of a variant DHFR with a low affinity for antifolate drug(s) used for the selection of resistance, and (4) defective polyglutamation. Each resistance mechanism was not necessarily induced at random, but appeared to relate to the biochemical and pharmacological properties of the drug exposed, biological dispositions of the cells, drug-exposure manners to, or culture conditions of the cells. Since it has been shown that a minor modification at the specified position of the folate structure resulted in a drastic change in its pharmacological properties, many new compounds have been rationally designed on the basis of the knowledge of relationships between structure modifications and pharmacological properties. The step-by-step approach to the development of new analogues led to the discoveries of several promising antifolate drugs such as trimetrexate and raltitrexed, which can overcome the acquired and natural resistance to methotrexate, a classical antifolate, and clinical trials of these newer classes of antifolate compounds are currently underway.
Takemura
Y
Y
Department of Laboratory Medicine, National Defense Medical College, Tokai University School of Medicine. yutakemu@interlink.or.jp
Kobayashi
H
H
Miyachi
H
H
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D058973:Folate Receptors, GPI-Anchored; D005493:Folic Acid Antagonists; D015870:Gene Expression; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D008727:Methotrexate; D009154:Mutation; D010453:Peptide Synthases / Q000378:metabolism; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism; D011956:Receptors, Cell Surface; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D016597:Trimetrexate; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D005493:Folic Acid Antagonists; D011624:Pteroylpolyglutamic Acids; D011956:Receptors, Cell Surface; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D016597:Trimetrexate; D008727:Methotrexate